What are benzodiazepines?

Benzodiazepines are drugs that belong to the group of medicines called central nervous system (CNS) depressants or sedatives, which are medicines that slows down messages traveling between your brain and your body. Other central nervous system (CNS) depressants include alcohol, cannabis and heroin. The central nervous system (brain and spinal cord) effects of benzodiazepines are believed to be mediated by activation of gamma aminobutyric acid (GABA) A receptors and modulation of their inhibition of neurotransmission ¹⁾. Because benzodiazepines are controlled substances with abuse potential, they are available only with your doctor’s prescription with special attention directed toward the patient’s addiction history before these agents are prescribed.

Benzodiazepines are also minor tranquilizers, usually prescribed by doctors to relieve stress and anxiety and to help people sleep. Benzodiazepines can also be used to treat alcohol withdrawal symptoms and epilepsy. However, medical professionals have become concerned about their risks, particularly when they are used for a long time.

Benzodiazepines may be prescribed to:

• treat the symptoms of anxiety disorders
• relieve insomnia
• help with treatment of symptoms experienced by cancer patients
• control epilepsy
• help relax muscles during certain medical procedures (such as endoscopy)
• treat alcohol withdrawal.

Benzodiazepines are relatively safe and, with overdose, rarely result in death. However, used chronically, benzodiazepines can be addicting. These agents are often taken in combination with other drugs of abuse by patients with addiction disorders. Some people misuse benzodiazepines to get high or to help with the ‘come down’ effects of stimulants such as amphetamines or cocaine.

Benzodiazepines can cause a person to overdose, particularly when used with alcohol or other drugs. Benzodiazepines are associated with dependence and withdrawal symptoms, even after a short period of use which is why benzodiazepines are not the first option for pharmacological treatment of insomnia (difficulty falling asleep or staying asleep), anxiety or other health concerns ²⁾.

Benzodiazepines are known by their chemical (generic) name or their brand name. In each case the drug is the same – it’s just made by a different company. Some common benzodiazepines are:

Table 1. Benzodiazepines pharmaceutical names

More than a dozen benzodiazepines are available by prescription. The following is a list of benzodiazepines in current use, with their initial brand name and year of approval: alprazolam (Xanax, 1981), chlordiazepoxide (Librium, 1960), clonazepam (Klonopin, 1997), clorazepate (Tranxene, 1972), diazepam (Valium, 1963), estazolam (ProSom, 1990), flurazepam (Dalmane, 1970), lorazepam (Ativan, 1977), midazolam (Versed, 1985), oxazepam (Serax, 1965), quazepam (Doral, 1985), temazepam (Restoril, 1981), triazolam (Halcion, 1982), and most recently clobazam (2011).

Benzodiazepines all share similar activity and clinical effects, but variability in dosing, pharmacokinetics, rapidity of uptake and half-life make them more suited for one or another of these indications. Thus, estazolam, flurazepam, quazepam, temazepam and triazolam are generally used as sleeping pills, whereas alprazolam, chlordiazepoxide, diazepam, and lorazepam are used largely for the treatment of anxiety. Clobazam, clonazepam, and clorazepate are used as anticonvulsants, and high dose, parenteral diazepam and lorazepam are used for status epilepticus. Parenteral midazolam, diazepam and lorazepam are also used as anesthetics or anesthetic premedications. Alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium) and lorazepam (Ativan) are listed among the top 100 most commonly prescribed medications in United States ⁴⁾. According to the American Psychiatric Association report on benzodiazepines, 11 to 15 percent of the adult population has taken a benzodiazepine one or more times during the preceding year, but only 1 to 2 percent have taken benzodiazepines daily for 12 months or longer ⁵⁾. In psychiatric treatment settings and in substance-abuse populations, however, the prevalence of benzodiazepine use, abuse and dependence is substantially higher than that in the general population ⁶⁾.

Does alcohol affect my benzodiazepines?

Alcohol can increase the sedative effect of benzodiazepines. If you drink alcohol whilst taking benzodiazepines you are likely to feel more tired.

Can I drive when taking benzodiazepines?

Taking benzodiazepines can affect the way you drive. For example, they can:

• affect your judgement,
• make your reaction times slower, and
• make you tired

If you are affected by your medication you should not drive until the effects wear off.

It is illegal to drive if you are affected by drugs such as benzodiazepines. Ask your doctor if you are safe to drive whilst taking your medication.

You should tell the DMV if you are taking medication that may affect your driving. You should also tell them if you have a medical condition that could affect your driving.

What else should I consider before taking benzodiazepines?

• Sex. Benzodiazepines do not have any known effects on sexual performance. But drowsiness might have an impact on your sex life.
• Pregnancy. Benzodiazepines should not be used regularly during pregnancy. They should only be used to help control seizures. If benzodiazepines are taken during pregnancy, this can affect the baby when it is born. The baby can get withdrawal symptoms. The baby can have breathing problems and low body temperature. Tell your midwife and other healthcare professionals if you’ve been taking benzodiazepines through your pregnancy. But there is no evidence to say that taking benzodiazepines before pregnancy will have a negative effect on pregnancy or birth.
• Breastfeeding. You should not breastfeed while taking benzodiazepines. Medication you take will be in your breast milk.

How do benzodiazepines work?

Benzodiazepines are central nervous system depressants and they all increase activity at receptors for the neurotransmitter gamma-aminobutyric acid (GABA). The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) inhibits the activity of neurons, slowing down the workings of your brain and nervous system. Benzodiazepines enhance the affinity of the recognition site for GABA by inducing conformational changes that make GABA binding more efficacious. Activation of the benzodiazepine-GABA-chloride ionophor complex is responsible for producing the therapeutic anxiolytic effects of benzodiazepines and for mediating many of the side effects and, possibly, dependence and withdrawal from these drugs ⁷⁾.

Similarly, other sites for drug and neurotransmitter binding are associated with the GABA receptor complex, which serves as a primary site of action of benzodiazepines, barbiturates and other sedative-hypnotics, such as alcohol ⁸⁾. Benzodiazepines and barbiturates act at separate binding sites on the receptor to potentiate the inhibitory action of GABA. They do so by allosterically altering the receptor (changing its conformation) so that it has a greater binding affinity for GABA. Ethanol modifies the receptor by altering the membrane environment so that it has increased affinity for GABA and the other sedative-hypnotic drugs. That benzodiazepines, barbiturates and ethanol all have related actions on a common receptor type, which explains their pharmacologic synergy and cross tolerance. Thus, benzodiazepines are used during alcohol detoxification.

With long-term high-dose use of benzodiazepines (or ethanol), there is an apparent decrease in the efficacy of GABA-A receptors, presumably a mechanism of tolerance ⁹⁾. When high-dose benzodiazepines or ethanol are abruptly discontinued, this “down-regulated” state of inhibitory transmission is unmasked, leading to characteristic withdrawal symptoms such as anxiety, insomnia, autonomic hyperactivity and, possibly, seizures.

Benzodiazepines differ mainly in how quickly they are absorbed, how long their effects last, and how long they take to leave the body. Benzodiazepines only treat symptoms of anxiety or insomnia, and do not solve the underlying causes of these conditions.

The effects of benzodiazepines depend on the strength of the dose, the physical make-up of the person taking them and their state of mind.

Common effects of benzodiazepines include:

• relief from anxiety
• muscle relaxation
• sleepiness
• a sense of being disconnected or detached from reality
• dizziness
• loss of inhibitions.

Benzodiazepines can be highly addictive, whether they are taken under medical supervision or used recreationally.

Types of benzodiazepines

There are three types of benzodiazepines: long, intermediate and short-acting. Short-acting benzodiazepines have stronger withdrawal or ‘come down’ effects and can be more addictive than long-acting ones ¹⁰⁾.

• Benzodiazepines used as sleeping pills (hypnotics) are shorter acting. They are mostly used for treating sleep problems such as insomnia.
• Benzodiazepines used to treat anxiety (anxiolytics) are longer lasting. They are mostly used for treating anxiety.

Table 2. Benzodiazepines used as sleeping pills (hypnotics)

Table 3. Benzodiazepines used to treat anxiety (anxiolytics)

Potency and Half-Life of various benzodiazepines

High-potency benzodiazepines

• Drugs with a short half-life
  • Alprazolam (Xanax)
  • Lorazepam (Ativan)
  • Triazolam (Halcion)
• Drugs with a long half-life
  • Clonazepam (Klonopin)

Low-potency benzodiazepines

• Drugs with a short half-life
  • Oxazepam (Serax)
  • Temazepam (Restoril)
• Drugs with a long half-life
  • Chlordiazepoxide (Librium)
  • Clorazepate (Tranxene)
  • Diazepam (Valium)
  • Flurazepam (Dalmane)

Benzodiazepines uses

Benzodiazepines are central nervous system (CNS) depressants that are commonly prescribed in medicine to treat anxiety, stress, panic disorders, insomnia, alcohol withdrawal symptoms, muscle relaxation, epilepsy and to sedate people before certain medical procedures. It is generally recommended that benzodiazepines only be used for a short term – just days or weeks at a time.

Benzodiazepines clinical uses ¹¹⁾

• Anxiety disorders
  • Acute anxiety
  • Generalized anxiety disorder
  • Panic disorder
  • Phobias (social, simple)
  • Post-traumatic stress disorder (PTSD)
  • Obsessive-compulsive disorder (OCD)
• Insomnia
• Anxiety associated with medical illness
  • Cardiovascular
  • Gastrointestinal
  • Somatoform disorder
• Convulsive disorders
• Acute status epilepticus
  • Neonatal seizures or febrile convulsions
  • Preeclampsia
  • Tetanus
• Adjunct to other anticonvulsants
• Amnestic (before surgery or procedure)
• Spastic disorders and other types of acute muscle spasm
  • Cerebral palsy
  • Multiple sclerosis (MS)
  • Paraplegia secondary to spinal trauma
• Involuntary movement disorders
  • Restless leg syndrome
  • Akathisia associated with neuroleptic use
  • Choreiform disorders
  • Myoclonus
• Detoxification from alcohol and other substances
• Agitation or anxiety associated with other psychiatric conditions
  • Acute mania
  • Psychotic illness
  • Anxiety associated with depression
  • Impulse control disorders
  • Catatonia or mutism
• Other adjunctive uses
  • Surgery
  • Dentistry
  • Diagnostic studies, such as computed tomography, magnetic resonance imaging and endoscopy
  • Cardioversion
  • Chemotherapy

Severe anxiety

You may be given benzodiazepines for the short-term relief of severe anxiety. You should not be given them for long term relief.

Panic disorders

You may be given benzodiazepines:

• When you first start taking antidepressants, OR
• if you don’t respond to antidepressants.

Insomnia

Benzodiazepines can be used to treat insomnia. Insomnia means that you find it difficult to fall asleep or stay asleep.

You should only be offered benzodiazepines to treat insomnia if it is severe, disabling or is causing you a lot of distress.

Benzodiazepines should only be offered for short term use.

Acute alcohol withdrawal

Long acting benzodiazepines are used to help with the effects of acute alcohol withdrawal.

You should stay in hospital during alcohol withdrawal if you have severe alcohol dependence. Alcohol withdrawal without medical support can cause dangerous side effects such as seizures.

Recreational use of benzodiazepines

Some people take benzodiazepines illegally for recreational use. They may use them to feel a sense of euphoria (or high) or mix them with other drugs such as stimulants (cocaine, amphetamines, ecstasy) to ‘come down’. Benzodiazepines can be dangerous when mixed with other drugs (including alcohol) and can put you at risk of overdose or harm.

Some people may give them to others intentionally or without their consent (such as spiking their drink).

Benzodiazepines abuse

Benzodiazepines are rarely the preferred or sole drug of abuse. An estimated 80 percent of benzodiazepine abuse is part of polydrug abuse, most commonly with opioids ¹²⁾. A two-year treatment outcome study by the National Institute on Drug Abuse found that 15 percent of heroin users also used benzodiazepines daily for more than one year, and 73 percent used benzodiazepines more often than weekly ¹³⁾. Studies indicate that from 5 percent to as many as 90 percent of methadone users are also regular users of benzodiazepines. High-dose benzodiazepine abuse is especially prevalent in patients who are taking methadone ¹⁴⁾.

Studies indicate that 3 to 41 percent of alcoholic persons report that they abused benzodiazepines at some time, often to modulate intoxication or withdrawal effects ¹⁵⁾. The contemporary alcoholic is usually a multiple-drug user. As many as 80 percent of alcoholics under the age of 30 have been addicted to or use at least one other drug ¹⁶⁾.

Medical prescriptions constitute the primary source of supply for people who abuse benzodiazepines. Prescriptions may also have a street value, which encourages rerouting to illicit sources. Benzodiazepines have multiple uses for polydrug addicts: they are used to enhance the euphoriant effects of opioids (such as to “boost” methadone doses), to alleviate withdrawal or abstinence syndromes (such as between heroin “fixes”), to temper cocaine highs, to augment alcohol synergistically and to modulate withdrawal states.

As potential drugs of abuse, short-acting benzodiazepines seem to be preferred among addicts because of the rapidity of their onset of action ¹⁷⁾. In general, mood-altering substances are most highly reinforcing in patients with chemical dependence if the agent has a rapid onset of action, a high potency, a brief duration of action, high purity and water solubility (for intravenous use) or high volatility (ability to vaporize if smoked) ¹⁸⁾. Data suggest that highly lipophilic benzodiazepines (for example, those that cross the blood-brain barrier more rapidly), such as diazepam, and agents with a short half-life and high potency, such as lorazepam or alprazolam, are the most reinforcing benzodiazepines and, therefore, the ones most likely to be associated with abuse ¹⁹⁾.

Clonazepam is a high-potency benzodiazepine with a long half-life. It is widely prescribed for a variety of psychiatric and neurologic conditions. Although clonazepam is perceived as “safe,” addiction medicine specialists have found that it is also frequently abused as a street drug. On the other hand, oxazepam (Serax), clorazepate (Tranxene) and chlordiazepoxide appear to have lower reinforcing effects than other benzodiazepines.

Compared with generic formulations, trade-name prescription drugs can be worth twice as much per tablet when they are sold on the street because they are readily recognizable as the “real thing” when compared with the photographs of tablets in the Physicians’ Desk Reference ²⁰⁾. Generic pills are often unrecognizable and hence are worth less when diverted for street sale. In many U.S. cities, the street value of Xanax or Klonopin may be $5 to $10 per pill, depending on dosage strength.

Benzodiazepine withdrawal syndrome

Benzodiazepines are addictive ²¹⁾, ²²⁾, ²³⁾. You should not take them for longer than one month. You should only be prescribed benzodiazepine for the shortest amount of time possible. Taking benzodiazepine regularly for a few weeks or more can lead to addiction. Doctors recommend that you only take benzodiazepine for 2-4 weeks. Intermittent benzodiazepine use may help to avoid addiction. Intermittent means that you don’t take it regularly. For example, you don’t take benzodiazepine every day. The risk of addiction is higher if you have a history of drug or alcohol abuse. Or if you have a personality disorder. For patients on less than 4 weeks of benzodiazepine medication, it should be possible to stop benzodiazepine use without tapering ²⁴⁾, ²⁵⁾. Benzodiazepine discontinuation is usually beneficial as it is followed by improved psychomotor and cognitive functioning, particularly in the elderly ²⁶⁾. However, caution should be exercised with people who are at risk of seizures.

Benzodiazepines withdrawal symptoms may include:

• headaches
• aching or twitching muscles
• dizziness and tremors
• nausea, vomiting and stomach pains
• bizarre dreams, difficulty sleeping and fatigue
• poor concentration
• anxiety and irritability
• altered perception and heightening of senses
• delusions, hallucinations and paranoia
• seizures.

Common physical symptoms of benzodiazepines withdrawal:

• Stiffness
• Weakness
• Stomach problems
• Flu-like symptoms
• Visual problems

Common psychological symptoms of benzodiazepines withdrawal:

• Anxiety
• Insomnia
• Nightmares
• Depersonalization (the persistent feeling of observing oneself from outside one’s body or having a sense that one’s surroundings aren’t real)
• Problems with memory and concentration
• Depression
• Hallucinations. This is when you see, her, smell or feel things that are not there.
• Delusions. This is where you have beliefs that don’t match reality.

Protracted benzodiazepine withdrawal symptoms may include ²⁷⁾:

• Anxiety
• Depression
• Diarrhea, constipation, bloating
• Insomnia
• Irritability
• Muscle aches
• Poor concentration and memory
• Restlessness
• Less commonly, perceptual disturbances and panic attacks
• Occasionally, seizures and symptoms of psychosis.

These protracted benzodiazepine withdrawal symptoms do not occur in all benzodiazepine patients ²⁸⁾, but have a reported incidence between 15% and 44% among those taking benzodiazepines on a regular rather than an as-needed (PRN) basis ²⁹⁾.

Benzodiazepine withdrawal is possible for most people on longer term benzodiazepines, although the process of reduction may be difficult and lengthy ³⁰⁾. Up to 15% of people who experience benzo withdrawal will go on to have protracted symptoms lasting months to years ³¹⁾. Benzodiazepine withdrawal syndrome can happen if you have been taking benzodiazepine regularly for 4-6 weeks. Benzodiazepine withdrawal symptoms vary from person to person and are different depending on the type of benzodiazepine being taken. The benzodiazepine withdrawal symptoms can last from a few weeks to a year. Talk to your doctor about stopping if you have been taking benzodiazepine regularly for more than 4-6 weeks. They will be able to help you stop taking benzodiazepine. Abruptly discontinuing benzodiazepine after you have been taking it daily for more than one month is potentially dangerous; withdrawal can be severe or even life-threatening ³²⁾. It is safer to reduce your benzodiazepine slowly with your doctor’s support and with specialist support where needed. This is because your body will be used to the benzodiazepine and you might experience withdrawal symptoms. It is recommended to withdraw from benzodiazepines slowly, over a period of months, under medical supervision. Benzodiazepine reduction requires a team approach with regular communication between the prescriber and other practitioners involved in the patient’s care (e.g., pharmacist, counsellor, psychiatrist, addiction services).

The clearest strategy for withdrawing benzodiazepines is to taper the medication (Figure 2) ³³⁾. Benzodiazepine withdrawal strategies should be individualized, considering factors such as lifestyle, personality, environmental stressors, reasons for taking benzodiazepine, the type of dependence (therapeutic dose, prescribed high dose, recreational high dose or polydrug) and amount of available personal and clinical support. Because anticipatory anxiety is often related to benzo withdrawal syndrome, benzodiazepines are commonly tapered slowly, with psychological support emphasized during the process to help patients learn alternative coping skills ³⁴⁾. A common first step in benzo withdrawal is to substitute diazepam for the benzodiazepine being taken ³⁵⁾. Switching to a longer-acting benzodiazepine equivalent may allow for a smoother taper experience ³⁶⁾. The slower elimination of diazepam creates a smoother taper in blood level ³⁷⁾.

Two-thirds of patients can achieve benzodiazepine cessation with gradual reduction of dose alone. Others need additional psychological therapies and a limited number of patients benefit from additional pharmacotherapy ³⁸⁾. Cognitive behavioral therapy (CBT) performed in a single, extended (20-minute) consultation with a doctor, with a handout, has been shown to increase non-use at 1 year from 15% to 45% ³⁹⁾. A systematic review comparing routine care to brief interventions, gradual dose reduction and psychological interventions found all interventions increased benzodiazepine discontinuation over routine care, with gradual dose reduction plus psychological interventions the most effective ⁴⁰⁾.

Figure 1. Benzodiazepine withdrawal syndrome symptoms

Figure 2. Recommendations for tapering benzodiazepines

Benzodiazepine withdrawal syndrome treatment

Evidence-based recommendations for general management of benzodiazepine withdrawal are difficult due to a lack of clinical data ⁴³⁾. The following are general principles for managing benzodiazepine withdrawal syndrome ⁴⁴⁾, ⁴⁵⁾, ⁴⁶⁾:

• Review the patients’ prescription records and discuss the situation to those receiving long-term benzodiazepines.
• Send patients letters suggesting methods of tapering off benzodiazepines (this may be enough to motivate them to withdraw).
• Teach patients ways to deal with anxiety and insomnia (either as primary conditions or due to withdrawal).
• Acknowledge that withdrawing from benzodiazepines can be stressful.
• Encourage family and friends to provide encouragement and practical help during withdrawal.
• Refer patients to appropriate services (eg psychologist or support groups). Only refer to drug or alcohol dependence services if the service has shown specific interest in benzodiazepine
• dependence or the patient also has a drug or alcohol problem.
• Advise patients to make changes in lifestyle such as regular exercise.
• Advise patients to avoid alcohol.
• Advise patients to avoid mild stimulants (eg coffee and chocolate [theobromine]) as these can cause anxiety, panic and insomnia.
• Postpone advice on smoking cessation until after the benzodiazepine has been withdrawn ⁴⁷⁾

Benzodiazepine reduction requires a team approach with regular communication between the prescriber and other practitioners involved in the patient’s care (eg pharmacist, counsellor, psychiatrist, addiction services).

The clearest strategy for withdrawing benzodiazepines is to taper the medication (see Figure 2) ⁴⁸⁾. There are three basic approaches to taper a benzodiazepine ⁴⁹⁾, ⁵⁰⁾:

1. Use the same medication for tapering;
2. Switch to a longer-acting equivalent; and
3. Use add-on medications to help reduce potential withdrawal symptoms.

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms (e.g., rebound anxiety, agitation, insomnia or seizures) particularly when use exceeds 8 weeks ⁵¹⁾. However, clear evidence for the optimal rate of tapering is lacking. The dosage reduction mainly depends on the starting dose and whether the patient is tapering as an inpatient or outpatient. For safety reasons, outpatient tapers usually need to be slower than inpatient tapers. Patients taking higher dosages of benzodiazepines can usually tolerate larger reductions than those taking lower dosages ⁵²⁾, ⁵³⁾. The initial reduction typically ranges between 5% and 25% of the starting dose, with further reductions of 5% to 25% every one to four weeks as tolerated. The British National Formulary recommends a minimum of 6 weeks ⁵⁴⁾, while Lader recommends a maximum of 6 months ⁵⁵⁾. The exact rate of benzodiazepine reduction should be individualized according to the drug, dose and duration of treatment. A common first step in benzo withdrawal is to substitute diazepam for the benzodiazepine being taken ⁵⁶⁾. Switching to a longer-acting benzodiazepine equivalent may allow for a smoother taper experience ⁵⁷⁾. The slower elimination of diazepam creates a smoother taper in blood level ⁵⁸⁾. A suggested benzodiazepine taper schedule is available at https://www.va.gov/PAINMANAGEMENT/docs/OSI_6_Toolkit_Taper_Benzodiazepines_Clinicians.pdf

Supratherapeutic doses can initially be reduced by 25% to 30%, then further reduced by 5% to 10% daily, weekly, or monthly as appropriate, based on how well the patient tolerates withdrawal symptoms during the taper. Addition of an anticonvulsant (e.g., gabapentin [Neurontin]) should be considered for high-dosage withdrawal. Studies have shown that add-on medications, such as carbamazepine (Tegretol), imipramine, divalproex (Depakote), and trazodone, can mitigate some of the withdrawal discomfort ⁵⁹⁾. Use of antidepressants, such as duloxetine (Cymbalta) or amitriptyline, may help patients with chronic pain. There is limited evidence that antidepressants help in benzodiazepine withdrawal, unless depression (or anxiety disorders/panic disorders) are present or emerge during withdrawal ⁶⁰⁾.

For complex cases, stabilizing the dose at a 50% reduction for several months before resuming the taper may improve tolerability ⁶¹⁾. At the end of the taper, some patients may need to reduce the pace with nearly homeopathic dosage reductions to tolerate the withdrawal. Compounding pharmacies can be used to obtain very small doses near the end of the taper.

All patients on a tapering regime must obtain prescriptions from one prescriber and through one pharmacy, where time-limited dispensing may be required (e.g., once or twice a week at a specified time) ⁶²⁾. Plans should be in place to cover absences of the usual prescribing doctor from the practice ⁶³⁾. Consider working closely with the patient’s pharmacist with staged supply or supervised dosing to assist the patient with dose reduction and cessation, if they are unable to manage this themselves ⁶⁴⁾.

Other considerations

Patients with benzodiazepine use disorder will have more difficulty reducing or stopping the dosage because of cravings. They may report intolerable withdrawal symptoms, request early refills, use benzodiazepines for reasons other than why they were prescribed, or report a need for benzodiazepines to perform normal daily activities. These patients may not be able to taper off without more intensive follow-up and intervention. A taper may be a litmus test for addiction; these patients may benefit from a referral to an addiction specialist ⁶⁵⁾.

Patients taking ‘therapeutic benzodiazepine doses’

For people who have early or mild benzodiazepine dependence, minimal interventions such as advisory letters, other information provision or doctor advice should be offered. Where benzodiazepine dependence is established, gradual dose reduction of prescribed benzodiazepine is recommended ⁶⁶⁾.

Switching from a short half-life benzodiazepine to a long half-life benzodiazepine before gradual taper should be reserved for patients having problematic withdrawal symptoms on reduction ⁶⁷⁾.

Additional psychological therapies increase the effectiveness of gradual dose reduction, particularly in patients with insomnia and panic disorder. Consideration should be given to targeted use of these interventions ⁶⁸⁾.

Patient taking high doses of benzodiazepines or who are users of illicit drugs (polydrug users)

So called ‘harm-reduction dosing’ or maintenance prescribing of benzodiazepines for patients using polydrugs cannot be recommended on the basis of existing evidence, as prescribing benzodiazepines does not appear to prevent use of other drugs ⁶⁹⁾. There are some evidence that maintenance dosing of benzodiazepines may reduce high-dose problematic benzodiazepine use in some patients ⁷⁰⁾.

Benzodiazepines drug interactions

When used alone, benzodiazepines carry an extremely low risk of acute toxicity. However, benzodiazepines often are used with other types of medications, including other drugs with abuse potential, and these drugs can enhance the toxic effects of benzodiazepines. Tell your doctor about any medicines you are taking before you start to take benzodiazepines. This includes any supplements or herbal medicines you take. Benzodiazepines can react with other types of medication and cause more side effects such as extra tiredness or low blood pressure.

Medication that can react with benzodiazepines includes ⁷¹⁾:

• antidepressants,
• other hypnotics,
• antipsychotic medication,
• neuroleptics,
• anticonvulsants,
• alcohol,
• antihistamines, and
• beta-blockers.

Fatal overdoses in addicted patients often involve the combination of benzodiazepines and alcohol, with or without opiates ⁷²⁾. In addition, pharmacokinetic drug interactions may occur. For instance, selective serotonin reuptake inhibitors (SSRIs) may increase diazepam blood levels ⁷³⁾ and nefazadone (Serzone) may increase alprazolam levels ⁷⁴⁾ through hepatic enzyme inhibition, leading to increased sedative-hypnotic effects or side effects.

Benzodiazepines side effects

Benzodiazepines are addictive. You should not take them for longer than one month.

Not everyone who takes benzodiazepines will get side effects. Talk to your doctor if you are worried about side effects.

Benzodiazepines common side effects include:

• drowsiness or sleepiness
• dizziness
• headache
• confusion
• numbed emotions
• reduced awareness
• muscle weakness
• tremor
• Ataxia (impaired balance or coordination). Such as:
  • balance and walking
  • speaking
  • swallowing
  • your motor skills, such as writing and eating
  • vision

You have an increased risk of falls and associated fractures if you are elderly and use benzodiazepines.

Benzodiazepines rare or less common side effects include:

• stomach upset and diarrhea
• nausea,
• vomiting
• constipation
• depression
• insomnia
• dry mouth
• increased appetite
• memory loss
• delusions
• aggression

Depression and emotional blunting

An association has been noted between benzodiazepine use and depressive symptoms and, in some cases, the emergence of suicidal ideation. Some evidence indicates that higher benzodiazepine dosages are associated with an increased risk of depression and that reducing the dosage or discontinuing therapy may resolve the depressive symptoms ⁷⁵⁾. Although the mechanism of this action is unclear, benzodiazepine-related depression might occur as a physiologic result of a reduction in central monoamine activity.

“Emotional anesthesia” may also be seen in clinical practice. This effect may be sought by drug addicts who become progressively more incapable of tolerating their emotions and life stressors.

Psychomotor slowing

Psychomotor slowing may be especially profound following initial administration of a benzodiazepine or with a sudden dosage increase. It also may be noted in patients, such as the elderly, who have decreased rates of metabolism or greater susceptibility to central nervous system depression ⁷⁶⁾. Psychomotor symptoms include drowsiness, poor concentration, ataxia, dysarthria, motor incoordination, diplopia, muscle weakness, vertigo and mental confusion ⁷⁷⁾. Studies of the psychomotor effects suggest that benzodiazepines slow reaction time and impair driving skills, increasing the risk of motor vehicle crashes in patients who are taking these agents ⁷⁸⁾.

Memory impairment

Benzodiazepines induce anterograde amnesia, which accounts for the beneficial effects of benzodiazepines such as midazolam (Versed) for presurgical medication. These specific amnestic effects appear to be separate from sedation ⁷⁹⁾. Episodic memory (the remembering of recent events and the circumstances in which they occurred and their time sequences) is particularly impaired and more markedly so in heavy alcohol drinkers who also use benzodiazepines. Specific deficits in visuospatial ability and sustained attention have also been described in patients who have taken therapeutic doses of benzodiazepines regularly for longer than one year ⁸⁰⁾.

Paradoxical disinhibition

Increased excitement, irritability, aggression, hostility and impulsivity may occur in some patients who take benzodiazepines. This paradoxical disinhibition may, in rare cases, result in attacks of rage or violence, or other indiscretionary or antisocial behaviors ⁸¹⁾. Such reactions may be due to disinhibition of behavioral tendencies normally suppressed by social restraints (as can also be the case with alcohol). These reactions occur most commonly in children, in the elderly and in persons with developmental disabilities.

Benzodiazepines addiction

You should only be prescribed benzodiazepines for the shortest amount of time possible. Taking benzodiazepines regularly for a few weeks or more can lead to addiction. Doctors recommend that you only take them for 2-4 weeks.

Intermittent use may help to avoid addiction. Intermittent means that you don’t take it regularly. For example, you don’t take it every day.

The risk of addiction is higher if you have a history of drug or alcohol abuse. Or if you have a personality disorder.

Benzodiazepines long-term effects

Using benzodiazepines on a regular basis can lead to significant health problems, including:

• impaired thinking or memory loss
• anxiety and depression
• irritability, paranoia and aggression
• personality change
• weakness, lethargy and lack of motivation
• drowsiness, sleepiness and fatigue
• difficulty sleeping or disturbing dreams
• headaches
• nausea
• skin rashes and weight gain
• addiction
• withdrawal symptoms.

What if I want to stop taking benzodiazepines?

Withdrawal symptoms from benzodiazepines can happen if you have been taking the medication regularly for 4-6 weeks. Benzodiazepines withdrawal symptoms vary from person to person and are different depending on the type of benzodiazepine being taken. The benzodiazepines withdrawal symptoms can last from a few weeks to a year. Talk to your doctor about stopping if you have been taking benzodiazepines regularly for more than 4-6 weeks. They will be able to help you stop taking them. Abruptly discontinuing benzodiazepines after you have been taking them daily for more than one month is potentially dangerous; withdrawal can be severe or even life-threatening ⁸²⁾. It is safer to reduce your medication slowly with your doctor’s support. This is because your body will be used to the medication and you might experience withdrawal symptoms. It is recommended to withdraw from benzodiazepines slowly, over a period of months, under medical supervision.

Taper schedules should be individualized, considering factors such as lifestyle, personality, environmental stressors, reasons for taking benzodiazepines, and amount of available personal and clinical support. Because anticipatory anxiety is often related to withdrawal, benzodiazepines are commonly tapered slowly, with psychological support emphasized during the process to help patients learn alternative coping skills ⁸³⁾.

Benzodiazepines withdrawal symptoms may include:

• headaches
• aching or twitching muscles
• dizziness and tremors
• nausea, vomiting and stomach pains
• bizarre dreams, difficulty sleeping and fatigue
• poor concentration
• anxiety and irritability
• altered perception and heightening of senses
• delusions, hallucinations and paranoia
• seizures.

Common physical side effects of benzodiazepines withdrawal:

• Stiffness
• Weakness
• Stomach problems
• Flu-like symptoms
• Visual problems

Common psychological side effects of benzodiazepines withdrawal:

• Anxiety
• Insomnia
• Nightmares
• Depersonalization (the persistent feeling of observing oneself from outside one’s body or having a sense that one’s surroundings aren’t real)
• Problems with memory and concentration
• Depression
• Hallucinations. This is when you see, her, smell or feel things that are not there.
• Delusions. This is where you have beliefs that don’t match reality.

How to taper benzodiazepines

There are three basic approaches to a benzodiazepine taper ⁸⁴⁾:

1. Use the same medication for tapering;
2. Switch to a longer-acting equivalent; and
3. Use adjunctive medications to help mitigate potential withdrawal symptoms.

The dosage reduction mainly depends on the starting dose and whether the patient is tapering as an inpatient or outpatient. For safety reasons, outpatient tapers usually need to be slower than inpatient tapers. Patients taking higher dosages of benzodiazepines can usually tolerate larger reductions than those taking lower dosages ⁸⁵⁾, ⁸⁶⁾. The initial reduction typically ranges between 5% and 25% of the starting dose, with further reductions of 5% to 25% every one to four weeks as tolerated. A suggested taper schedule is available at https://www.va.gov/PAINMANAGEMENT/docs/OSI_6_Toolkit_Taper_Benzodiazepines_Clinicians.pdf

Supratherapeutic doses can initially be reduced by 25% to 30%, then further reduced by 5% to 10% daily, weekly, or monthly as appropriate, based on how well the patient tolerates withdrawal symptoms during the taper. Addition of an anticonvulsant (e.g., gabapentin [Neurontin]) should be considered for high-dosage withdrawal. Studies have shown that adjunctive medications, such as carbamazepine (Tegretol), imipramine, divalproex (Depakote), and trazodone, can mitigate some of the withdrawal discomfort ⁸⁷⁾. Use of antidepressants, such as duloxetine (Cymbalta) or amitriptyline, may help patients with chronic pain. Switching to a longer-acting benzodiazepine equivalent may allow for a smoother taper experience ⁸⁸⁾.

For complex cases, stabilizing the dose at a 50% reduction for several months before resuming the taper may improve tolerability ⁸⁹⁾. At the end of the taper, some patients may need to reduce the pace with nearly homeopathic dosage reductions to tolerate the withdrawal. Compounding pharmacies can be used to obtain very small doses near the end of the taper.

Other considerations

Patients with benzodiazepine use disorder will have more difficulty reducing or stopping the dosage because of cravings. They may report intolerable withdrawal symptoms, request early refills, use benzodiazepines for reasons other than why they were prescribed, or report a need for benzodiazepines to perform normal daily activities. These patients may not be able to taper off without more intensive follow-up and intervention. A taper may be a litmus test for addiction; these patients may benefit from a referral to an addiction specialist ⁹⁰⁾.

When will benzodiazepines withdrawal side effects stop?

Your benzodiazepines withdrawal side effects will usually stop after a few weeks. But they can last longer for a small amount of people. You may not get benzodiazepines withdrawal side effects when you stop your benzodiazepine medication. You should talk to your doctor or local pharmacist if you are worried about the withdrawal effects of benzodiazepines.

Is there anything that can help with my symptoms through benzodiazepines withdrawal?

Antidepressant and mood stabilizing drugs may help with the withdrawal effects of benzodiazepines.

If you have insomnia you may benefit from treatment with melatonin.

If you have a panic disorder you may benefit from cognitive behavioral therapy (CBT) whilst you are coming off the medication.

Benzodiazepine overdose

In larger doses, benzodiazepines produce a similar effect to drunkenness. Benzodiazepine overdose signs and symptoms may include:

• lose coordination
• slur their speech
• have problems with thinking, concentration and memory
• have severe mood swings and aggression
• be jittery and excitable
• experience nausea
• have sleeping problems.

Benzodiazepines overdoses are usually characterized by slow, shallow breathing which may lead to unconsciousness, coma and potentially death. This is more common if benzodiazepines are combined with other drugs such as alcohol, painkillers, antidepressants, antihistamines, or heroin.

If you suspect an overdose, call your local emergency services number for an ambulance immediately.

Benzodiazepines and pregnancy

There is a risk that benzodiazepines can be harmful to babies. Benzodiazepines cross the placenta and are classified as class D teratogens. If you are pregnant or breastfeeding, it is best to avoid them. Benzodiazepines may lead to the development of dependence and consequent withdrawal symptoms in the fetus ⁹¹⁾. Benzodiazepines are excreted in breast milk and thus are usually contraindicated in breast-feeding mothers.

Benzodiazepine dependence

Taking benzodiazepines regularly may not only lead to physical dependence (addiction), but can also lead to psychological dependence where people may feel they need the drug to cope with daily life. Benzodiazepines dependence will develop sooner (such as in one to two months) in a patient who is taking a high dosage of a high-potency agent such as alprazolam than in a patient who is receiving a relatively low dosage of a long-acting, low-potency agent such as chlordiazepoxide. The best way to prevent benzodiazepine dependence for high-risk patients is to adhere to treatment recommendations and emphasize nonpharmacologic therapies for anxiety and insomnia ⁹²⁾. If benzodiazepines are used, they should be prescribed for short-term, intermittent use (two to four weeks at no more than three times per week), intermittent brief courses (daily use for no more than two weeks in cases of extreme stress and anxiety), or occasional doses to limit the potential for new, long-term users ⁹³⁾.

As a result of physiologic dependence, withdrawal symptoms emerge with rapid dose reduction or abrupt discontinuation of the drug.

Psychologically, long-term use of benzodiazepines may lead to overreliance on the need for the agent, loss of self-confidence and varying degrees of drug-seeking behavior ⁹⁴⁾. Patients may be reluctant to discontinue the drug because of misplaced fears or anticipatory anxiety. Some patients combine alcohol with benzodiazepines when they are not able to acquire the desired or “needed” effects.

Treating benzodiazepine dependence

Treatment options for drug dependence may include detoxification, individual counseling and group therapy. See your doctor for information and referral, or contact an alcohol and drug service (https://www.drugabuse.gov) to find the appropriate referral for you.

Benzodiazepine tolerance

After only a short amount of time, a person can develop a tolerance, which means they need to take larger and larger doses to achieve the same effect. Some people may begin to experience benzodiazepine tolerance after only a few days. Over time, the body comes to depend on benzodiazepines to function at its best.

Tolerance to all of the actions of benzodiazepines can develop, although at variable rates and to different degrees. Tolerance to the hypnotic effects tends to develop rapidly, which may be beneficial in daytime anxiolysis but makes long-term management of insomnia difficult ⁹⁵⁾. Patients typically notice relief of insomnia initially, followed by a gradual loss of efficacy ⁹⁶⁾. Tolerance to the anxiolytic effect seems to develop more slowly than does tolerance to the hypnotic effects, but there is little evidence to indicate that benzodiazepines retain their efficacy after four to six months of regular use ⁹⁷⁾. Benzodiazepine therapy is often continued to suppress withdrawal states, which usually mimic symptoms of anxiety. Dosage escalation often maintains the cycle of tolerance and dependence, and patients may have difficulty discontinuing drug therapy.

Benzodiazepines in elderly patients

Benzodiazepine use in the elderly is associated with an increased rate of falls that cause hip and femur fractures and an increased likelihood of motor vehicle crashes ⁹⁸⁾. Cognitive impairment is common, although memory impairment may be reversible when benzodiazepines are discontinued ⁹⁹⁾.

Cognitive deterioration associated with normal aging processes and dementia can be worsened by benzodiazepine side effects. Cortical suppression mechanisms may be disturbed in the elderly, and disinhibited behaviors may increase with benzodiazepine use. With less cognitive and social reserve in the elderly patient, the short- and long-term withdrawal symptoms and other benzodiazepine side effects may lead the patient to frequently visit or telephone the physician. The physician may feel “trapped”into arguing against the use of benzodiazepines and prescribing benzodiazepines to elderly patients. In one study, this impasse was broken by referring elderly patients to inpatient detoxification, which resulted in a dramatic decrease in annual physician visits ¹⁰⁰⁾.

Alprazolam

Alprazolam (Xanax or Niravam) is a benzodiazepine that is used to treat anxiety disorders, panic disorders, and anxiety caused by depression. Talk to your doctor about the possible risks of using alprazolam for your condition. Alprazolam is available only with your doctor’s prescription.

Alprazolam is available in the following dosage forms: a tablet, an extended-release tablet, an orally disintegrating tablet (tablet that dissolves quickly in the mouth), and a concentrated solution (liquid) to be taken by mouth. Alprazolam tablet, orally disintegrating tablet, and concentrated solution usually are taken two to four times a day. The extended-release tablet is taken once daily, usually in the morning. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take alprazolam exactly as directed.

To take the concentrated liquid, use only the dropper that came with your prescription. Draw into the dropper the amount prescribed for one dose. Squeeze the dropper contents into a liquid or semisolid food such as water, juice, soda, applesauce, or pudding. Stir the liquid or food gently for a few seconds. The concentrated liquid will blend completely with the food. Drink or eat the entire mixture immediately. Do not store for future use.

Remove the orally disintegrating tablet from the bottle just before it is time for your dose. With dry hands, open the bottle, remove the tablet, and immediately place it on your tongue. The tablet will dissolve and can be swallowed with saliva. The orally disintegrating tablet can be taken with or without water.

Swallow the extended-release tablets whole; do not chew, crush, or break them.

Your doctor will probably start you on a low dose of alprazolam and gradually increase your dose, not more than once every 3 or 4 days.

Alprazolam special precautions

You should not take alprazolam if:

• you also take antifungal medicine such as itraconazole or ketoconazole; or
• you have a history of allergic reaction to any benzodiazepine (alprazolam, lorazepam, diazepam, Ativan, Valium, Versed, Klonopin, and others).

To make sure alprazolam is safe for you, tell your doctor if you have ever had:

• breathing problems;
• drug or alcohol addiction;
• depression, mood problems, or suicidal thoughts or behavior; or
• kidney or liver disease.

Tell your doctor if you are pregnant or plan to become pregnant. If you use alprazolam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks.

You should not breastfeed whilst taking alprazolam. If you do breastfeed, tell your doctor if you notice drowsiness or feeding problems in the baby.

Alprazolam is not approved for use by anyone younger than 18 years old.

Before taking alprazolam:

• tell your doctor and pharmacist if you are allergic to alprazolam, chlordiazepoxide (Librium, in Librax), clonazepam (Klonopin), clorazepate (Gen-Xene, Tranxene), diazepam (Diastat, Valium), estazolam, flurazepam, lorazepam (Ativan), oxazepam, quazepam (Doral), temazepam (Restoril), triazolam (Halcion), any other medications, or any of the ingredients in alprazolam products. Ask your pharmacist for a list of the ingredients.
• tell your doctor if you are taking itraconazole (Onmel, Sporanox) or ketoconazole (Nizoral). Your doctor will probably tell you not to take alprazolam.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements, you are taking. Be sure to mention any of the following: amiodarone (Cordarone, Nexterone, Pacerone); antidepressants (‘mood elevators’) such as desipramine (Norpramin), imipramine (Tofranil), and nefazodone; antifungals such as fluconazole (Diflucan), posaconazole (Noxafil), or voriconazole (Vfend); antihistamines; cimetidine (Tagamet); clarithromycin (Biaxin, in Prevpac); cyclosporine (Gengraf, Neoral, Sandimmune); diltiazem (Cardizem, Cartia XT, Tiazac); ergotamine (Ergomar, in Cafergot, in Migergot); erythromycin (E.E.S., ERYC, others); isoniazid (Laniazid, in Rifamate, in Rifater); medications for mental illness and seizures; nicardipine (Cardene); nifedipine (Adalat, Afeditab CR, Procardia); oral contraceptives (birth control pills); selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Brisdelle, Paxil, Pexeva), and sertraline (Zoloft); sedatives; sleeping pills; and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor and pharmacist what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have glaucoma (increased pressure in the eye that may cause loss of sight). Your doctor may tell you not to take alprazolam.
• tell your doctor if you have or have ever had seizures or lung, kidney, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. Alprazolam may harm the fetus. If you become pregnant while taking alprazolam, call your doctor.
• talk to your doctor about the risks and benefits of taking this medication if you are 65 years of age or older. Older adults should receive low doses of alprazolam because higher doses may not work better and may cause serious side effects.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking alprazolam.
• you should know that alprazolam may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.

Special dietary instructions

Do not eat grapefruit or drink grapefruit juice while you’re taking alprazolam.

Alprazolam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking alprazolam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using alprazolam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Boceprevir
• Clarithromycin
• Cobicistat
• Conivaptan
• Flumazenil
• Idelalisib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Nefazodone
• Nelfinavir
• Posaconazole
• Saquinavir
• Telaprevir
• Telithromycin
• Voriconazole

Using alprazolam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abametapir
• Acepromazine
• Alfentanil
• Amiodarone
• Amobarbital
• Amprenavir
• Anileridine
• Aprepitant
• Aripiprazole
• Aripiprazole Lauroxil
• Asenapine
• Atazanavir
• Baclofen
• Benperidol
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Buspirone
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbamazepine
• Carbinoxamine
• Carisoprodol
• Carphenazine
• Ceritinib
• Cetirizine
• Chloral Hydrate
• Chlordiazepoxide
• Chlorpromazine
• Chlorzoxazone
• Cimetidine
• Ciprofloxacin
• Clobazam
• Clonazepam
• Clorazepate
• Clozapine
• Codeine
• Crizotinib
• Cyclobenzaprine
• Cyclosporine
• Dantrolene
• Darunavir
• Dasabuvir
• Delavirdine
• Dexmedetomidine
• Diacetylmorphine
• Diazepam
• Dichloralphenazone
• Difenoxin
• Digoxin
• Dihydrocodeine
• Diltiazem
• Diphenhydramine
• Diphenoxylate
• Domperidone
• Doxylamine
• Dronedarone
• Droperidol
• Elagolix
• Enflurane
• Erythromycin
• Esketamine
• Estazolam
• Eszopiclone
• Ethchlorvynol
• Ethopropazine
• Ethylmorphine
• Fentanyl
• Fexinidazole
• Flibanserin
• Fluconazole
• Flunitrazepam
• Fluphenazine
• Flurazepam
• Fluspirilene
• Fluvoxamine
• Fosamprenavir
• Fosaprepitant
• Fosnetupitant
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Halazepam
• Halothane
• Hexobarbital
• Hydrocodone
• Hydromorphone
• Hydroxyzine
• Imatinib
• Isoflurane
• Ivacaftor
• Ketamine
• Ketazolam
• Ketobemidone
• Larotrectinib
• Lemborexant
• Letermovir
• Levocetirizine
• Levorphanol
• Lofexidine
• Lomitapide
• Lorazepam
• Loxapine
• Magnesium Oxybate
• Meclizine
• Melperone
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Meptazinol
• Mesoridazine
• Metaxalone
• Methadone
• Methdilazine
• Methocarbamol
• Methohexital
• Methotrimeprazine
• Methylene Blue
• Metoclopramide
• Mibefradil
• Midazolam
• Mifepristone
• Mirtazapine
• Molindone
• Moricizine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Netupitant
• Nicomorphine
• Nilotinib
• Nitrazepam
• Nitrous Oxide
• Olanzapine
• Opium
• Opium Alkaloids
• Orphenadrine
• Oxazepam
• Oxycodone
• Oxymorphone
• Palbociclib
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Perampanel
• Perazine
• Periciazine
• Perphenazine
• Phenobarbital
• Pimozide
• Piperacetazine
• Piperaquine
• Pipotiazine
• Piritramide
• Potassium Oxybate
• Prazepam
• Pregabalin
• Primidone
• Prochlorperazine
• Promazine
• Promethazine
• Propofol
• Quazepam
• Quetiapine
• Ramelteon
• Ranitidine
• Ranolazine
• Remifentanil
• Remimazolam
• Remoxipride
• Ritonavir
• Scopolamine
• Secobarbital
• Sertindole
• Sodium Oxybate
• Sufentanil
• Sulpiride
• Suvorexant
• Tapentadol
• Temazepam
• Thiethylperazine
• Thiopental
• Thiopropazate
• Thioridazine
• Tilidine
• Tizanidine
• Tolonium Chloride
• Topiramate
• Tramadol
• Trazodone
• Triazolam
• Trifluoperazine
• Trifluperidol
• Triflupromazine
• Trimeprazine
• Verapamil
• Voxelotor
• Zaleplon
• Zolpidem
• Zopiclone
• Zotepine

Using alprazolam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Fluoxetine
• Kava
• Rifapentine
• Roxithromycin
• Sertraline
• St John’s Wort
• Theophylline
• Troleandomycin

Other interactions

Using alprazolam with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use alprazolam, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol
• Grapefruit Juice

Other medical problems

The presence of other medical problems may affect the use of alprazolam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, history of or
• Depression, or history of or
• Lung or breathing problems (eg, respiratory depression) or
• Mania, or history of or
• Mental health problems, or history of or
• Seizures, or history of—Use with caution. May make these conditions worse.
• Glaucoma, acute narrow angle—Should not be used in patients with this condition.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Alprazolam uses

Alprazolam is used to treat anxiety disorders and panic disorder (sudden, unexpected attacks of extreme fear and worry about these attacks).

Alprazolam is also sometimes used to treat depression, fear of open spaces (agoraphobia), and premenstrual syndrome.

Alprazolam may also be prescribed for other uses; ask your doctor or pharmacist for more information.

Alprazolam dosage

The dose of alprazolam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of alprazolam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For anxiety

• For oral dosage forms (solution, tablets, or orally disintegrating tablets):
  • Adults—At first, 0.25 to 0.5 milligram (mg) 3 times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 4 mg per day.
  • Older adults—At first, 0.25 mg 2 or 3 times a day. Your doctor may increase your dose as needed.
  • Children—Use and dose must be determined by your doctor.

For panic disorder

• For oral dosage form (extended-release tablets):
  • Adults—At first, 0.5 to 1 milligram (mg) taken in the morning once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 10 mg per day.
  • Older adults—At first, 0.5 mg taken in the morning once a day. Your doctor may increase your dose as needed.
  • Children—Use and dose must be determined by your doctor.
• For oral dosage forms (solution, tablets, or orally disintegrating tablets):
  • Adults—At first, 0.5 milligram (mg) 3 times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 10 mg per day.
  • Older adults—At first, 0.25 mg 2 or 3 times a day. Your doctor may increase your dose as needed.
  • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of alprazolam, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Alprazolam side effects

Alprazolam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• light-headedness
• headache
• tiredness
• dizziness
• irritability
• talkativeness
• difficulty concentrating
• dry mouth
• increased salivation
• changes in sex drive or ability
• nausea
• constipation
• changes in appetite
• weight changes
• difficulty urinating
• joint pain

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• shortness of breath
• seizures
• severe skin rash
• yellowing of the skin or eyes
• confusion
• problems with speech
• problems with coordination or balance

Alprazolam may cause other side effects. Call your doctor if you have any unusual problems while taking alprazolam.

Chlordiazepoxide

Chlordiazepoxide (Librium) is a benzodiazepine that is used to treat anxiety disorders. Chlordiazepoxide may also be used short-term to treat symptoms of alcohol withdrawal, or anxiety you may have before a surgery. Chlordiazepoxide is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. Chlordiazepoxide is available only with your doctor’s prescription.

Chlordiazepoxide comes as a tablet and capsule to take by mouth. It usually is taken one to four times a day with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take chlordiazepoxide exactly as directed.

Chlordiazepoxide special precautions

You should not use chlordiazepoxide if you are allergic to it.

Tell your doctor if you have ever had:

• depression, a mood disorder, suicidal thoughts or actions;
• alcoholism or drug addiction; or
• liver or kidney disease.

Tell your doctor if you are pregnant or plan to become pregnant. Chlordiazepoxide may harm an unborn baby. Avoid taking chlordiazepoxide during the first trimester of pregnancy.

Ask a doctor if it is safe to breastfeed while using chlordiazepoxide.

Chlordiazepoxide is not approved for use by anyone younger than 6 years old.

Before taking chlordiazepoxide:

• tell your doctor and pharmacist if you are allergic to chlordiazepoxide, alprazolam (Xanax), clonazepam (Klonopin), clorazepate (Gen-Xene, Tranxene), diazepam (Diastat, Valium), estazolam, flurazepam, lorazepam (Ativan), oxazepam, temazepam (Restoril), triazolam (Halcion), any other medications, or any of the ingredients in tablets and capsules. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antihistamines; cimetidine (Tagamet); digoxin (Lanoxin); disulfiram (Antabuse); fluoxetine (Prozac, Sarafem, Selfemra); isoniazid (Laniazid, in Rifamate, in Rifater); ketoconazole (Nizoral); levodopa (in Ritary, in Sinemet, in Stalevo); medications for depression, seizures, Parkinson’s disease, asthma, colds, or allergies; metoprolol (Lopressor, Toprol XL, others); muscle relaxants; oral contraceptives; probenecid (Probalan, in Col-Probenecid); propranolol (Inderal, Innopran); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); sedatives; sleeping pills; theophylline (Elixophyllin, Theo 24, Theochron); tranquilizers; and valproic acid (Depakene). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had glaucoma; seizures; or lung, heart, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking chlordiazepoxide, call your doctor immediately.
• talk to your doctor about the risks and benefits of taking chlordiazepoxide if you are 65 years of age or older. Older adults should not usually take chlordiazepoxide because it is not as safe or effective as other medication(s) that can be used to treat the same condition.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking chlordiazepoxide.
• you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Chlordiazepoxide drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking chlordiazepoxide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using chlordiazepoxide with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using chlordiazepoxide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lacosamide
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using chlordiazepoxide with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ketoconazole
• Rifapentine
• St John’s Wort
• Theophylline

Other interactions

Using chlordiazepoxide with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use chlordiazepoxide, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other medical problems

The presence of other medical problems may affect the use of chlordiazepoxide. Make sure you tell your doctor if you have any other medical problems, especially:

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
• Porphyria (genetic disorder)—Use with caution. May make this condition worse.

Chlordiazepoxide uses

Chlordiazepoxide is used to relieve anxiety and to control agitation caused by alcohol withdrawal. Chlordiazepoxide may also be used short-term to treat anxiety you may have before a surgery. Chlordiazepoxide is also used to treat irritable bowel syndrome (IBS).

Chlordiazepoxide dosage

The dose of chlordiazepoxide will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of chlordiazepoxide. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (capsules)

• For anxiety:
  • Adults—5 to 25 milligrams (mg) three or four times a day.
  • Older adults—5 milligrams (mg) two to four times a day.
  • Children 6 years of age and older—At first, 5 milligrams (mg) two to four times a day. Your doctor may increase your dose if needed.
  • Children younger than 6 years of age—Use and dose must be determined by your doctor.
• For apprehension and anxiety before a surgery:
  • Adults—5 to 10 milligrams (mg) three or four times a day, taken several days before the surgery.
  • Children—Use and dose must be determined by your doctor.
• For symptoms of alcohol withdrawal:
  • Adults—At first, 50 to 100 milligrams (mg). The dose may be repeated until agitation is controlled. However, the dose is usually not more than 300 mg per day.
  • Children—Use and dose must be determined by your doctor.

Missed dose

If you take several doses per day and miss a dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Chlordiazepoxide side effects

Chlordiazepoxide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness
• tiredness
• weakness
• dry mouth
• diarrhea
• upset stomach
• changes in appetite

Tell your doctor if any of these symptoms are severe or do not go away:

• restlessness or excitement
• constipation
• difficulty urinating
• frequent urination
• blurred vision
• changes in sex drive or ability

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical help:

• shuffling walk
• persistent, fine tremor or inability to sit still
• fever
• difficulty breathing or swallowing
• severe skin rash
• yellowing of the skin or eyes
• irregular heartbeat.

Clobazam

Clobazam (Onfi or Sympazan) is a benzodiazepine that is used with other medications to treat seizures caused by Lennox-Gastaut syndrome, in people who are at least 2 years old.

Clobazam comes as a tablet and a suspension (liquid) to take by mouth, and as a film to apply on the tongue. It is usually taken once or twice a day, with or without food. Take clobazam at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.

If you are unable to swallow the tablets whole, you may break them in half on the score mark or crush and mix them with a small amount of applesauce.

The liquid comes an adapter and two oral dosing syringes. Use only one of the two oral dosing syringes to measure your dose and save the second syringe. If the first oral syringe is damaged or lost, the second provided syringe may be used as a replacement.

To take the Clobazam liquid, follow these steps:

1. Before the first use, uncap the bottle and firmly insert the adapter into the neck of the bottle until the adapter top is even with the bottle top. Do not remove the adapter during the period of time you are using this bottle.
2. Shake the liquid well before each use to mix the medication evenly.
3. To measure your dose, push the plunger of the syringe all the way down and insert the syringe into the adapter of the upright bottle. Then turn the bottle upside down and slowly pull the plunger back until the black ring is in line with your prescribed dose.
4. Remove the syringe from the bottle adapter and slowly squirt the liquid from the syringe into the corner of your mouth.
5. Place the bottle cap over the adapter after each use.
6. Wash the oral syringe after each use. To wash the syringe, remove the plunger completely, wash the barrel and plunger with soap and water, rinse, and allow to dry. Do not place the syringe parts in the dishwasher.

To take the Clobazam film, follow these steps:

1. Open the foil pouch and remove the film. Be sure that your hands are dry and clean.
2. Place the film on the top of your tongue.
3. Close your mouth and swallow your saliva normally. Do not chew, spit, or talk while the film dissolves. Do not take with liquids.
4. Wash your hands.

If your doctor has told you to take more than one film per dose, wait until the first film has completely dissolved before applying the second film.

Your doctor will probably start you on a low dose of clobazam and gradually increase your dose, not more than once every week.

Some people may respond differently to clobazam based on their heredity or genetic makeup. Your doctor may order a blood test to help find the dose of clobazam that is best for you.

Clobazam may help control your condition but will not cure it. Continue to take clobazam even if you feel well. Do not stop taking clobazam without talking to your doctor.

Clobazam most common side effects are dose related and include dizziness, somnolence, impaired concentration, nervousness, aggression, antegrade amnesia, headache, fatigue, nausea and weakness. Clobazam can also lead to physical dependence and sudden discontinuation can cause withdrawal symptoms and rebound seizure activity.

Clobazam special precautions

You should not take clobazam if you are allergic to it.

Tell your doctor if you have ever had:

• breathing problems or lung disease;
• depression, mood problems, or suicidal thoughts or behavior;
• a drug or alcohol addiction; or
• liver or kidney disease.

Some people have thoughts about suicide while taking seizure medicine. Stay alert to changes in your mood or symptoms. Your family or caregivers should also watch for sudden changes in your behavior.

If you use clobazam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks.

Do not start or stop seizure medication during pregnancy without your doctor’s advice. Clobazam may harm an unborn baby, but having a seizure during pregnancy could harm both mother and baby. Preventing seizures may outweigh these risks. Tell your doctor right away if you become pregnant.

There may be other seizure medications that are safer to use during pregnancy.

Clobazam can make hormonal birth control less effective, including birth control pills, injections, implants, skin patches, and vaginal rings. Use a back-up barrier birth control to prevent pregnancy: condom, diaphragm, cervical cap, or contraceptive sponge. Keep using birth control for at least 28 days after your last dose of clobazam.

If you are breastfeeding, tell your doctor if you notice drowsiness or feeding problems in the nursing baby.

Clobazam is not approved for use by anyone younger than 2 years old.

Before taking clobazam:

• tell your doctor and pharmacist if you are allergic to clobazam, any other medications, or any of the ingredients in clobazam tablets, suspension, or film. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: antihistamines; dextromethorphan (Delsym, in Nuedexta, in Robitussin DM); fluconazole (Diflucan); fluvoxamine (Luvox); omeprazole (Prilosec, in Zegerid); or ticlopidine. Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with clobazam, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have or have ever had thoughts about harming or killing yourself, or planning or trying to do so or lung, kidney, or liver disease.
• tell your doctor if you are pregnant or plan to become pregnant. If you take clobazam regularly during the last few months of your pregnancy, your baby may experience withdrawal symptoms after birth. Tell your baby’s doctor right away if your baby experiences any of the following symptoms: irritability, hyperactivity, abnormal sleep, high-pitched cry, uncontrollable shaking of a part of the body, vomiting, or diarrhea. If you become pregnant while taking clobazam, call your doctor.
• if you are using hormonal contraceptives (birth control pills, patches, rings, implants, injections, or intrauterine devices), you should know that this type of birth control may not work well when used with clobazam. Hormonal contraceptives should not be used as your only method of birth control while you are taking clobazam and for 28 days after your final dose. Talk to your doctor about nonhormonal birth control methods that will work for you.
• tell your doctor if you are breastfeeding. If you are breastfeeding while taking clobazam, tell your doctor if your baby is not feeding well or is extremely drowsy.
• talk to your doctor about the risks and benefits of taking this medication if you are 65 years of age or older. Older adults should receive low doses of clobazam because higher doses may not work better and may cause serious side effects.
• you should know that clobazam may make you drowsy and affect your thinking, ability to make decisions, and coordination. Do not drive a car, operate machinery, or do other dangerous activities until you know how this medication affects you.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking clobazam. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants, such as clobazam, to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); thinking about harming or killing yourself, or planning or trying to do so; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Clobazam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking clobazam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using clobazam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil
• Thioridazine

Using clobazam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acepromazine
• Alfentanil
• Alprazolam
• Anileridine
• Aripiprazole
• Asenapine
• Baclofen
• Benperidol
• Benzhydrocodone
• Bromazepam
• Buprenorphine
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Carphenazine
• Cetirizine
• Chloral Hydrate
• Chlordiazepoxide
• Chlorpromazine
• Chlorzoxazone
• Clonazepam
• Clorazepate
• Clozapine
• Codeine
• Cyclobenzaprine
• Dantrolene
• Desogestrel
• Dexmedetomidine
• Diacetylmorphine
• Diazepam
• Dichloralphenazone
• Dienogest
• Difenoxin
• Dihydrocodeine
• Diphenhydramine
• Diphenoxylate
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Doxylamine
• Droperidol
• Drospirenone
• Enflurane
• Esketamine
• Eslicarbazepine Acetate
• Estazolam
• Estradiol
• Eszopiclone
• Ethchlorvynol
• Ethinyl Estradiol
• Ethopropazine
• Ethylmorphine
• Ethynodiol
• Etonogestrel
• Fentanyl
• Flibanserin
• Flunitrazepam
• Fluphenazine
• Flurazepam
• Fluspirilene
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Gestodene
• Halazepam
• Haloperidol
• Halothane
• Hexobarbital
• Hydrocodone
• Hydromorphone
• Isoflurane
• Ketamine
• Ketazolam
• Ketobemidone
• Lemborexant
• Levocetirizine
• Levonorgestrel
• Levorphanol
• Lofexidine
• Lorazepam
• Loxapine
• Magnesium Oxybate
• Meclizine
• Medroxyprogesterone
• Melperone
• Meperidine
• Mephenesin
• Meprobamate
• Meptazinol
• Mesoridazine
• Mestranol
• Metaxalone
• Methadone
• Methdilazine
• Methocarbamol
• Methotrimeprazine
• Methylene Blue
• Metoclopramide
• Midazolam
• Mirtazapine
• Modafinil
• Molindone
• Moricizine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nicomorphine
• Nifedipine
• Nitrazepam
• Nitrous Oxide
• Nomegestrol
• Norelgestromin
• Norethindrone
• Norgestimate
• Norgestrel
• Olanzapine
• Opium
• Opium Alkaloids
• Orlistat
• Orphenadrine
• Oxazepam
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Perampanel
• Perazine
• Periciazine
• Perphenazine
• Pimozide
• Piperacetazine
• Piperaquine
• Pipotiazine
• Piritramide
• Potassium Oxybate
• Prazepam
• Pregabalin
• Primidone
• Prochlorperazine
• Promazine
• Promethazine
• Propofol
• Quazepam
• Quetiapine
• Ramelteon
• Remifentanil
• Remimazolam
• Remoxipride
• Scopolamine
• Segesterone
• Sertindole
• Sodium Oxybate
• Sufentanil
• Sulpiride
• Suvorexant
• Tamoxifen
• Tapentadol
• Temazepam
• Thiethylperazine
• Thiopropazate
• Tilidine
• Tolonium Chloride
• Topiramate
• Tramadol
• Trazodone
• Triazolam
• Trifluoperazine
• Trifluperidol
• Triflupromazine
• Trimeprazine
• Ulipristal
• Zaleplon
• Zolpidem
• Zopiclone
• Zotepine

Using clobazam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Etravirine
• Felbamate
• Fosphenytoin
• Ginkgo
• Ketoconazole
• Phenytoin
• Rifapentine
• St John’s Wort
• Theophylline

Other interactions

Using clobazam with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use clobazam, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other medical problems

The presence of other medical problems may affect the use of clobazam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or
• Depression, history of or
• Drug abuse or dependence, or history of or
• Lung or breathing problems (eg, respiratory depression) or
• Mood or behavior disorder, history of—Use with caution. May make these conditions worse.
• Liver disease, mild to moderate—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Clobazam uses

Clobazam was approved for use in the United States in 2011 as an anticonvulsant to be used either alone or in combination with other agents as therapy of the severe form of childhood epilepsy known as Lennox-Gastaut syndrome. Clobazam is used with other medication(s) to control seizures in adults and children 2 years of age and older who have Lennox-Gastaut syndrome (a disorder that causes seizures and often causes developmental delays).

Clobazam dosage

The dose of clobazam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of clobazam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage forms (film, suspension, or tablets)

• For seizures:
  • Adults and children 2 years of age and older weighing more than 30 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. The starting dose is usually 10 milligrams (mg) per day, given as 2 divided doses per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 40 mg per day.
  • Adults and children 2 years of age and older weighing 30 kg or less—Dose is based on body weight and must be determined by your doctor. The starting dose is usually 5 mg as a single dose per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 20 mg per day.
  • Older adults—Dose is based on body weight and must be determined by your doctor. The starting dose is usually 5 mg as a single dose per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 40 mg per day.
  • Children younger than 2 years of age—Use and dose must be determined by your doctor.

Missed dose

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Clobazam side effects

Clobazam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• tiredness
• problems with coordination
• difficulty speaking or swallowing
• drooling
• change in appetite
• vomiting
• constipation
• cough
• joint pain

Some side effects can be serious. If you experience any of these symptoms or those listed in the SPECIAL PRECAUTIONS or IMPORTANT WARNING sections, call your doctor immediately or get emergency medical treatment:

• difficult, painful, or frequent urination
• cough, difficulty breathing, fever
• sores in your mouth, rash, hives, peeling or blistering skin
• fever

Clobazam may cause other side effects. Call your doctor if you have any unusual problems while taking clobazam.

Clonazepam

Clonazepam (Klonopin) is a benzodiazepine that is used to treat certain seizure disorders (including absence seizures or Lennox-Gastaut syndrome) in adults and children. Clonazepam is also used to treat panic disorder (including agoraphobia) in adults. Clonazepam is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

Clonazepam comes as a tablet and an orally disintegrating tablet (tablet that dissolves quickly in the mouth) to take by mouth. Clonazepam usually is taken one to three times a day with or without food. Take clonazepam at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.

Do not try to push the orally disintegrating tablet through the foil. Instead, use dry hands to peel back the foil packaging. Immediately take out the tablet and place it in your mouth. The tablet will quickly dissolve and can be swallowed with or without liquid.

Your doctor will probably start you on a low dose of clonazepam and gradually increase your dose, not more often than once every 3 days.

Clonazepam may help control your condition, but will not cure it. It may take a few weeks or longer before you feel the full benefit of clonazepam. Continue to take clonazepam even if you feel well. Do not stop taking clonazepam without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood, If you suddenly stop taking clonazepam, you may experience withdrawal symptoms such as new or worsening seizures, hallucinating (seeing things or hearing voices that do not exist), changes in behavior, sweating, uncontrollable shaking of a part of your body, stomach or muscle cramps, anxiety, or difficulty falling asleep or staying asleep. Your doctor will probably decrease your dose gradually.

Clonazepam special precautions

You should not take clonazepam if you allergic to it or if you have:

• narrow-angle glaucoma;
• severe liver disease; or
• a history of allergic reaction to any benzodiazepine (including alprazolam, diazepam, lorazepam, Valium, Xanax, Versed, and others).

To make sure clonazepam is safe for you, tell your doctor if you have ever had:

• kidney or liver disease;
• breathing problems;
• depression, mood problems, or suicidal thoughts or behavior; or
• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system).

Some people have thoughts about suicide while taking clonazepam. Stay alert to changes in your mood or symptoms. Your family or caregivers should also watch for sudden changes in your behavior.

Tell your doctor if you are pregnant or plan to become pregnant. If you use clonazepam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks.

Do not start or stop seizure medication during pregnancy without your doctor’s advice. Clonazepam may harm an unborn baby, but having a seizure during pregnancy could harm both mother and baby. Preventing seizures may outweigh these risks. Tell your doctor right away if you become pregnant.

Ask a doctor if it is safe to breastfeed while using clonazepam.

Do not give clonazepam to a child without medical advice. Clonazepam is not approved to treat panic disorder in anyone younger than 18 years old.

Before taking clonazepam:

• tell your doctor and pharmacist if you are allergic to clonazepam, other benzodiazepines such as alprazolam (Xanax), chlordiazepoxide (Librium, in Librax), clorazepate (Gen-Xene, Tranxene), diazepam (Diastat, Valium), estazolam, flurazepam, lorazepam (Ativan), midazolam (Versed), oxazepam, temazepam (Restoril), triazolam (Halcion), any other medications, or any of the ingredients in clonazepam tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: amiodarone (Cordarone, Nexterone, Pacerone); certain antibiotics such as clarithromycin (Biaxin, in Prevpac), erythromycin (Erythrocin, E-mycin, others), and troleandomycin (TAO) (not available in the US); antidepressants; certain antifungal medications such as itraconazole (Onmel. Sporanox) and ketoconazole (Nizoral); antihistamines; certain calcium channel blockers such as diltiazem (Cardizem, Tiazac, others) and verapamil (Calan, Covera, Verelan, in Tarka); cimetidine (Tagamet); HIV protease inhibitors including indinavir (Crixivan), nelfinavir (Viracept), and ritonavir (Norvir, in Kaletra); medications for anxiety, colds or allergies, or mental illness; other medications for seizures such as carbamazepine (Epitol, Tegretol, Teril), phenobarbital, phenytoin (Dilantin, Phenytek), or valproic acid (Depakene); muscle relaxants; nefazodone; rifampin (Rifadin, Rimactane); sedatives; certain selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine (Luvox); other sleeping pills; and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have or have ever had glaucoma (increased pressure in the eye that may cause vision loss) or liver disease. Your doctor may tell you not to take clonazepam.
• tell your doctor if you have or have ever had lung or kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. Clonazepam may harm the fetus. If you become pregnant while taking clonazepam, call your doctor.
• talk to your doctor about the risks and benefits of taking this medication if you are 65 years of age or older. Older adults should receive low doses of clonazepam because higher doses may not work better and may cause serious side effects.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking clonazepam.
• you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that your mental health may change in unexpected ways, and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking clonazepam for the treatment of epilepsy, mental illness, or other conditions. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as clonazepam to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as clonazepam, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood), talking or thinking about wanting to hurt yourself or end your life, withdrawing from friends and family; preoccupation with death and dying, giving away prized possessions, or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Special dietary instructions

Do not eat grapefruit or drink grapefruit juice while you’re taking clonazepam.

Clonazepam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking clonazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using clonazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using clonazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbamazepine
• Carbinoxamine
• Carisoprodol
• Ceritinib
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clarithromycin
• Clobazam
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Ketoconazole
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Orlistat
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using clonazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone
• Desipramine
• Ginkgo
• Nevirapine
• Rifapentine
• Ritonavir
• St John’s Wort
• Theophylline

Other interactions

Using clonazepam with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use clonazepam, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other medical problems

The presence of other medical problems may affect the use of clonazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of or
• Depression, history of or
• Lung or breathing problems or
• Porphyria—Use with caution. May make these conditions worse.
• Glaucoma, narrow angle, acute or
• Liver disease—Should not be used in patients with these conditions.
• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Clonazepam uses

Clonazepam is a benzodiazepine that works in the brain to prevent seizures. Clonazepam is used alone or in combination with other medications to control certain types of seizures (eg, Lennox-Gastaut syndrome, akinetic, myoclonic, and absence seizures). Clonazepam is also used to treat panic disorder to relieve panic attacks (sudden, unexpected attacks of extreme fear and worry about these attacks).

Clonazepam dosage

The dose of clonazepam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of clonazepam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage forms (tablets or disintegrating tablets)

For seizures

• Adults and children 10 years and older—At first, 0.5 milligram (mg) 3 times per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 20 mg per day.
• Children up to 10 years or 30 kilograms (kg) of body weight—Dose is based on body weight and must be determined by your doctor. The dose is usually 0.01 to 0.03 mg per kg of body weight per day, given in 2 or 3 divided doses. However, the dose is usually not more than 0.05 mg per kg of body weight. Your doctor may adjust your dose as needed.

For panic disorder:

• Adults—At first, 0.25 milligram (mg) 2 times per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 4 mg per day.
• Children—Use and dose must be determined by your doctor.

Missed dose

If you miss a dose of clonazepam, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Clonazepam side effects

Clonazepam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness
• unsteadiness
• problems with coordination
• difficulty thinking or remembering
• increased saliva
• muscle or joint pain
• frequent urination
• blurred vision
• changes in sex drive or ability

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• rash
• hives
• swelling of the eyes, face, lips, tongue, or throat
• difficulty breathing or swallowing
• hoarseness
• difficulty breathing.

Clorazepate

Clorazepate (Tranxene T-Tab or Tranxene SD) is a benzodiazepine that is used to treat anxiety disorders, partial seizures, or alcohol withdrawal symptoms. Clorazepate is available only with your doctor’s prescription.

Clorazepate comes as a tablet to take by mouth. It is usually taken one to three times a day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take clorazepate exactly as directed.

If you are taking clorazepate to treat anxiety or seizures, your doctor will probably start you on a low dose of clorazepate and gradually increase your dose. If you are taking clorazepate to treat alcohol withdrawal, your doctor will probably start you on a high dose of clorazepate and gradually decrease your dose as your symptoms are controlled.

Clorazepate may help to control seizures and anxiety, but it will not cure these conditions. Continue to take clorazepate even if you feel well.

Clorazepate special precautions

You should not use clorazepate if you are allergic to it, or if you have:

• narrow-angle glaucoma.

Tell your doctor if you have ever had:

• liver or kidney disease;
• mood problems, depression, psychosis; or
• suicidal thoughts or actions.

Some people have thoughts about suicide while taking clorazepate. Stay alert to changes in your mood or symptoms. Your family or caregivers should also watch for sudden changes in your behavior.

Tell your doctor if you are pregnant or plan to become pregnant. Clorazepate may harm an unborn baby. Avoid taking this medicine during the first trimester of pregnancy.

If you use clorazepate during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks.

If you take clorazepate for seizures, do not start or stop taking it during pregnancy without your doctor’s advice. Having a seizure during pregnancy could harm both mother and baby.

Do not breastfeed whilst taking clorazepate.

Clorazepate is not approved for use by anyone younger than 9 years old.

Before taking clorazepate:

• tell your doctor and pharmacist if you are allergic to clorazepate; other benzodiazepines such as alprazolam ( Xanax), chlordiazepoxide (Librium, in Librax), clonazepam (Klonopin), diazepam (Diastat, Valium), estazolam, flurazepam, lorazepam (Ativan), oxazepam, temazepam (Restoril), or triazolam (Halcion); any other medications; or any of the ingredients in clorazepate tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: barbiturates such as phenobarbital and secobarbital (Seconal); chlorpromazine; cimetidine (Tagamet); disulfiram (Antabuse); levodopa (in Ritary, in Sinemet, in Stalevo); or monoamine oxidase inhibitors such as isocarboxazid (Marplan), linezolid (Zyvox), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); medications for depression, nausea, mental illness, and seizures; sedatives; sleeping pills; and tranquilizers.Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had glaucoma. Your doctor may tell you not to take clorazepate.
• tell your doctor if you have or have ever had liver or kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking clorazepate, call your doctor.
• talk to your doctor about the risks and benefits of taking clorazepate if you are 65 years of age or older. Older adults should not usually take clorazepate because it is not as safe or effective as other medications that can be used to treat the same condition.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking clorazepate.
• you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that your mental health may change in unexpected ways, and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking clorazepate for the treatment of epilepsy, mental illness, or other conditions A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as clorazepate to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as clorazepate, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood), talking or thinking about wanting to hurt yourself or end your life, withdrawing from friends and family; preoccupation with death and dying, giving away prized possessions, or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Clorazepate drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking clorazepate, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using clorazepate with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using clorazepate with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Omeprazole
• Orlistat
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using clorazepate with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amprenavir
• Ginkgo
• Rifapentine
• St John’s Wort
• Theophylline

Other medical problems

The presence of other medical problems may affect the use of clorazepate. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of or
• Depression, history of or
• Lung or breathing problems (eg, respiratory depression) or
• Mental health problems, history of—Use with caution. May make these conditions worse.
• Glaucoma, narrow angle—Should not be used in patients with this condition.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Clorazepate uses

Clorazepate is used to relieve symptoms of anxiety. Clorazepate is also used along with other medications to treat partial seizures. Clorazepate is also used to relieve unpleasant symptoms that may be experienced by people who have stopped drinking alcohol after drinking large amounts for a long time.

Clorazepate dosage

The dose of clorazepate will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of clorazepate. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (tablets)

• For anxiety:
  • Adults—30 milligrams (mg) per day, taken in divided doses. Your doctor may adjust your dose if needed.
  • Older adults—At first, 7.5 to 15 mg per day, taken at bedtime or in divided doses. Your doctor may increase your dose if needed.
  • Children—Use and dose must be determined by your doctor.
• For symptoms of alcohol withdrawal:
  • Adults—At first, 30 milligrams (mg), followed by 30 to 60 mg in divided doses. Your doctor will set up a schedule that will gradually adjust your dose until your symptoms improve. The dose is usually not more than 90 mg per day.
  • Children—Use and dose must be determined by your doctor.
• For partial seizures:
  • Adults and children 13 years of age and older—At first, 7.5 milligrams (mg) 3 times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 90 mg per day.
  • Children 9 to 12 years of age—The starting dose is up to 7.5 mg 2 times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 60 mg per day.
  • Children up to 9 years of age—Use is not recommended.

Missed dose

Take the missed dose as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule.

Clorazepate side effects

Clorazepate may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness
• tiredness
• headache
• nervousness
• confusion
• dry mouth

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• blurred or double vision
• uncontrollable shaking of a part of the body
• slurred speech
• difficulty keeping your balance
• rash

Clorazepate may cause other side effects. Call your doctor if you have any unusual problems while you are taking clorazepate.

Diazepam

Diazepam (Valium) is a benzodiazepine that is used to treat anxiety disorders or alcohol withdrawal symptoms. Diazepam is sometimes also used with other medications to treat muscle spasms and stiffness, or control seizures (eg, seizure clusters, acute repetitive seizures) in patients who have epilepsy. Diazepam is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. Diazepam is available only with your doctor’s prescription.

Diazepam comes as a tablet, a solution, and as a concentrate (liquid) to take by mouth. It is usually taken 1 to 4 times a day and may be taken with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take diazepam exactly as directed.

Diazepam concentrate comes with a specially marked dropper for measuring the dose. Ask your pharmacist to show you how to use the dropper. Dilute the concentrate in water, juice, or carbonated beverages just before taking it. It also may be mixed with applesauce or pudding just before taking the dose. Stir the mixture gently for a few seconds. Take the entire mixture immediately; do not store it for future use.

If you are taking diazepam along with other medications to control seizures, do not stop taking diazepam without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. If you suddenly stop taking diazepam, your seizures may get worse. Your doctor will probably decrease your dose gradually.

Diazepam special precautions

You should NOT use diazepam if you are allergic to it, or if you have:

• myasthenia gravis (a muscle weakness disorder);
• a severe breathing problem;
• sleep apnea (breathing stops during sleep);
• narrow-angle glaucoma;
• untreated or uncontrolled open-angle glaucoma; or
• severe liver disease.

Diazepam should NOT be given to a child younger than 6 months old. Do NOT give diazepam to a child without a doctor’s advice.

Diazepam may harm an unborn baby. Do not use if you are pregnant or may become pregnant. If you use diazepam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks. However, do not start or stop seizure medication during pregnancy without your doctor’s advice. Diazepam may harm an unborn baby, but having a seizure during pregnancy could harm both mother and baby. Preventing seizures may outweigh these risks. Tell your doctor right away if you become pregnant. There may be other seizure medications that are safer to use during pregnancy. You should not breastfeed whilst taking diazepam.

Do not stop using diazepam without asking your doctor. You may have increased seizures or life-threatening withdrawal symptoms if you stop using the medicine suddenly after long-term use.

To make sure diazepam is safe for you, tell your doctor if you have ever had:

• breathing problems;
• glaucoma;
• kidney or liver disease;
• seizures (unless you are taking diazepam to treat a seizure disorder);
• a drug or alcohol addiction; or
• depression, a mood disorder, or suicidal thoughts or behavior.

Some people have thoughts about suicide while taking diazepam. Stay alert to changes in your mood or symptoms. Your family or caregivers should also watch for sudden changes in your behavior.

Before taking diazepam:

• tell your doctor and pharmacist if you are allergic to diazepam, alprazolam (Xanax), chlordiazepoxide (Librium, in Librax), clonazepam (Klonopin), clorazepate (Gen-Xene, Tranxene), estazolam, flurazepam, lorazepam (Ativan), oxazepam, temazepam (Restoril), triazolam (Halcion), any other medications, or any of the ingredients in diazepam products. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements, you are taking. Be sure to mention any of the following: antihistamines; barbiturates such as phenobarbital (Luminal); cimetidine (Tagamet); digoxin (Lanoxin); disulfiram (Antabuse); fluoxetine (Prozac); fluvoxamine (Luvox); isoniazid (Laniazid, in Rifamate, in Rifater); ketoconazole; medications for anxiety, depression, mental illness, seizures, Parkinson’s disease, asthma, colds, or allergies; metoprolol (Lopressor, Toprol XL); monoamine oxidase (MAO) inhibitors including isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); muscle relaxants; phenothiazine medications for mental illness or nausea such as chlorpromazine, fluphenazine, prochlorperazine (Compro, Procomp), and promethazine (Promethegan); omeprazole (Prilosec); probenecid (Probalan, in Col-Probenecid); propranolol (Hemangeol, Inderal, Innopran); ranitidine (Zantac); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); sedatives; sleeping pills; theophylline (Elixophyllin, Theo 24, Theochron); tranquilizers; or valproic acid (Depakene). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have myasthenia gravis (a disorder of the nervous system that causes muscle weakness), sleep apnea (condition in which a person briefly stops breathing many times during the night), or lung or liver disease. Also, tell your doctor if you have narrow angle glaucoma (a serious eye condition that may cause loss of vision. Your doctor will probably tell you not to take diazepam. Diazepam should not be used in infants younger than 6 months of age.
• tell your doctor if you have or have ever had open-angle glaucoma (increase in internal eye pressure that damages the optic nerve); depression or other mental illness; seizures; or heart disease.
• tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking diazepam, call your doctor immediately.
• tell your doctor if you are breastfeeding. Do not breastfeed while you are taking diazepam.
• talk to your doctor about the risks and benefits of taking diazepam if you are 65 years of age or older. Older adults should not usually take diazepam because it is not as safe as other medications that can be used to treat the same conditions.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking diazepam.
• you should know that this drug may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking diazepam for the treatment of epilepsy. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as diazepam to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as diazepam, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Special dietary instructions

Do not eat grapefruit or drink grapefruit juice while you’re taking diazepam.

Diazepam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving diazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using diazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using diazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abametapir
• Alfentanil
• Alprazolam
• Amobarbital
• Anileridine
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Cobicistat
• Codeine
• Conivaptan
• Dantrolene
• Diacetylmorphine
• Difenoxin
• Dihydrocodeine
• Diphenoxylate
• Doxylamine
• Esketamine
• Eslicarbazepine Acetate
• Ethchlorvynol
• Ethylmorphine
• Etravirine
• Fentanyl
• Fexinidazole
• Flibanserin
• Fosnetupitant
• Fosphenytoin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Ketobemidone
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Netupitant
• Nicomorphine
• Opium
• Opium Alkaloids
• Orlistat
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Phenytoin
• Piritramide
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remifentanil
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tilidine
• Tramadol
• Trazodone
• Zolpidem

Using diazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amitriptyline
• Amprenavir
• Clarithromycin
• Dalfopristin
• Desogestrel
• Dienogest
• Disulfiram
• Drospirenone
• Erythromycin
• Estradiol
• Ethinyl Estradiol
• Ethynodiol
• Fluvoxamine
• Gestodene
• Ginkgo
• Isoniazid
• Levonorgestrel
• Mestranol
• Nomegestrol
• Norethindrone
• Norgestimate
• Norgestrel
• Quinupristin
• Rifapentine
• Roxithromycin
• St John’s Wort
• Theophylline
• Troleandomycin

Other medical problems

The presence of other medical problems may affect the use of diazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol and drug abuse or dependence, or history of—Dependence on diazepam may develop.
• Glaucoma, acute narrow angle—Should not be used in patients with this condition.
• Glaucoma, open angle or
  Lung or breathing problems (eg, asthma, pneumonia)—Use with caution. May make these conditions worse.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Diazepam uses

Diazepam is used to relieve anxiety and to control agitation caused by alcohol withdrawal. Diazepam is also used along with other medications to control muscle spasms and spasticity caused by certain neurological disorders such as cerebral palsy (condition that causes difficulty with movement and balance), paraplegia (inability to move parts of the body), athetosis (abnormal muscle contractions), and stiff-man syndrome (a rare disorder with muscle rigidity and stiffness). Diazepam is also used along with other medications to control seizures.

Diazepam dosage

The dose of diazepam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of diazepam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Adult dose for Anxiety

Use: Management of anxiety disorders and short-term relief of anxiety symptoms

• Oral: 2 to 10 mg orally 2 to 4 times a day
• Parenteral:
  • Moderate Anxiety Disorders and Symptoms: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary
  • Severe Anxiety Disorders and Symptoms: 5 to 10 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Oral doses should be determined by the severity of symptoms.
• Anxiety associated with the stress of everyday life usually does not require treatment with this drug.

Adult dose for Muscle Spasm

Use: Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

• Oral: 2 to 10 mg orally 3 to 4 times a day
• Parenteral: 5 to 10 mg IM or IV, then 5 to 10 mg IM or IV in 3 to 4 hours if necessary

Comment: Larger parenteral doses may be necessary for patients with tetanus.

Adult dose for Alcohol Withdrawal

Use: Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal

• Oral:
  • Initial dose: 10 mg orally 3 to 4 times a day for the first 24 hours
  • Maintenance dose: 5 mg orally 3 to 4 times a day as needed
• Parenteral: 10 mg IM or IV once, then 5 to 10 mg IM or IV in 3 to 4 hours if necessary

Adult dose for Seizures

Uses:

• Management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs who require intermittent use of diazepam to control bouts of increased seizure activity
• Adjunctive treatment for convulsive disorders

Oral: 2 to 10 mg orally 2 to 4 times a day

Rectal:

• Initial dose: 0.2 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
• If necessary, a second dose of 0.2 mg/kg may be given rectally 4 to 12 hours after the first dose.
• Maximum Frequency: May be used to treat up to 1 seizure episode every 5 days, and no more than 5 episodes/month

Adult dose for Status Epilepticus

Use: Adjunct to status epilepticus and severe recurrent convulsive seizures

Parenteral:

• Initial dose: 5 to 10 mg IV once, repeated at 10 to 15 minute intervals to a maximum dose of 30 mg if necessary

Comments:

• The IV route is preferred; however, the IM route may be used if IV administration is impossible.
• Treatment may be repeated every 2 to 4 hours, but active metabolites may persist during readministration.
• Patients with chronic lung disease or unstable cardiovascular conditions should be given this drug with extreme caution.

Geriatric dose for Seizures

Uses:

• Management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs who require intermittent use of this drug to control bouts of increased seizure activity
• Adjunctive treatment in convulsive disorders

Oral:

• Initial dose: 2 to 2.5 mg orally once to 2 times a day

Rectal:

• Initial dose: 0.2 mg/kg rectally, rounded downward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
• If necessary, a second dose of 0.2 mg/kg may be given rectally 4 to 12 hours after the first dose.
• Maximum Frequency: May be used to treat up to 1 seizure episode every 5 days, and no more than 5 episodes/month

Comment: Oral doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount

Geriatric dose for Alcohol Withdrawal

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral:

• Initial dose: 2 to 2.5 mg orally once to 2 times a day

Parenteral:

• Initial dose: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Geriatric dose for Anxiety

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral:

• Initial dose: 2 to 2.5 mg orally once to 2 times a day

Parenteral:

• Initial dose: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Geriatric dose for Muscle Spasm

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral:

• Initial dose: 2 to 2.5 mg orally once to 2 times a day

Parenteral:

• Initial dose: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Adult dose for Light Anesthesia

Use: Premedication for the relief of anxiety and tension in patients undergoing surgical procedures

Parenteral:

• Preoperative Medication: 10 mg IM once before surgery

Comments:

• The IM route is preferred when given as a preoperative medication.
• Atropine, scopolamine, and other premedications should be administered in separate syringes.

Adult dose for Endoscopy or Radiology Premedication

Uses:

• Adjunct prior to endoscopic procedures if apprehension, anxiety, or acute stress reactions are present and to diminish recall of the procedures
• Prior to cardioversion for the relief of anxiety and tension and to diminish the patient’s recall of the procedure

Parenteral:

• Cardioversion: 5 to 15 mg IV once 5 to 10 minutes before the procedure

Endoscopic Procedures:

• IV: Usually less than 10 mg, but some patients require up to 20 mg IV, especially when narcotics are omitted
• IV titration: The IV dose should be titrated to desired sedative response (e.g., slurring of speech) with slow administration immediately before the procedure.
• IM: 5 to 10 mg IM once 30 minutes prior to the procedure

Comments:

• Narcotic dosing should be reduced by approximately 33%, and may be omitted in some patients.
• The IV route is preferred, but IM administration may be used if IV administration is not possible.

Pediatric dose for Seizures

Uses:

• Management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs who require intermittent use of this drug to control bouts of increased seizure activity
• Adjunctive treatment in convulsive disorders

Oral:

• 6 months and older:
• Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Rectal:

• 2 to 5 years:
  • Initial dose: 0.5 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
  • If necessary, a second dose of 0.5 mg/kg may be given rectally 4 to 12 hours after the first dose.
  • Maximum Frequency: 1 episode every 5 days, and no more than 5 episodes/month
• 6 to 11 years:
  • Initial dose: 0.3 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
  • If necessary, a second dose of 0.3 mg/kg may be given rectally 4 to 12 hours after the first dose.
  • Maximum Frequency: 1 episode every 5 days, and no more than 5 episodes/month
• 12 years and older:
  • Initial dose: 0.2 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
  • If necessary, a second dose of 0.2 mg/kg may be given rectally 4 to 12 hours after the first dose.
  • Maximum Frequency: May be used to treat up to 1 seizure episode every 5 days, and no more than 5 episodes/month

Comment: Oral doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.

Pediatric dose for Status Epilepticus

Use: Adjunct in status epilepticus and severe recurrent convulsive seizures

Parenteral:

• IV Injection:
  • 30 days to less than 5 years: 0.2 to 0.5 mg slow IV injection every 2 to 5 minutes, up to a maximum dose of 5 mg. Repeat in 2 to 4 hours if needed.
  • 5 years and older: 1 mg slow IV injection every 2 to 5 minutes, up to a maximum dose of 10 mg. Repeat in 2 to 4 hours if needed.

Comment: EEG monitoring may be helpful to monitor seizure activity.

Pediatric dose for Seizure Prophylaxis

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral:

• 6 months and older:
  • Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Pediatric dose for Muscle Spasm

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral:

• 6 months and older:
  • Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Pediatric dose for Tetanus

Use: Tetanus

Parenteral:

• 30 days to 5 years: 1 to 2 mg IM or slow IV injection, repeated every 3 to 4 hours as necessary
• 5 years and older: 5 to 10 mg IM or slow IV injection, repeated every 3 to 4 hours as necessary to control spasms

Comment: Respiratory assistance should be available for patients.

Pediatric dose for Anxiety

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral:

• 6 months and older:
  • Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Missed dose

Take diazepam as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

Diazepam side effects

Diazepam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness
• tiredness
• muscle weakness
• headache
• dry mouth
• nausea
• constipation
• confusion
• difficulty urinating
• frequent urination
• changes in sex drive or ability

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• loss of control of bodily movements
• uncontrollable shaking of a part of the body
• slurred speech
• slowed breathing and heartbeat

Diazepam may cause other side effects. Call your doctor if you have any unusual problems while taking diazepam.

Estazolam

Estazolam (Eurodin or ProSom) is a benzodiazepine that is used for the short-term treatment insomnia (trouble falling or staying asleep). Estazolam is available only with your doctor’s prescription. Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with estazolam and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions.

Estazolam comes as a tablet to take by mouth. It is usually taken as needed at bedtime or after going to bed and having difficulty falling asleep. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take estazolam exactly as directed.

You will probably become very sleepy after you take estazolam and may remain sleepy for some time. Plan to go to bed right after you take estazolam and to stay in bed for a full night. Do not take estazolam if you will be unable to remain asleep for a full night after you take the medication.

Your sleep problems should improve within 7 to 10 days after you start taking estazolam. Call your doctor if your sleep problems do not improve during this time, if they worsen at any time during your treatment, or if you notice any unusual changes in your thoughts or behavior.

If your doctor has told you to take estazolam regularly, talk to your doctor before you stop taking this medication. Your doctor will probably decrease your dose gradually. If you suddenly stop taking estazolam, you may experience withdrawal symptoms such as difficulty falling asleep or staying asleep, uncontrollable shaking of a part of the body, stomach and muscle cramps, vomiting, sweating, sad mood, seeing things or hearing sounds that do not exist, and seizures.

Estazolam special precautions

You should not use estazolam if you are allergic to it, or:

• if you are pregnant; or
• if you are also using itraconazole or ketoconazole.

Estazolam may cause birth defects. Do not use if you are pregnant. If you use estazolam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks. Use effective birth control while using estazolam. Tell your doctor if you become pregnant.

Tell your doctor if you have ever had:

• breathing problems;
• drug or alcohol addiction;
• suicidal thoughts or actions;
• depression or mental illness; or
• liver or kidney disease.

Do not breastfeed whilst taking estazolam.

Estazolam is not approved for use by anyone younger than 18 years old.

Before taking estazolam:

• tell your doctor and pharmacist if you are allergic to estazolam; any other medications, or any of the ingredients in estazolam tablets. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor if you are taking ketoconazole (Nizoral) or itraconazole (Onmel, Sporanox). Your doctor will probably tell you not to take estazolam if you are taking either of these medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: certain antibiotics such as erythromycin (E.E.S., Erythrocin, E-Mycin); antidepressants; antihistamines; barbiturates such as phenobarbital or pentobarbital; cimetidine (Tagamet); digoxin (Lanoxin); diltiazem (Cardizem, Tiazac); disulfiram (Antabuse); fluvoxamine (Luvox); isoniazid (Laniazid, in Rifamate, in Rifater); medications for mental illness or nausea; medications for seizures such as carbamazepine (Equetro, Tegretol, Teril) and phenytoin (Dilantin, Phenytek); monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); nefazodone; rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); sedatives; sleeping pills; and tranquilizers. Many other medications may also interact with estazolam, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have ever thought about killing or harming yourself or planned or tried to do so and if you have or have ever had seizures, breathing problems or lung disease, or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking estazolam, call your doctor immediately.
• talk to your doctor about the risks and benefits of taking estazolam if you are 65 years of age or older. Older adults should not usually take estazolam because it is not as safe as other medications that can be used to treat the same condition.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking estazolam.
• you should know that this medication may make you drowsy during the daytime. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that some people who took medications for sleep got out of bed and drove their cars, prepared and ate food, had sex, made phone calls, or were involved in other activities while partially asleep. After they woke up, these people were usually unable to remember what they had done. Call your doctor right away if you find out that you have been driving or doing anything else while you were sleeping.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Estazolam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking estazolam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using estazolam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using estazolam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clarithromycin
• Clobazam
• Cobicistat
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using estazolam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Rifapentine
• St John’s Wort
• Theophylline

Other medical problems

The presence of other medical problems may affect the use of estazolam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of, or
• Breathing problems or lung disease, severe or
• Depression, history of—Use with caution. May make these conditions worse.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Estazolam uses

Estazolam is used for the short-term treatment of insomnia (difficulty falling asleep or staying asleep). Estazolam is for short-term use only, usually 7 to 10 days.

Estazolam dosage

The dose of estazolam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of estazolam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (tablets):

• For insomnia:
  • Adults—At first, 1 milligram (mg) at bedtime. Your doctor may adjust your dose if needed.
  • Older adults—At first, 0.5 milligram (mg) at bedtime. Your doctor may adjust your dose if needed.
  • Children—Use and dose must be determined by your doctor.

Missed dose

You will probably be told to take estazolam as needed. If your doctor tells you to take estazolam regularly and you miss a dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one and do not take estazolam unless you are ready to go to bed and stay asleep for a full night.

Estazolam side effects

Estazolam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• hangover effect (grogginess)
• drowsiness
• dizziness
• weakness
• dry mouth
• constipation
• aggression
• agitation
• changes in behavior
• slowed or uncoordinated movements
• muscle stiffness
• leg pain

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• fever
• blisters
• rash
• hives
• swelling of the eyes, face, lips, tongue, throat, arms, hands, feet, ankles, or lower legs
• difficulty breathing or swallowing

Estazolam may cause other side effects. Call your doctor if you have any unusual problems while you are taking estazolam.

Flurazepam

Flurazepam (Dalmane) is a benzodiazepine that is used to treat insomnia (trouble falling or staying asleep). Flurazepam may be prescribed for other uses; ask your doctor or pharmacist for more information. Flurazepam is available only with your doctor’s prescription.

Flurazepam comes as a capsule to take by mouth. It is usually taken as needed at bedtime. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take flurazepam exactly as directed.

Flurazepam starts working slowly and continues to work for a short time after you stop taking it. You may experience more benefit from flurazepam on the second and third nights after you start taking it. You may continue to feel the effects of flurazepam for one to two nights after you stop taking the medication.

Your sleep problems should improve within 7 to 10 days after you start taking flurazepam. Call your doctor if your sleep problems do not improve during this time, if they get worse at any time during your treatment, or if you notice any changes in your thoughts or behavior.

Flurazepam special precautions

You should not use flurazepam if you are allergic to any benzodiazepine (flurazepam, alprazolam, diazepam, lorazepam, Valium, Xanax, Versed, Klonopin, and others).

Do not use if you are pregnant. If you use flurazepam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks. Use effective birth control while using flurazepam. Stop using flurazepam and tell your doctor if you become pregnant.

Tell your doctor if you have ever had:

• drug or alcohol addiction;
• depression or mental illness; or
• suicidal thoughts or actions.

Do not breastfeed whilst taking flurazepam.

Flurazepam is not approved for use by anyone younger than 18 years old.

Before taking flurazepam:

• tell your doctor and pharmacist if you are allergic to flurazepam, any other medications, or any of the ingredients in flurazepam capsules. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take during your treatment with flurazepam and for several days afterward. Be sure to mention any of the following: antihistamines; cimetidine; clozapine (Clozaril, Versacloz); digoxin; medications for anxiety, depression, mental illness, or seizures; muscle relaxants; sedatives; other sleeping pills; and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had sleep apnea (a sleep disorder that causes breathing to stop for short periods during sleep) or lung, kidney, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking flurazepam, call your doctor immediately.
• talk to your doctor about the risks and benefits of taking flurazepam if you are 65 years of age or older. Older adults should not usually take flurazepam because it is not as safe as other medications that can be used to treat the same condition.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking flurazepam.
• you should know that this medication may make you drowsy and may increase the risk that you could fall. Take extra care to be sure you do not fall, especially if you get out of bed in the middle of the night. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that some people who took medications for sleep got out of bed and drove their cars, prepared and ate food, had sex, made phone calls, or were involved in other activities while partially asleep. After they woke up, these people were usually unable to remember what they had done. Call your doctor right away if you find out that you have been driving or doing anything else while you were sleeping.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Flurazepam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking flurazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using flurazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using flurazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using flurazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amprenavir
• Rifapentine
• St John’s Wort
• Theophylline

Other medical problems

The presence of other medical problems may affect the use of flurazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or
• Breathing problems or lung disease or
• Depression, or history of or
• Drug abuse or dependence, or history of or
• Mental health problems, or history of—Use with caution. May make these conditions worse.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Flurazepam uses

Flurazepam is used to treat insomnia (difficulty falling asleep and staying asleep). Flurazepam helps you get to sleep faster and sleep through the night.

Flurazepam dosage

The dose of flurazepam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of flurazepam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (capsules)

• For insomnia:
  • Adults
    • Dalmane®: 30 milligrams (mg) at bedtime. Your doctor may adjust your dose if needed.
    • Flurazepam:
      • Men: 15 or 30 mg at bedtime. Your doctor may increase your dose if needed.
      • Women: At first, 15 mg at bedtime.
    • Older adults—15 mg at bedtime. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.

Missed dose

Flurazepam should only be taken at bedtime. If you forget to take flurazepam at bedtime, you are unable to fall asleep, and you will still be able to stay in bed for a full night’s sleep, you may take flurazepam at that time. Do not take a double dose of flurazepam to make up for a missed dose.

Flurazepam side effects

Flurazepam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness or lightheadedness
• loss of coordination
• headache
• heartburn
• nausea
• vomiting
• stomach pain
• diarrhea
• constipation
• nervousness
• irritability
• talking more than usual
• weakness
• joint pain

Some side effects can be serious. If you experience any of the following side effects or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• rash
• hives
• swelling of the face, throat, tongue, lips, or eyes
• hoarseness
• difficulty breathing or swallowing
• pounding heartbeat
• chest pain
• coma (loss of consciousness for a period of time)

Lorazepam

Lorazepam (Ativan) is a benzodiazepine that is used to treat anxiety disorders. Lorazepam is also used for short-term relief of the symptoms of anxiety or anxiety caused by depression. Lorazepam is available only with your doctor’s prescription. Talk to your doctor about the possible risks of using lorazepam for your condition.

Lorazepam comes as a tablet and concentrate (liquid) to take by mouth. It usually is taken two or three times a day and may be taken with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take lorazepam exactly as directed.

Lorazepam concentrate (liquid) comes with a specially marked dropper for measuring the dose. Ask your pharmacist to show you how to use the dropper. Dilute the concentrate in 1 ounce (30 milliliters) or more of water, juice, or carbonated beverages just before taking it. It also may be mixed with applesauce or pudding just before taking the dose.

Lorazepam special precautions

You should not use lorazepam if you have:

• narrow-angle glaucoma; or
• a history of allergic reaction to any benzodiazepine (lorazepam, alprazolam, diazepam, Valium, Xanax, Versed, Klonopin, and others).

To make sure lorazepam is safe for you, tell your doctor if you have ever had:

• asthma, chronic obstructive pulmonary disease (COPD), sleep apnea, or other breathing disorder;
• drug or alcohol addiction;
• depression, mood problems, or suicidal thoughts or behavior;
• kidney or liver disease;
• seizures; or
• an allergy to aspirin or yellow food dye.

Tell your doctor if you are pregnant or plan to become pregnant. If you use lorazepam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks.

You should not breastfeed while you are taking lorazepam. If you do breastfeed, tell your doctor if you notice drowsiness, feeding problems, or slow weight gain in the nursing baby.

Lorazepam is not approved for use by anyone younger than 12 years old. Extended-release lorazepam should not be used by anyone younger than 18 years old.

Before taking lorazepam:

• tell your doctor and pharmacist if you are allergic to lorazepam, alprazolam (Xanax), chlordiazepoxide (Librium, in Librax), clonazepam (Klonopin), clorazepate (Gen-Xene, Tranxene), diazepam (Valium), estazolam, flurazepam, oxazepam, temazepam (Restoril), triazolam (Halcion), any other medications, or any of the ingredients in lorazepam tablets or concentrate. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antihistamines; digoxin (Lanoxin); levodopa (in Ritary, in Sinemet, in Stalevo); medications for depression, seizures, Parkinson’s disease, asthma, colds, or allergies; muscle relaxants; oral contraceptives; probenecid (Probalan, in Col-Probenecid); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); sedatives; sleeping pills; theophylline (Elixophyllin, Theo 24, Theochron); tranquilizers; and valproic acid (Depakene).Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have glaucoma. Your doctor will probably tell you not to take lorazepam.
• tell your doctor if you have or have ever had seizures; or lung, heart, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking lorazepam, call your doctor immediately.
• talk to your doctor about the risks and benefits of taking this medication if you are 65 years of age or older. Older adults should take lower doses of lorazepam because higher doses may not be more effective and are more likely to cause serious side effects.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking lorazepam.
• you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Lorazepam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking lorazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using lorazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using lorazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Anileridine
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Codeine
• Dantrolene
• Dezocine
• Diacetylmorphine
• Difenoxin
• Dihydrocodeine
• Diphenoxylate
• Doxylamine
• Esketamine
• Ethchlorvynol
• Ethylmorphine
• Fentanyl
• Flibanserin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Ketobemidone
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Meptazinol
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nicomorphine
• Opium
• Opium Alkaloids
• Orlistat
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Piritramide
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remifentanil
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tilidine
• Tramadol
• Trazodone
• Zolpidem

Using lorazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Desogestrel
• Dienogest
• Drospirenone
• Estradiol
• Ethinyl Estradiol
• Ethynodiol
• Gestodene
• Levonorgestrel
• Mestranol
• Nomegestrol
• Norethindrone
• Norgestimate
• Norgestrel
• Posaconazole
• Probenecid
• Pyrimethamine
• Rifapentine
• St John’s Wort
• Theophylline
• Valproic Acid

Other medical problems

The presence of other medical problems may affect the use of lorazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of or
• Lung or breathing problems (eg, COPD, respiratory depression, sleep apnea) or
• Seizures, or history of—Use with caution. May make these conditions worse.
• Depression or
• Mental problems (eg, psychosis)—Use is not recommended in patients with these conditions.
• Glaucoma, acute narrow-angle—Should not be used in patients with this condition.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Lorazepam uses

Lorazepam is used to treat anxiety disorders. Lorazepam is also used to treat irritable bowel syndrome (IBS), epilepsy, insomnia, and nausea and vomiting from cancer treatment and to control agitation caused by alcohol withdrawal.

Lorazepam dosage

The dose of lorazepam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of lorazepam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (oral solution)

• For anxiety:
  • Adults and children 12 years of age and older—2 to 6 milligrams (mg) in divided doses per day. Your doctor may adjust your dose as needed.
  • Older adults—At first, 1 to 2 mg in divided doses per day. Your doctor may adjust your dose as needed.
  • Children younger than 12 years of age—Use and dose must be determined by your doctor.

For oral dosage form (tablets):

• For anxiety:
  • Adults and children 12 years of age and older—At first, 2 to 3 milligrams (mg) in divided doses per day. Your doctor may adjust your dose as needed.
  • Older adults—At first, 1 to 2 mg in divided doses per day. Your doctor may adjust your dose as needed and tolerated.
  • Children younger than 12 years of age—Use and dose must be determined by your doctor.
• For insomnia caused by anxiety or transient situational stress:
  • Adults and children 12 years of age and older—2 to 4 milligrams (mg) taken as a single dose at bedtime. Your doctor may adjust your dose as needed.
  • Children younger than 12 years of age—Use and dose must be determined by your doctor.

For oral dosage form (extended-release capsules):

• For anxiety:
  • Adults—One capsule once a day in the morning. Dose is based on the total daily dose of lorazepam tablets, which you take three times a day in equally divided doses. Your doctor may adjust your dose as needed.
  • Children—Use and dose must be determined by your doctor.

Missed dose

If you take several doses per day and miss a dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Lorazepam side effects

Lorazepam may cause side effects. Call your doctor if any of the following symptoms are severe or do not go away:

• drowsiness
• dizziness
• tiredness
• weakness
• dry mouth
• diarrhea
• nausea
• changes in appetite
• restlessness or excitement
• constipation
• difficulty urinating
• frequent urination
• blurred vision
• changes in sex drive or ability

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNINGS section, call your doctor immediately or get emergency medical treatment:

• shuffling walk
• persistent, fine tremor or inability to sit still
• fever
• severe skin rash
• yellowing of skin or eyes
• irregular heartbeat

Lorazepam may cause other side effects. Call your doctor if you have any unusual problems while you are taking lorazepam.

Midazolam

Midazolam (Versed) is a benzodiazepine that is used to help you relax before having a minor surgery, dental work, or other medical procedure. Midazolam is given only by or under the immediate supervision of a doctor trained to use this medicine.

Midazolam comes as a syrup to take by mouth. It is usually given as a single dose by a doctor or nurse before a medical procedure or surgery.

Midazolam special precautions

You should not use midazolam if you are allergic to it, or if you have:

• narrow-angle glaucoma;
• untreated or uncontrolled open-angle glaucoma; or
• an allergy to cherries.

Tell your doctor if you have ever had:

• glaucoma;
• breathing problems; or
• congestive heart failure.

Tell your doctor if you are pregnant or breastfeeding.

Before your child receives midazolam:

• tell your child’s doctor and pharmacist if he or she is allergic to midazolam, any other medications, or cherries.
• tell your child’s doctor if your child is taking certain medications for human immunodeficiency virus (HIV) including amprenavir (Agenerase), atazanavir (Reyataz), darunavir (Prezista), delavirdine (Rescriptor), efavirenz (Sustiva, in Atripla), fosamprenavir (Lexiva), indinavir (Crixivan),lopinavir (in Kaletra), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), saquinavir (Invirase), and tipranavir (Aptivus). Your child’s doctor may decide not to give midazolam to your child if he or she is taking one or more of these medications.
• tell your child’s doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements your child is taking or plans to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: amiodarone (Cordarone, Pacerone); aminophylline (Truphylline); antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral); certain calcium channel blockers such as diltiazem (Cartia, Cardizem, Tiazac, others) and verapamil (Calan, Isoptin, Verelan, others); cimetidine (Tagamet); clarithromycin (Biaxin); dalfopristin-quinupristin (Synercid); erythromycin (E-mycin, E.E.S.); fluvoxamine (Luvox); certain medications for seizures such as carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin); methylphenidate (Concerta, Metadate, Ritalin, others); nefazodone; ranitidine (Zantac); rifabutin (Mycobutin); and rifampin (Rifadin, Rimactane). Your child’s doctor may need to change the doses of your child’s medications or monitor your child carefully for side effects. Many other medications may also interact with midazolam, so be sure to tell your child’s doctor about all the medications your child is taking, even those that do not appear on this list.
• tell your child’s doctor what herbal products your child is taking, especially St. John’s wort.
• tell your child’s doctor if your child has glaucoma. Your child’s doctor may decide not to give your child midazolam.
• tell your child’s doctor if your child has or has ever had kidney or liver disease.
• tell your child’s doctor if your child is or may be pregnant, or is breast-feeding.
• you should know that midazolam may make your child very drowsy and may affect his or her memory, thinking, and movements. Do not allow your child to ride a bicycle, drive a car, or do other activities that require him or her to be fully alert for at least 24 hours after receiving midazolam and until the effects of the medication have worn off. Watch your child carefully to be sure that he or she does not fall while walking during this time.
• you should know that alcohol can make the side effects of midazolam worse.

Special dietary instructions

Do not let your child eat grapefruit or drink grapefruit juice while taking midazolam.

Midazolam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving midazolam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using midazolam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amprenavir
• Atazanavir
• Boceprevir
• Cobicistat
• Darunavir
• Delavirdine
• Flumazenil
• Fosamprenavir
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• Telaprevir
• Tipranavir

Using midazolam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Anileridine
• Aprobarbital
• Baclofen
• Belzutifan
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Buspirone
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Ceritinib
• Cetirizine
• Chloral Hydrate
• Chlordiazepoxide
• Chlorpromazine
• Chlorzoxazone
• Ciprofloxacin
• Clarithromycin
• Clobazam
• Clonazepam
• Clorazepate
• Codeine
• Conivaptan
• Cyclobenzaprine
• Dantrolene
• Dexmedetomidine
• Dezocine
• Diacetylmorphine
• Diazepam
• Difenoxin
• Dihydrocodeine
• Diphenhydramine
• Diphenoxylate
• Doxylamine
• Dronedarone
• Duvelisib
• Elagolix
• Esketamine
• Estazolam
• Eszopiclone
• Ethchlorvynol
• Ethylmorphine
• Fentanyl
• Fexinidazole
• Flibanserin
• Flunitrazepam
• Flurazepam
• Fosnetupitant
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Halazepam
• Hydrocodone
• Hydromorphone
• Hydroxyzine
• Idelalisib
• Imatinib
• Isavuconazonium Sulfate
• Ivosidenib
• Ketamine
• Ketazolam
• Ketobemidone
• Larotrectinib
• Lefamulin
• Lemborexant
• Letermovir
• Levocetirizine
• Levorphanol
• Lofexidine
• Lorazepam
• Lorlatinib
• Loxapine
• Lumacaftor
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Meptazinol
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Methotrimeprazine
• Metoclopramide
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nefazodone
• Netupitant
• Nicomorphine
• Nilotinib
• Nitrazepam
• Opium
• Opium Alkaloids
• Orlistat
• Orphenadrine
• Oxazepam
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Perampanel
• Periciazine
• Phenobarbital
• Piritramide
• Posaconazole
• Potassium Oxybate
• Prazepam
• Pregabalin
• Primidone
• Promethazine
• Propofol
• Quazepam
• Ramelteon
• Remifentanil
• Remimazolam
• Ribociclib
• Scopolamine
• Secobarbital
• Simeprevir
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Temazepam
• Thiopental
• Thioridazine
• Tilidine
• Tizanidine
• Topiramate
• Tramadol
• Trazodone
• Triazolam
• Zaleplon
• Zolpidem
• Zopiclone

Using midazolam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aprepitant
• Armodafinil
• Carbamazepine
• Cimetidine
• Crizotinib
• Cyclosporine
• Dalfopristin
• Diltiazem
• Echinacea
• Erythromycin
• Fluconazole
• Fluvoxamine
• Fosaprepitant
• Fosphenytoin
• Ginkgo Biloba
• Goldenseal
• Halothane
• Laropiprant
• Mitotane
• Phenytoin
• Quinupristin
• Rifapentine
• Roxithromycin
• St John’s Wort
• Telithromycin
• Theophylline
• Verapamil
• Voriconazole

Other interactions

Using midazolam with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use midazolam, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Using midazolam with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use midazolam, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other medical problems

The presence of other medical problems may affect the use of midazolam. Make sure you tell your doctor if you have any other medical problems, especially:

• Apnea (temporary stopping of breathing) or
• Heart disease or
• Hypoventilation (slow breathing) or
• Infections or
• Lung disease, severe or
• Lung or airway blockage—Use with caution. May increase risks for more serious side effects.
• Congestive heart failure or
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
• Glaucoma, acute narrow-angle—Should not be used in patients with this condition.

Midazolam uses

Midazolam is used to produce sleepiness or drowsiness and to relieve anxiety before a minor surgery, dental work, or other medical procedure. Midazolam is also given to produce amnesia (loss of memory) so that the patient will not remember any discomfort or undesirable effects that may occur after a surgery or procedure. Midazolam is given to children before medical procedures or before anesthesia for surgery to cause drowsiness, relieve anxiety, and prevent any memory of the event.

Midazolam dosage

Midazolam will be given to you or to your child in a hospital or clinic by a doctor trained to use this medicine. If you or your child will be receiving midazolam during surgery, your doctor or anesthesiologist will give you the medicine.

After you receive midazolam, you or your child will be watched closely to make sure this medicine is working. Your breathing, blood pressure, nervous system, and heart will also be watched closely to make sure the medicine is not causing unwanted side effects.

Midazolam side effects

Midazolam may cause side effects. Tell your child’s doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• rash

Some side effects can be serious. If your child experiences any of these symptoms, call his or her doctor immediately:

• agitation
• restlessness
• uncontrollable shaking of a part of the body
• stiffening and jerking of the arms and legs
• aggression
• slow or irregular heartbeat

Midazolam may cause other side effects. Call your child’s doctor if your child has any unusual problems while taking midazolam.

Oxazepam

Oxazepam (Serax) is a benzodiazepine that is used to treat anxiety disorders, including anxiety caused by depression. Oxazepam may also be used short-term to treat symptoms of alcohol withdrawal. Oxazepam can also be used to treat tension, agitation, and irritability in older patients. Oxazepam may be prescribed for other uses (e.g., irritable bowel syndrome). Talk to your doctor about the possible risks of using this medication for your condition. Oxazepam is available only with your doctor’s prescription.

Oxazepam comes as a capsule to take by mouth. It is usually taken three or four times a day and may be taken with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take oxazepam exactly as directed.

Oxazepam may help control your symptoms but will not cure your condition. Continue to take oxazepam even if you feel well. Do not skip doses even if you feel that you do not need them.

Oxazepam special precautions

You should not use oxazepam if you are allergic to oxazepam, or if you have mental illness and psychosis.

Tell your doctor if you have ever had:

• depression, mental illness, suicidal thoughts;
• alcoholism or drug addiction; or
• low blood pressure.

Oxazepam may harm an unborn baby. Avoid taking oxazepam during the first trimester of pregnancy.

If you use oxazepam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks.

Ask a doctor if it is safe to breastfeed while using oxazepam.

Oxazepam is not approved for use by anyone younger than 6 years old.

Before taking oxazepam:

• tell your doctor and pharmacist if you are allergic to oxazepam, any other medications, or any of the ingredients in oxazepam capsules. Ask your doctor or pharmacist for more information.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antihistamines; digoxin (Lanoxin); levodopa (in Ritary, in Sinemet, in Stalevo); medication for depression, seizures, Parkinson’s disease, asthma, colds, or allergies; muscle relaxants; oral contraceptives; phenytoin (Dilantin, Phenytek); probenecid (Probalan, in Col-Probenecid); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); sedatives; sleeping pills; theophylline (Elixophyllin, Theo 24, Theochron); or tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had glaucoma or seizures, or lung, heart, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking oxazepam, call your doctor immediately.
• talk to your doctor about the risks and benefits of taking oxazepam if you are 65 years of age or older. Older adults should take lower doses of oxazepam because higher doses may not be more effective and are more likely to cause serious side effects.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking oxazepam.
• you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Oxazepam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking oxazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using oxazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using oxazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using oxazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Rifapentine
• St John’s Wort
• Theophylline

Other interactions

Using oxazepam with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use oxazepam, or give you special instructions about the use of food, alcohol, or tobacco.

• Cabbage

Other medical problems

The presence of other medical problems may affect the use of oxazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of or
• Depression, or history of or
• Hypotension (low blood pressure) or
• Lung or breathing problems (eg, respiratory depression) or
• Mental health problems, or history of—Use with caution. May make these conditions worse.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
• Mental illness (eg, bipolar disorder, schizophrenia)—Should not be used in patients with this condition.

Oxazepam uses

Oxazepam is used to relieve symptoms of anxiety, including anxiety caused by depression, and including anxiety caused by alcohol withdrawal (symptoms that may develop in people who stop drinking alcohol after drinking large amounts for a long time). Oxazepam can also be used to treat tension, agitation, and irritability in older patients. Oxazepam is also used to treat irritable bowel syndrome (IBS).

Oxazepam dosage

The dose of oxazepam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of oxazepam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (capsules):

• For anxiety:
  • Adults—10 to 30 milligrams (mg) 3 or 4 times a day.
  • Older adults—At first, 10 mg 3 times a day. Your doctor may increase your dose if needed.
  • Children 6 years of age and older—Use and dose must be determined by your doctor.
  • Children younger than 6 years of age—Use is not recommended.

For alcohol withdrawal:

• Adults—15 to 30 milligrams (mg) 3 or 4 times a day.
• Children—Use and dose must be determined by your doctor.

Missed dose

Take the missed dose as soon as you remember it. However, if it is almost time for your next dose skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Oxazepam side effects

Oxazepam may cause side effects. Call your doctor if any of the symptoms are severe or do not go away:

• drowsiness
• dizziness
• tiredness
• weakness
• dry mouth
• diarrhea
• upset stomach
• changes in appetite
• restlessness or excitement
• constipation
• difficulty urinating
• frequent urination
• blurred vision
• changes in sex drive or ability

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• shuffling walk
• persistent, fine tremor or inability to sit still
• fever
• difficulty breathing or swallowing
• severe skin rash
• yellowing of the skin or eyes
• irregular heartbeat

Oxazepam may cause other side effects. Call your doctor if you experience any unusual problems during your treatment with oxazepam.

Quazepam

Quazepam (Doral) is a benzodiazepine that is used to treat insomnia (trouble falling or staying asleep). Quazepam is for short-term (usually 7 to 10 days) use only. Quazepam is available only with your doctor’s prescription.

Quazepam was approved in the United States in 2007, but is now not commonly used, having been replaced by non-benzodiazepines that bind to the benzodiazepine receptor on the GABA-A receptor complex, which have a shorter duration of action and are better tolerated. Quazepam is available in tablets of 7.5 and 15 mg under the brand name Doral. The recommended initial oral dose for adults is 15 mg at bedtime, which can be decreased to 7.5 mg nightly.

Quazepam most common side effects are dose related and include daytime drowsiness, lethargy, ataxia, dysarthria and dizziness. Tolerance develops to these side effects, but tolerance may also develop to the effects on insomnia.

Quazepam special precautions

You should not use quazepam if you are allergic to it, or if you have:

• a chronic breathing disorder;
• sleep apnea (breathing stops during sleep); or
• an allergy to sleep medicine or to other benzodiazepines (such as alprazolam, diazepam, lorazepam, midazolam, Ativan, Valium, Tranxene, Versed, Xanax, and others).

May cause birth defects. Do not use if you are pregnant. If you use quazepam during pregnancy, your baby could be born with life-threatening withdrawal symptoms, and may need medical treatment for several weeks. Use effective birth control while using quazepam. Tell your doctor if you become pregnant.

Tell your doctor if you have ever had:

• breathing problems;
• drug or alcohol addiction;
• suicidal thoughts or actions;
• depression or mental illness; or
• liver or kidney disease.

Do not breastfeed whilst taking quazepam.

Quazepam is not approved for use by anyone younger than 18 years old.

Quazepam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking quazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using quazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using quazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using quazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Rifapentine
• St John’s Wort
• Theophylline

Other medical problems

The presence of other medical problems may affect the use of quazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, history of or
• Breathing problems or lung disease or
• Depression, history of or
• Mental health problems, history of—Use with caution. May make these conditions worse.
• Pulmonary insufficiency or
• Sleep apnea (temporary stopping of breathing during sleep)—Should not be used in patients with these conditions.

Quazepam uses

Quazepam is used to treat insomnia (trouble sleeping). Quazepam is for short-term (usually 7 to 10 days) use only.

Quazepam dosage

The dose of quazepam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of quazepam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (tablets)

• For insomnia:
  • Adults and older adults—At first, 7.5 milligrams (mg) (half-tablet) at bedtime. Your doctor may adjust your dose as needed.
  • Children—Use and dose must be determined by your doctor.

Missed dose

If you miss a dose of quazepam, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Use quazepam only when you cannot sleep. You do not need to keep a regular dosage schedule for taking it. Do not use two doses at the same time.

Quazepam side effects

Quazepam may cause a severe allergic reaction. Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; nausea, vomiting; swelling of your face, lips, tongue, or throat.

Quazepam can slow or stop your breathing, especially if you have recently used an opioid medication or alcohol. A person caring for you should seek emergency medical attention if you have slow breathing with long pauses, blue colored lips, or if you are hard to wake up.

Call your doctor at once if you have:

• confusion, agitation, hallucinations;
• unusual thoughts or behavior;
• suicidal thoughts; or
• worsening depression.

Some people using quazepam have engaged in activity such as driving, eating, walking, making phone calls, or having sex and later having no memory of the activity. Tell your doctor if this happens to you.

Drowsiness or dizziness may last longer in older adults. Use caution to avoid falling or accidental injury.

Quazepam common side effects may include:

• drowsiness, dizziness;
• headache;
• feeling tired;
• dry mouth; or
• upset stomach.

After you stop using quazepam, get medical help right away if you have symptoms such as: unusual muscle movements, being more active or talkative, sudden and severe changes in mood or behavior, confusion, hallucinations, seizures, suicidal thoughts or actions.

Some withdrawal symptoms may last up to 12 months or longer after stopping this medicine suddenly. Tell your doctor if you have ongoing anxiety, depression, problems with memory or thinking, trouble sleeping, ringing in your ears, a burning or prickly feeling, or a crawling sensation under your skin.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Temazepam

Temazepam (Restoril) is a benzodiazepine that is used short term to treat insomnia (trouble falling or staying asleep). Temazepam is for short-term (usually 7 to 10 days) use only. Temazepam may be prescribed for other uses; ask your doctor or pharmacist for more information.  Temazepam is available only with your doctor’s prescription. Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with temazepam and each time you refill your prescription.

Temazepam comes as a capsule to take by mouth. It is usually taken as needed at bedtime. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take temazepam exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

You will probably become very sleepy soon after you take temazepam and will remain sleepy for some time after you take the medication. Plan to go to bed right after you take temazepam and to stay in bed for 7 to 8 hours. Do not take temazepam if you will be unable to remain asleep for 7 to 8 hours after taking the medication. If you get up too soon after taking temazepam, you may experience memory problems.

Your sleep problems should improve within 7 to 10 days after you start taking temazepam. Call your doctor if your sleep problems do not improve during this time, if they get worse at any time during your treatment, or if you notice any changes in your thoughts or behavior.

Temazepam special precautions

You should not use temazepam if you are allergic to it.

Do not use temazepam if you are pregnant or may become pregnant. This medicine could harm the unborn baby.

To make sure temazepam is safe for you, tell your doctor if you have ever had:

• lung disease or breathing problems;
• depression, mental illness, suicidal thoughts;
• alcoholism or drug addiction; or
• liver or kidney disease.

Ask a doctor if it is safe to breastfeed while using temazepam.

Temazepam is not approved for use by anyone younger than 18 years old.

Before taking temazepam:

• tell your doctor and pharmacist if you are allergic to temazepam, any other medications, or any of the ingredients in temazepam capsules. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antidepressants; antihistamines such as diphenhydramine (Benadryl); digoxin (Lanoxin); and medications for anxiety, mental illness, or seizures; sedatives; other sleeping pills; and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have ever thought about killing yourself or tried to do so, and if you have or have ever had any condition that affects your breathing, seizures, or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You should not take temazepam if you are pregnant or planning to become pregnant. If you become pregnant while taking temazepam, call your doctor immediately. Temazepam may harm the fetus.
• talk to your doctor about the risks and benefits of taking temazepam if you are 65 years of age or older. Older adults should usually take lower doses of temazepam because higher doses may not be more effective and are more likely to cause serious side effects.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking temazepam.
• you should know that this medication may make you drowsy during the daytime, may decrease your mental alertness, and may increase the risk that you could fall. Take extra care to be sure
• you do not fall, especially if you get out of bed in the middle of the night. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that some people who took medications for sleep got out of bed and drove their cars, prepared and ate food, had sex, made phone calls, or were involved in other activities while partially asleep. After they woke up, these people were usually unable to remember what they had done. Call your doctor right away if you find out that you have been driving or doing anything else while you were sleeping.
• you should know that your mental health may change in unexpected ways while you are taking this medication. It is hard to tell if these changes are caused by temazepam or if they are caused by physical or mental illnesses that you already have or suddenly develop. Tell your doctor right away if you experience any of the following symptoms: aggressiveness, strange or unusually outgoing behavior, hallucinations (seeing things or hearing voices that do not exist), feeling as if you are outside of your body, memory problems, difficulty concentrating, new or worsening depression, thinking about killing yourself, confusion, and any other changes in your usual thoughts, mood, or behavior. Be sure that your family knows which symptoms may be serious so that they can call the doctor if you are unable to seek treatment on your own.

Special dietary instructions

Unless your doctor tells you otherwise, continue your normal diet.

Temazepam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking temazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using temazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using temazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Codeine
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remimazolam
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Zolpidem

Using temazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Desogestrel
• Dienogest
• Drospirenone
• Estradiol
• Ethinyl Estradiol
• Ethynodiol
• Gestodene
• Levonorgestrel
• Mestranol
• Nomegestrol
• Norethindrone
• Norgestimate
• Norgestrel
• Rifapentine
• St John’s Wort
• Theophylline

Other interactions

Using temazepam with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use temazepam, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other medical problems

The presence of other medical problems may affect the use of temazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of or
• Breathing problems or lung disease or
• Depression, history of or
• Mental health problems, history of—Use with caution. May make these conditions worse.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Temazepam uses

Temazepam is used on a short-term basis to treat insomnia (difficulty falling asleep or staying asleep). Temazepam is for short-term (usually 7 to 10 days) use only.

Temazepam dosage

The dose of temazepam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of temazepam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (capsules):

• For insomnia (trouble sleeping):
  • Adults—The usual dose is 15 milligrams (mg) at bedtime. Some patients may need 7.5 mg or 30 mg. Your doctor may adjust your dose as needed.
  • Older adults—At first, 7.5 mg at bedtime. Your doctor may adjust your dose if needed.
  • Children—Use and dose must be determined by your doctor.

Missed dose

Temazepam should only be taken at bedtime. If you did not take temazepam at bedtime and you are unable to fall asleep, you may take temazepam if you will be able to remain in bed for 7 to 8 hours afterwards. Do not take temazepam if you are not ready to go to sleep right away and stay asleep for at least 7 to 8 hours.

Temazepam side effects

Temazepam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• hangover effect (feeling groggy the day after you take temazepam)
• drowsiness
• dizziness
• nausea
• vomiting

Some side effects can be serious. If you experience any of the following symptoms, or those listed in the IMPORTANT WARNING and special precautions sections, call your doctor immediately or get emergency medical treatment:

• rash
• hives
• swelling of the face, throat, tongue, lips, or eyes
• hoarseness
• difficulty breathing or swallowing

Temazepam may cause other side effects. Call your doctor if you have any unusual problems while you are taking temazepam.

Triazolam

Triazolam (Halcion) is a benzodiazepine that is used short term (7 to 10 days) to treat insomnia (difficulty falling asleep or staying asleep). Triazolam works by slowing activity in your brain to allow sleep. Triazolam is usually taken as needed at bedtime but not with or shortly after a meal. Triazolam may not work well if it is taken with food. Triazolam may also be prescribed for other uses; ask your doctor or pharmacist for more information. Triazolam is classified as a schedule 4 controlled substance, indicating that it has a potential for physical and psychological dependence and abuse. Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with triazolam and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions.

Triazolam was approved in the United States in 1982 and was formerly the most common prescription sleeping pill used in the United States ¹⁰¹⁾. Concerns over its safety led to its withdrawal from use in the UK, and the availability of other potent, shorter acting sleeping pills has caused its decrease in general use in the United States. Current indications are for the short term management of insomnia.

Triazolam comes as a tablet to be taken by mouth and is available in multiple generic forms and under the brand name Halcion in tablets of 0.125 and 0.25 mg. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take triazolam exactly as directed.

Triazolam recommended initial dose for adults is 0.125 mg immediately before bedtime, increasing to 0.25 as needed; rarely, higher doses are used.

You will probably become very sleepy soon after you take triazolam and will remain sleepy for some time after you take the medication. Plan to go to bed right after you take triazolam and to stay in bed for 7 to 8 hours. Do not take triazolam if you will be unable to remain asleep for 7 to 8 hours after taking the medication. If you get up too soon after taking triazolam, you may experience memory problems.

Your sleep problems should improve within 7 to 10 days after you start taking triazolam. Call your doctor if your sleep problems do not improve during this time, if they get worse at any time during your treatment, or if you notice any changes in your thoughts or behavior.

Triazolam should normally be taken for short periods of time (usually 7 to 10 days). You should not take triazolam for more than 2 to 3 weeks without talking to your doctor. If you take triazolam for 7 to 10 days or longer, triazolam may not help you sleep as well as it did when you first began to take the medication, and you may wake up more easily during the last third of the night. You may also start to feel anxious or nervous during the day, and you may develop dependence (‘addiction’; a need to continue taking the medication) on triazolam. Talk to your doctor about the risks of taking triazolam for 2 weeks or longer.

You may have more difficulty falling asleep or staying asleep on the first few nights after you stop taking triazolam than you did before you started taking the medication. This is normal and usually gets better without treatment after one or two nights.

The most common side effects of triazolam are dose related and include daytime drowsiness, lethargy, ataxia, dysarthria and dizziness. Tolerance develops to these side effects, but tolerance may also develop to the soporific effects.

Triazolam special precautions

You should not use triazolam if you are allergic to triazolam or similar medicines (such as alprazolam, diazepam, lorazepam, Valium, Xanax, Versed, Klonopin, and others).

Before taking triazolam:

• tell your doctor and pharmacist if you are allergic to triazolam; other benzodiazepines; any other medications; or any of the ingredients in triazolam tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor if you are taking any of the following medications: antifungal medications including itraconazole (Onmel, Sporanox) and ketoconazole (Nizoral); certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) including indinavir (Crixivan), lopinavir (in Kaletra), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); and nefazodone. Your doctor will probably tell you not to take triazolam.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: amiodarone (Nexterone, Pacerone); certain antibiotics such as clarithromycin (Biaxin, in Prevpac), erythromycin (Erythrocin, E-mycin), telithromycin (Ketek), and troleandomycin (TAO) (not available in the US); antidepressants; certain antifungal medications; antihistamines; certain calcium channel blockers such as diltiazem (Cardizem, Dilacor, Tiazac, others), nicardipine (Cardene), nifedipine (Adalat, Afeditab, Procardia), and verapamil (Calan, Verelan); cyclosporine (Gengraf, Neoral, Sandimmune); ergotamine (Cafergot, Ergomar, Migranal, others); certain histamine-2 receptor blockers (H2 blockers) such as cimetidine (Tagamet) and ranitidine (Zantac); hormonal contraceptives (birth control pills, patches, rings, implants, or injections); isoniazid (Laniazid, in Rifamate, in Rifater); medications for anxiety, colds or allergies, mental illness, or seizures; muscle relaxants; sedatives; certain selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine (Luvox), paroxetine (Brisdelle, Paxil, Pexeva), and sertraline (Zoloft); other sleeping pills; and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with triazolam, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have ever thought about killing yourself or tried to do so, and if you have or have ever had any condition that affects your breathing, sleep apnea (condition in which a person briefly stops breathing many times during the night), seizures, or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking triazolam, call your doctor immediately. Triazolam may harm the fetus.
• talk to your doctor about the safe use of triazolam if you are 65 years of age or older. Older adults should usually take lower doses of triazolam because higher doses may not be more effective and are more likely to cause serious side effects.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking triazolam.
• you should know that triazolam may make you drowsy during the daytime, may decrease your mental alertness, and may increase the risk that you could fall. Take extra care to be sure you do not fall, especially if you get out of bed in the middle of the night. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that some people who took medications for sleep got out of bed and drove their cars, prepared and ate food, had sex, made phone calls, or were involved in other activities while partially asleep. After they woke up, these people were usually unable to remember what they had done. Call your doctor right away if you find out that you have been driving or doing anything else while you were sleeping.
• you should know that your mental health may change in unexpected ways while you are taking this medication. It is hard to tell if these changes are caused by triazolam or if they are caused by physical or mental illnesses that you already have or suddenly develop. Tell your doctor right away if you experience any of the following symptoms: aggressiveness, strange or unusually outgoing behavior, hallucinations (seeing things or hearing voices that do not exist), feeling as if you are outside of your body, memory problems, difficulty concentrating, slowed speech or movements, new or worsening depression, thinking about killing yourself, confusion, and any other changes in your usual thoughts, mood, or behavior. Be sure that your family knows which symptoms may be serious so that they can call the doctor if you are unable to seek treatment on your own.

Special dietary instructions

Do not eat grapefruit or drink grapefruit juice while you’re taking triazolam.

Triazolam drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking triazolam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using triazolam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amprenavir
• Atazanavir
• Boceprevir
• Cobicistat
• Darunavir
• Delavirdine
• Flumazenil
• Fosamprenavir
• Idelalisib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Nefazodone
• Nelfinavir
• Ritonavir
• Saquinavir
• Telaprevir
• Tipranavir

Using triazolam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alprazolam
• Amobarbital
• Aprobarbital
• Belzutifan
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Ceritinib
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clarithromycin
• Clobazam
• Codeine
• Conivaptan
• Dantrolene
• Dihydrocodeine
• Doxylamine
• Duvelisib
• Esketamine
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Fluconazole
• Fosnetupitant
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ivosidenib
• Ketamine
• Larotrectinib
• Lefamulin
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Lorlatinib
• Loxapine
• Lumacaftor
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Mibefradil
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Netupitant
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remimazolam
• Scopolamine
• Secobarbital
• Simeprevir
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tramadol
• Trazodone
• Voriconazole
• Zolpidem

Using triazolam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Dehydroepiandrosterone
• Desogestrel
• Dienogest
• Diltiazem
• Drospirenone
• Erythromycin
• Estradiol
• Ethinyl Estradiol
• Ethynodiol
• Fluvoxamine
• Gestodene
• Levonorgestrel
• Mestranol
• Modafinil
• Nomegestrol
• Norethindrone
• Norgestimate
• Norgestrel
• Omeprazole
• Ranitidine
• Rifampin
• Rifapentine
• Roxithromycin
• Rufinamide
• St John’s Wort
• Theophylline
• Troleandomycin

Other interactions

Using triazolam with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use triazolam, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Using triazolam with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use triazolam, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other medical problems

The presence of other medical problems may affect the use of triazolam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of or
• Breathing problems or lung disease, severe or
• Depression, or history of or
• Sleep apnea (temporary stopping of breathing during sleep)—Use with caution. May make these conditions worse.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Triazolam uses

Triazolam is a benzodiazepine that is widely used as a sleeping aid in the therapy of insomnia. Triazolam should only be taken at bedtime. If you did not take triazolam at bedtime and you are unable to fall asleep, you may take triazolam if you will be able to remain in bed for 7 to 8 hours afterward. Do not take triazolam if you are not ready to go to sleep right away and stay asleep for at least 7 to 8 hours.

Triazolam dosage

The dose of triazolam will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of triazolam. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For insomnia:
    • Adults—0.125 to 0.25 milligram (mg) at bedtime. Your doctor may adjust your dose as needed. However, the dose is usually not more than 0.5 mg per day.
    • Older adults—At first, 0.125 mg at bedtime. Your doctor may adjust your dose as needed. However, the dose is usually not more than 0.25 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Use triazolam only when you cannot sleep. You do not need to keep a schedule for taking it. Do not use two doses at the same time.

Triazolam side effects

Triazolam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness
• lightheadedness
• headache
• problems with coordination
• nervousness
• tingling of the skin
• nausea
• vomiting

Some side effects can be serious. If you experience any of these symptoms or those listed in the special precautions or IMPORTANT WARNING sections, call your doctor immediately or get emergency medical help:

• rash
• hives
• itching
• swelling of the eyes, face, lips, tongue, or throat
• feeling that the throat is closing
• difficulty breathing or swallowing
• hoarseness

Triazolam may cause other side effects. Call your doctor if you have any unusual problems while taking triazolam.

Mycophenolate mofetil

Mycophenolate mofetil also known as CellCept, MMF, Myfortic or mycophenolate is an immunosupressant or a drug that weakens your body’s immune system in order to help keep it from “rejecting” a transplanted organ also known as graft-versus-host disease (GVHD) that is used along with other medications to prevent organ rejection in adults and children at least 3 months of age and older who have received a kidney, heart, or liver transplant ¹⁾. Mycophenolate mofetil is also being studied in the prevention of graft-versus-host disease (GVHD) after stem cell transplants for cancer, and in the treatment of some autoimmune disorders. Mycophenolate mofetil should be prescribed only by physicians with experience in immunosuppression and management of its complications.

Mycophenolate mofetil was approved for use in the United States in 1995 and its current indications are for prevention of organ rejection after transplantation. It is also used off label in therapy of active and refractory forms of autoimmune diseases.

Mycophenolate mofetil comes as capsules of 250 mg and tablets of 500 mg and a oral suspension (200 mg/mL) called CellCept and as mycophenolic acid in 180 and 360 mg delayed-release tablets (releases the medication in your intestine) called Myfortic to be taken by mouth. Mycophenolate mofetil is also available as a sterile powder in a vial for injection, which contains the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt for intravenous administration.

Mycophenolate mofetil is usually taken twice a day on an empty stomach (1 hour before or 2 hours after eating or drinking), unless your doctor tells you otherwise. Take mycophenolate mofetil at about the same times every day, and try to space your doses about 12 hours apart. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take mycophenolate mofetil exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

In adults, the usual dose of mycophenolate mofetil ranges from 1.25 to 2 g day. The typical maintenance dose is 1 to 1.5 grams twice daily. In children, it is administered as a 600 mg/m² dose every 12 hours up to a maximum daily dose of 2 g. Dose reduction should be considered in patients with severe kidney impairment ²⁾, ³⁾.

Enteric-coated mycophenolate sodium is available as delayed-release tablets containing either 180 or 360 mg of Myfortic (mycophenolic acid). It can be used as an alternative in the patients with adverse mycophenolate mofetil-induced gastrointestinal effects ⁴⁾.

Mycophenolate mofetil in the delayed-release tablet (Myfortic) is absorbed differently by your body than Mycophenolate mofetil in the oral suspension, tablet, and capsule (CellCept). These products cannot be substituted for each other. Each time you have your prescription filled, make sure that you have received the right product. If you think you received the wrong medication, talk to your doctor and pharmacist right away.

Swallow the tablets, delayed-release tablets, and capsules whole; do not split, chew, or crush them. Do not open the capsules. If a capsule is accidentally opened, avoid contact with your skin or eyes and avoid breathing in the powder. If any contact occurs, wash the affected area well with soap and water; rinse eyes with water.

Do not mix mycophenolate mofetil suspension with any other medication.

Be careful not to spill the suspension or to splash it onto your skin. If you do get the suspension on your skin, wash the area well with soap and water. If you get the suspension in your eyes, rinse with plain water. Use wet paper towels to wipe up any spilled liquids.

Mycophenolate mofetil helps prevent organ transplant rejection only as long as you are taking the medication. Continue to take mycophenolate mofetil even if you feel well. Do not stop taking mycophenolate mofetil without talking to your doctor.

Mycophenolate mofetil most common dose-related side effects are gastrointestinal and genitourinary. Gastrointestinal symptoms include gastrointestinal upset, nausea, diarrhea, abdominal cramps, constipation, vomiting and anorexia while genitourinary symptoms include urgency, frequency, dysuria, hematuria and sterile pyuria ⁵⁾. Gastrointestinal symptoms are usually managed either by dose reduction or by splitting the total dose into three or four doses per day. Mycophenolate mofetil other side effects are headache, fatigue and dizziness. Uncommon but potentially severe adverse events include blood dyscrasias, gastrointestinal bleeding or ulceration, increased risk for lymphoma or other malignancies, increased risk for serious infections, and embryo-fetal toxicity.

Being an immunosuppressant, mycophenolate mofetil increases the risk of bacterial, fungal and viral infections and has a long-term risk of carcinogenicity like lymphomas and skin cancers.

Other reported adverse events include hematological (i.e., anemia, neutropenia, thrombocytopenia), neurologic (i.e., headache, tinnitus, insomnia), cutaneous (i.e., exanthematous eruptions, onycholysis), cardiorespiratory (i.e., dyspnea, chest pain, palpitations) and metabolic (i.e., hypercholesterolemia, hyperglycemia, hypophosphatemia and hypo/hyperkalemia).

Figure 1. Mycophenolate mofetil chemical structure

Mycophenolate mofetil special precautions

Before taking mycophenolate mofetil:

• tell your doctor and pharmacist if you are allergic to mycophenolate mofetil, mycophenolic acid, any other medications, or any of the ingredients in the mycophenolate mofetil or mycophenolic acid product you are taking. If you are taking mycophenolate mofetil liquid, tell your doctor and pharmacist if you are allergic to aspartame or sorbitol. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Also be sure
• tell your doctor if you stop taking any of your medications. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• if you are taking sevelamer (Renagel, Renvela), or antacids that contain magnesium or aluminum, take them 2 hours after you take mycophenolate mofetil.
• tell your doctor if you have or have ever had Lesch-Nyhan syndrome or Kelley-Seegmiller syndrome (inherited diseases that cause high levels of a certain substance in the blood, joint pain, and problems with motion and behavior); anemia (a lower than normal number of red blood cells); neutropenia (less than normal number of white blood cells); ulcers or any disease that affects your stomach, intestines, or digestive system; or kidney or liver disease.
• you should not breastfeed while using mycophenolate mofetil.
• you should know that mycophenolate mofetil may make you drowsy, confused, dizzy, lightheaded, or cause uncontrollable shaking of a part of the body. Do not drive a car or operate machinery until you know how this medication affects you.
• do not have any vaccinations without talking to your doctor.
• if you have phenylketonuria (PKU, an inherited condition in which a special diet must be followed to prevent damage to your brain that can cause severe intellectual disability), you should know that mycophenolate mofetil suspension contains aspartame, a source of phenylalanine.

Mycophenolate mofetil can cause a miscarriage or birth defects, especially during the first 3 months of pregnancy. You will need to have a negative pregnancy test before and during treatment with this medicine. If you are able to get pregnant, you must use specific forms of birth control to prevent pregnancy while using mycophenolate mofetil, and for at least 6 weeks after your last dose. Sexually active men and their partners should use effective contraception during treatment and for at least 90 days after the last dose.

Mycophenolate mofetil can make birth control pills less effective. Ask your doctor about using an additional barrier form of birth control (condom, diaphragm, cervical cap, or contraceptive sponge) to prevent pregnancy.

You do not need to use additional birth control if you use an intrauterine device (IUD), if you have had a tubal ligation, or if your sexual partner has had a vasectomy.

This medicine comes with patient instructions about the most effective non-hormonal forms of birth control to use. Follow these directions carefully. Ask your doctor if you have any questions.

If a pregnancy occurs during treatment, do not stop taking mycophenolate mofetil. See your doctor for instructions.

Mycophenolate mofetil is sometimes given to pregnant women. Your doctor will decide whether you should use this medicine if you are unable to use other needed transplant medications.

What should I avoid while using mycophenolate mofetil?

Avoid driving or hazardous activity until you know how mycophenolate mofetil will affect you. Your reactions could be impaired.

Mycophenolate mofetil can make you sunburn more easily. Avoid sunlight or tanning beds. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Do not receive a “live” vaccine while using mycophenolate mofetil. The vaccine may not work as well and may not fully protect you from disease.

You must not donate blood or sperm while using this medicine, and for at least 6 weeks (for blood) or 90 days (for sperm) after your last dose.

Mycophenolate mofetil contraindications

Mycophenolate mofetil is absolutely contraindicated in patients with known hypersensitivity to any component of the drug and is included in pregnancy category C ⁶⁾, ⁷⁾. Peptic ulcer disease, kidney disease, liver disease, lactation and cardiopulmonary disease are the relative contraindications ⁸⁾

Safety and efficacy have not been established in patients younger than 3 months.

Consult WARNINGS section for additional precautions.

Mycophenolate mofetil drug interactions

Drugs such as acyclovir, ganciclovir and probenecid inhibit the tubular secretion of mycophenolate mofetil and hence, increase its level. Drugs like antacids (containing aluminum and magnesium), ferrous sulphate, metronidazole and fluoroquinolones decrease the absorption and bioavailability of mycophenolate mofetil and decrease its blood level. Cholestyramine inhibits enterohepatic recirculation of mycophenolate mofetil and decreases its level. Salicylates and furosemide compete with mycophenolate mofetil for plasma albumin binding and hence, increase the elimination of mycophenolate mofetil. Mycophenolic mofetil does not seem to interact with other immunosuppressive agents except azathioprine. A combination of mycophenolate mofetil and azathioprine should not be used as both block purine synthesis by the same pathway ⁹⁾, ¹⁰⁾

Mycophenolate mofetil mechanism of action

Mycophenolate mofetil is a prodrug (inactive drug) that is rapidly converted in your body by plasma esterase to active metabolite called mycophenolic acid (the active metabolite of mycophenolate mofetil) ¹¹⁾. Mycophenolic acid (MPA) is a potent immunosuppressive agent and acts as a selective, uncompetitive and reversible inhibitor of the enzyme, inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo purine biosynthesis pathway ¹²⁾, ¹³⁾, ¹⁴⁾. Inosine monophosphate dehydrogenase (IMPDH) is an enzyme required for the conversion of inosine monophosphate (IMP) and xanthine monophosphate (XMP) to guanosine monophosphate, which is an important substrate for the synthesis of DNA and RNA ¹⁵⁾, ¹⁶⁾, ¹⁷⁾. T and B lymphocytes are more dependent on de novo synthesis of purines for their proliferation than other cell types that can utilize the salvage pathway, i.e., hypoxanthine-guanine phosphoribosyl transferase pathway for their proliferation ¹⁸⁾. Mycophenolic acid (MPA) has more potent cytostatic effects on T and B lymphocytes and causes decreases in the levels of immunoglobulins and delayed type hypersensitivity responses ¹⁹⁾. Mycophenolate mofetil also prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in adhesion to endothelial cells. Therefore, it inhibits chemotaxis, impairs antigen presentation and induces immune tolerance ²⁰⁾. This is the principal mechanism by which mycophenolic acid (MPA) exerts immunosuppressive effects.

There are two isoforms of inosine monophosphate dehydrogenase (IMPDH): Type 1 and type 2. The IMPDH type 1 isoform is used by nonreplicating cells while the IMPDH type 2 isoform is predominantly used by proliferating lymphocytes. Mycophenolic acid (MPA) has five times higher binding affinity for the IMPDH type 2 isoform, which is expressed in activated lymphocytes, than of the type 1 isoform of IMPDH, which is expressed in most cell types and therefore, causing depletion of guanosine nucleotides, inhibition of DNA synthesis and the arrest of replicating lymphocytes in the S phase ²¹⁾. Therefore, MMF is more cytotoxic to proliferating T and B-lymphocytes.

Three other mechanisms may also contribute to the efficacy of mycophenolic acid (MPA) in preventing allograft rejection and other applications. First, mycophenolic acid can induce apoptosis of activated T-lymphocytes, which may eliminate clones of cells responding to antigenic stimulation. Second, by depleting guanosine nucleotides, mycophenolic acid suppresses glycosylation and the expression of some adhesion molecules, thereby decreasing the recruitment of lymphocytes and monocytes into sites of inflammation and graft rejection. Third, by depleting guanosine nucleotides mycophenolic acid also depletes tetrahydrobiopterin, a co-factor for the inducible form of nitric oxide synthase (iNOS). Mycophenolic acid therefore suppresses the production by inducible form of nitric oxide synthase (iNOS) of nitric oxide (NO) and consequent tissue damage mediated by peroxynitrite ²²⁾, ²³⁾, ²⁴⁾.

Figure 2. Mycophenolate mofetil mechanism of action

Mycophenolate mofetil uses

Mycophenolate mofetil (Cellcept or Myfortic) only U.S. Food and Drug Administration (FDA) approved indication is for the prevention of organ transplant rejection in conjunction with cyclosporine and corticosteroids ²⁶⁾, ²⁷⁾, ²⁸⁾. Mycophenolate mofetil is also used in the management of patients with serious autoimmune diseases.

Mycophenolate mofetil was first used in psoriasis in 1975 and since then, case reports and clinical trials document its use in various skin conditions as “off-label” indications ²⁹⁾:

• Psoriasis
• Vesiculobullous disorders
  • Pemphigus vulgaris
  • Pemphigus foliaceus
  • Paraneoplastic pemphigus
  • Bullous pemphigoid
  • Cicatricial pemphigoid
  • Linear IgA disease
  • Epidermolysis bullosa acquisita
• Connective tissue disease
  • Systemic lupus erythematosus (SLE)
  • Subacute cutaneous lupus erythematosus
  • Discoid lupus erythematosus
  • Dermatomyositis
  • Scleroderma
• Dermatitis
  • Atopic dermatitis
  • Dyshidrotic dermatitis
  • Chronic actinic dermatitis
• Vasculitis
  • Urticarial vasculitis
  • Takayasu’s arteritis
  • Microscopic polyangiitis
  • Polyarteritis nodosa
  • Wegener’s granulomatosis
• Others: Lichen planus, pyoderma gangrenosum, recurrent erythema multiforme, sarcoidosis, Weber-Christian disease and chronic idiopathic urticaria

Mycophenolate mofetil has been successfully used either as monotherapy or in combination with systemic steroids or as a steroid-sparing agent. Mycophenolate mofetil is best suited for individuals in whom other systemic immunotherapies are contraindicated because of hypertension, impaired renal function or liver disease (()Non-steroidal immunosuppressive drugs. In : Khopkar U, Pande S, Nischal KC. Hand book of Dermatological Drug Therapy. 1 st ed. New Delhi: Elsevier Publication: 2007. p. 127-38.).

Although early reports have shown good efficacy and tolerability of mycophenolate mofetil, randomized clinical trials with long surveillance periods are needed to document the efficacy and long-term safety of the drug in various skin diseases.

Mycophenolate mofetil (MMF) administration advice:

• The IV formulation should be administered within 24 hours following transplantation. The IV formulation can be administered for up to 14 days.
• Patients should be switched to the oral formulation as soon as they can tolerate oral medication.
• The IV formulation should only be administered by a slow IV infusion over at least 2 hours. It should never be administered by rapid or bolus IV injection.
• The IV formulation incompatible with 0.9% normal saline, Ringers and lactated Ringers solutions, and should not be mixed or given via the same catheter with other IV drugs or admixtures.
• The oral tablets should not be crushed or chewed.
• The oral capsules should not be opened.
• Doses may be taken with or without food.
• Take a missed dose as soon as possible, except if it is closer than 2 hours to the next scheduled dose.

Monitoring

Complete physical examination should be carried out at each visit or at least every 6-12 months to look for any opportunistic infections and malignancies. Complete blood counts should be performed at baseline and biweekly during the first 2-3 months and then, monthly through the first year. Liver function and renal function tests should be performed at baseline and serum transaminases should be repeated after one month and then, quarterly. During follow-up, treatment should be discontinued if the leukocyte count is less than 3500-4000 cells/mm³

Mycophenolate mofetil dosage

You must remain under the care of a doctor while you are using mycophenolate mofetil. Follow all directions on your prescription label and read all medication guides or instruction sheets. Use mycophenolate mofetil exactly as directed.

Mycophenolate mofetil injection is given as an infusion into a vein. A healthcare provider will give you this injection.

Take oral mycophenolate mofetil on an empty stomach, at least 1 hour before or 2 hours after a meal.

Swallow the capsule or tablet whole and do not crush, chew, break, or open it. Tell your doctor if you have trouble swallowing a tablet or capsule.

Read and carefully follow any Instructions for Use provided with your medicine. Ask your doctor or pharmacist if you do not understand these instructions.

Shake the oral suspension (liquid) before you measure a dose. Use only the dosing syringe provided with mycophenolate mofetil.

Mycophenolate mofetil (CellCept) and mycophenolic acid (Myfortic) are not absorbed equally in the body. Avoid medication errors by using only the brand, form, and strength of this medicine that your doctor has prescribed.

You will need frequent medical tests.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use. Throw away any unused liquid that is older than 60 days.

The liquid medicine may also be stored in the refrigerator. Do not freeze.

Adult dose for Organ Transplant

• Kidney transplantation: 1 g orally or IV 2 times a day (2 gm per day); [in clinical trials, 1.5 g orally or IV 2 times a day (3 gm per day) was used effectively, however, the safety profile for 3 gm a day was lower]
• Heart transplantation: 1.5 g orally or IV 2 times a day (3 gm per day)
• Liver transplantation: 1.5 gm orally or 1 gm IV 2 times a day (3 gm per day orally or 2 gm per day IV)

Comments:

• Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.
• The IV formulation should be administered over no less than 2 hours.
• IV administration is recommended in patients unable to take oral medication; oral administration should be initiated as soon as possible.

Elderly patient dose for Organ Transplant

• Kidney transplantation: 1 g orally or IV 2 times a day (2 gm per day)
• Heart transplantation: 1.5 g orally or IV 2 times a day (3 gm per day)
• Liver transplantation: 1.5 gm orally or 1 gm IV 2 times a day (3 gm per day orally or 2 gm per day IV)

Comments:

• Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.
• The IV formulation should be administered over no less than 2 hours.
• IV administration is recommended in patients unable to take oral medication; oral administration should be initiated as soon as possible.

Children dose for Organ Transplant

Kidney transplantation

• 3 months to 18 years of age: Oral Suspension: 600 mg/m² orally 2 times a day up to a maximum of 2 grams per day
• Children with a body surface area of 1.25 to 1.5 m² may be dosed with the oral capsules at 750 mg orally 2 times a day (1.5 g per day)
• Children with a body surface area greater than 1.5 m² may be dosed with the oral capsules at 1 g orally 2 times a day (2 g per day)

Comments:

• Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.
• The IV formulation should be administered over no less than 2 hours.
• IV administration is recommended in patients unable to take oral medication; oral administration should be initiated as soon as possible.

Dose Adjustments

• If a patient develops neutropenia (absolute neutrophil count less than 1300/mm³), dosing should be stopped or the dose reduced, and the patient should be managed appropriately.
• Close clinical monitoring is recommended if this drug is used in patients with liver disease.
• Doses greater than 2 g/day (especially in kidney dysfunction with CrCl less than 25 mL/min) are not recommended.
  Higher doses may lead to more severe gastrointestinal adverse reactions and enhanced immunosuppression.

What should I do if I forget a dose?

If you are taking mycophenolate mofetil tablet, capsule, or suspension (Cellcept) take the missed dose as soon as you remember it. However, if the next dose is less than 2 hours away, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If you are taking mycophenolate mofetil delayed release tablet (Myfortic) take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Mycophenolate mofetil side effects

Mycophenolate mofetil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• constipation
• nausea
• vomiting
• difficulty falling asleep or staying asleep
• pain, especially in the back, muscles, or joints
• headache
• gas
• prickling, tingling, or burning feeling on the skin
• swelling of the hands, arms, feet, ankles, or lower legs
• tremor

Mycophenolate mofetil affects your immune system and may increase your risk of cancer or serious infection. See your doctor right away if you have:

• fever of 100.5° F (38 °C) or higher, swollen glands, painful mouth sores, cold or flu symptoms, headache, ear pain, loss of smell or taste, stomach pain, vomiting, diarrhea, weight loss;
• weakness on one side of your body, loss of muscle control, confusion, thinking problems, loss of interest in things that normally interest you;
• pain around the transplanted kidney, pain or burning when you urinate, dark urine, jaundice (yellowing of the skin or eyes);
• tingly or painful blistering rash on one side of your body, swelling, warmth, redness, or oozing around a skin wound; or
• a new skin lesion, or a mole that has changed in size or color.

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, see your doctor immediately:

• sudden severe stomach pain, stomach pain that doesn’t go away, or diarrhea
• difficulty breathing
• chest pain
• rash
• itching
• dizziness, fainting, pale skin, lack of energy, shortness of breath, or fast heartbeat
• unusual bleeding or bruising; vomiting or spitting up blood or brown material that resembles coffee grounds; bloody or black, tarry stools; or blood in urine
• fever, muscle or joint stiffness or pain.

Get emergency medical help if you have symptoms of an allergic reaction to mycophenolate mofetil such as hives, difficult breathing, swelling of your face, lips, tongue, or throat.

Mycophenolate mofetil may cause a serious brain infection that can lead to disability or death. Call your doctor right away if you have problems with speech, thought, vision, or muscle movement. These symptoms may start gradually and get worse quickly.

Mycophenolate mofetil may cause other side effects. See your doctor if you have any unusual problems while taking mycophenolate mofetil.

Mycophenolate mofetil overdose

Mycophenolate mofetil overdose symptoms may include the following:

• stomach pain
• nausea
• vomiting
• heartburn
• diarrhea
• fever, sore throat, chills, cough and other signs of infection

Mycophenolic acid (the active metabolite) and the inactive glucuronide metabolite are not removed in significant amounts by hemodialysis.

Sirolimus

Sirolimus also known as Rapamune or Rapamycin is an immunosupressant or a drug that weakens your body’s immune system in order to help keep it from “rejecting” a transplanted organ that is used along with other medications to prevent rejection (attack of a transplanted organ by the immune system of a person receiving the organ) in people who have received a kidney transplant ¹⁾. Sirolimus is also given without other medicines to treat a rare lung disorder called lymphangioleiomyomatosis or LAM. Lymphangioleiomyomatosis (LAM) is a condition that affects the lungs, the kidneys, and the lymphatic system ²⁾. Lymphangioleiomyomatosis (LAM) is found almost exclusively in women. Lymphangioleiomyomatosis (LAM) often occurs as a feature of an inherited syndrome called tuberous sclerosis complex. When LAM occurs alone it is called isolated or sporadic LAM. Mutations in the TSC1 gene or more commonly the TSC2 gene, cause lymphangioleiomyomatosis (LAM). The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins, hamartin and tuberin, likely help regulate cell growth and size. The hamartin and tuberin proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way. Signs and symptoms of lymphangioleiomyomatosis (LAM) most often appear during a woman’s thirties. Affected women have an overgrowth of abnormal smooth muscle-like cells (LAM cells) in their lungs, resulting in the formation of lung cysts and the destruction of normal lung tissue. They may also have an accumulation of fluid in the cavity around the lungs (chylothorax). The lung abnormalities resulting from lymphangioleiomyomatosis (LAM) may cause difficulty breathing (dyspnea), chest pain, and coughing, which may bring up blood (hemoptysis). Many women with this disorder have recurrent episodes of collapsed lung (spontaneous pneumothorax). Women with lymphangioleiomyomatosis (LAM) may develop cysts in the lymphatic vessels of the chest and abdomen. These cysts are called lymphangioleiomyomas. Affected women may also develop tumors called angiomyolipomas made up of LAM cells, fat cells, and blood vessels. Angiomyolipomas usually develop in the kidneys. Internal bleeding is a common complication of angiomyolipomas. Sirolimus should be prescribed only by physicians with experience in immunosuppression and management of its complications.

Sirolimus comes as tablets of 0.5, 1 and 2 mg and a solution (liquid) of 1 mg/mL to be taken by mouth. Sirolimus is usually taken once a day, either always with food or always without food. To help you remember to take sirolimus, take it around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take sirolimus exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

The recommended initial dose of sirolimus is 1 mg orally once daily and the usual maintenance of dose in adults is 2 mg (~1 mg/m²) once daily to maintain a trough level ≤10 ng/mL (usually after the first week of initiating treatment) ³⁾.

Your doctor will probably adjust your dose of sirolimus during your treatment, usually not more than once every 7 to 14 days.

Continue to take sirolimus even if you feel well. Do not stop taking sirolimus without talking to your doctor.

Sirolimus solution may develop a haze when refrigerated. If this happens, let the bottle stand at room temperature and gently shake it until the haze goes away. The haze does not mean that the medication is damaged or unsafe to use.

Sirolimus has less kidney damaging adverse effect (nephrotoxicity) than the calcineurin inhibitors. Common side effects of sirolimus include anxiety, weakness, depression, dizziness, headache, gastrointestinal upset (dyspepsia, nausea & diarrhea), oral ulcers, edema, bone marrow suppression and rash. Uncommon but potentially severe adverse events include hypercholesterolemia, kidney failure, severe and opportunistic infections, delayed wound healing, pneumonitis, embryo-fetal toxicity, infertility, lower-extremity swelling, allergic reactions (hives, rash, or peeling skin) and anemia ⁴⁾. The adverse effects of sirolimus are reported to occur in the first few months of initiation of therapy, which are generally dose-related ⁵⁾. Talk to your doctor about the possible risks of using sirolimus for your condition.

Sirolimus special precautions

Before taking sirolimus:

• tell your doctor and pharmacist if you are allergic to sirolimus, any other medications, or any of the ingredients in sirolimus tablets or solution. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking. Be sure to mention any of the following: aminoglycoside antibiotics such as amikacin, gentamicin, kanamycin, neomycin (Neo-Fradin, Neo-Rx), streptomycin, and tobramycin (Tobi); amphotericin B (Abelcet, AmBisome, Amphocin, Fungizone); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik); antifungals such as clotrimazole (Lotrimin), fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend); bromocriptine (Cycloset, Parlodel); cimetidine (Tagamet); cisapride (Propulsid) (not available in the U.S.); clarithromycin (Biaxin); danazol (Danocrine); diltiazem (Cardizem, Dilacor, Tiazac); erythromycin (E.E.S., E-Mycin, Erythrocin); HIV protease inhibitors such as indinavir (Crixivan) and ritonavir (Norvir, in Kaletra); certain medications for cholesterol; medications for seizures such as carbamazepine (Tegretol), phenobarbital (Luminal), and phenytoin (Dilantin); metoclopramide (Reglan); nicardipine (Cardene); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); rifapentine (Priftin); telithromycin (Ketek); troleandomycin (TAO) (not available in the U.S.); and verapamil (Calan, Covera, Isoptin, Verelan). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• if you are taking cyclosporine (Neoral) soft gelatin capsules or solution, take them 4 hours before sirolimus.
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have or have ever had high cholesterol or triglycerides or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use an effective method of birth control before starting to take sirolimus, while taking sirolimus, and for 12 weeks after stopping sirolimus. If you become pregnant while taking sirolimus, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking sirolimus.
• do not have any vaccinations without talking to your doctor.

You should not use sirolimus if you have ever had a lung transplant or liver transplant.

Sirolimus may cause your body to overproduce white blood cells. This can lead to cancer, severe brain infection causing disability or death, or a viral infection causing kidney transplant failure.

See your doctor right away if you have: fever, flu symptoms, burning when you urinate, a new skin lesion, any change in your mental state, decreased vision, weakness on one side of your body, problems with speech or walking, or pain around your transplant.

Sirolimus drug interactions

Tell your doctor about all your current medicines. Many drugs can interact with sirolimus, especially:

• bromocriptine (Cycloset, Parlodel)
• cyclosporine
• danazol
• St. John’s wort
• tacrolimus
• cholesterol-lowering medication
• an antibiotic or antifungal medicine
• antiviral medicine to treat HIV or hepatitis C
• heart or blood pressure medication
• medicine to reduce stomach acid or treat an ulcer
• seizure medicine.

This list is not complete and many other drugs may affect sirolimus. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

What should I avoid while taking sirolimus?

Avoid exposure to sunlight or tanning beds. Sirolimus may increase your risk of skin cancer. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid getting sirolimus oral liquid on your skin. Wash the skin with soap and water if this happens. If sirolimus gets into your eyes, rinse them with plain water.

Grapefruit may interact with sirolimus and lead to unwanted side effects. Avoid the use of grapefruit and grapefruit juice while taking sirolimus.

Do not receive a “live” vaccine while using sirolimus. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), and zoster (shingles).

Sirolimus mechanism of action

Sirolimus is macrocyclic antibiotic with potent immunosuppressive activity that affects T cells and the cellular immune response ⁶⁾. In cells, sirolimus binds to the immunophilin FK binding protein 12 (FKBP-12), which in turn blocks the activation of mammalian target of rapamycin (mTOR) that interrupts several signal transduction pathways for several cytokines and growth factors including interlukin-2 (IL2) thereby inhibiting downstream protein biosynthesis, cell proliferation, and angiogenesis ⁷⁾, ⁸⁾, ⁹⁾, ¹⁰⁾. Sirolimus does not block the process of T-cell activation through the T-cell receptor but rather inhibits T-cell proliferation by binding to the mammalian target of rapamycin (mTOR) ¹¹⁾. However, the mTOR inhibition also leads to inhibition of lymphocyte activation which results in immunosuppression and might therefore be associated with an increased susceptibility to infections ¹²⁾. Sirolimus is used alone or in combination with calcineurin inhibitors and corticosteroids to prevent cellular rejection after kidney transplantation.

Sirolimus uses

Sirolimus (Rapamune or Rapamycin) was approved for use in the United States in 1999 and current US Food and Drug Administration (FDA) approvals are for prevention of organ rejection after kidney transplantation alone or in combination with calcineurin inhibitors or corticosteroids ¹³⁾, ¹⁴⁾, ¹⁵⁾. Sirolimus is also FDA approved as therapy for lymphangioleiomyomatosis (LAM) ¹⁶⁾, ¹⁷⁾, ¹⁸⁾. Sirolimus is an mTOR inhibitor that controls the abnormal proliferation and growth of smooth muscle cells in the lung tissue of patients with lymphangioleiomyomatosis (LAM). Sirolimus has shown in the MILES trial the ability to prevent the worsening of lung function (stabilization of FEV and improvement in FVC) and respiratory symptoms while improving the quality of life and reducing serum VEGF-D levels ¹⁹⁾.

Sirolimus has not been FDA approved for use in liver or lung transplantation but is used off-label for prevention of rejection after other forms of organ transplantation after failure or intolerance to tacrolimus. Sirolimus also is used sometimes to treat psoriasis.

To use Sirolimus bottles of solution, follow these steps:

1. Open the solution bottle. On first use, insert the plastic tube with stopper tightly into the bottle until it is even with the top of the bottle. Do not remove from the bottle once inserted.
2. For each use, tightly insert one of the amber syringes, with the plunger fully pushed in, into the opening in the plastic tube.
3. Draw up the amount of solution your doctor has prescribed by gently pulling out the plunger of the syringe until the bottom of the black line of the plunger is even with the correct mark on the syringe. Keep the bottle upright. If bubbles form in the syringe, empty the syringe into the bottle and repeat this step.
4. Empty the syringe into a glass or plastic cup containing at least 2 ounces (60 milliliters [1/4 cup]) of water or orange juice. Do not use apple juice, grapefruit juice, or other liquids. Stir vigorously for 1 minute and drink immediately.
5. Refill the cup with at least 4 ounces (120 milliliters [1/2 cup]) of water or orange juice. Stir vigorously and drink the rinse solution.
6. Dispose of the used syringe.

If you need to carry a filled syringe with you, snap a cap onto the syringe and put the syringe in the carrying case. Use the medication in the syringe within 24 hours.

Sirolimus dosage

Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use Sirolimus exactly as directed by your doctor. Sirolimus is usually taken once a day. If you also take cyclosporine, take it at least 4 hours before you take sirolimus. You may take sirolimus with or without food, but take it the same way every time.

Do not crush, chew, or break a sirolimus tablet. Tell your doctor if you have trouble swallowing the tablet whole.

Read and carefully follow any Instructions for Use provided with your medicine. Ask your doctor or pharmacist if you do not understand these instructions.

Sirolimus oral liquid must be mixed only with water or orange juice, no other juices or liquids. Measure the liquid carefully. Use the dosing syringe provided, or use a medicine dose-measuring device (not a kitchen spoon).

Sirolimus can increase your risk of infection by changing the way your immune system works. You will need frequent medical tests. Your dosing schedule may be delayed based on the results of these tests.

You should not stop using sirolimus without your doctor’s advice. Stopping suddenly could make your condition worse.

Store sirolimus tablets at room temperature, away from heat, moisture, and light.

Store sirolimus liquid in the refrigerator. Do not freeze. You may notice a slight haze to the liquid. This haze should disappear when the liquid reaches room temperature.

If you are using sirolimus oral liquid with a disposable syringe, you may store a loaded syringe in the carrying case provided. Keep the case at room temperature and use the medicine within 24 hours. Use a disposable syringe only once and then throw it away.

Adult dose for Organ Transplant

Use: As an immunosuppressive agent for the prevention of organ rejection in patients aged 13 years or older receiving kidney transplant.

For patients with low to moderate immunologic risk

Dosing by body weight

• Less than 40 kg:
  • Loading dose: 3 mg/m² on day 1
  • Maintenance dose: 1 mg/m² once daily
• Greater than or equal to 40 kg:
  • Loading dose: 6 mg orally on day 1
  • Maintenance dose: 2 mg orally once daily

For patients with high immunologic risk

Patients with high immunologic risk is defined as Black transplant recipients and/or repeat kidney transplant recipients who lost a previous allograft for immunologic reason and/or patients with high-panel reactive antibodies [PRA; peak PRA level greater than 80%]):

For patients receiving sirolimus with cyclosporine:

• Loading dose: Up to 15 mg on day one post-transplantation
• Maintenance dose: Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should be adjusted thereafter.

Antibody induction therapy may be used.

Comments:

• It is recommended that this sirolimus be used in a regimen with cyclosporine and corticosteroids.
• Sirolimus should be taken consistently with or without food.
• Once the sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring.

Maintenance therapy after withdrawal of cyclosporine

Cyclosporine withdrawal is not recommended in high-immunological risk patients. Following 2 to 4 months of combined therapy, withdrawal of cyclosporine may be considered in low-to-moderate risk patients. Cyclosporine should be discontinued over 4 to 8 weeks, and a necessary increase in the dosage of sirolimus (up to 4-fold) should be anticipated due to removal of metabolic inhibition by cyclosporine and to maintain adequate immunosuppressive effects. -Dose-adjusted trough target concentrations are typically 16 to 24 ng/mL for the first year post-transplant and 12 to 20 ng/mL thereafter (measured by chromatographic methodology).

Adult dose for Pulmonary Lymphangioleiomyomatosis (LAM)

Use: For the treatment of patients with lymphangioleiomyomatosis (LAM)

• Initial dose: 2 mg/day
• Sirolimus whole blood trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain concentrations between 5 and 15 ng/mL.

Comment:

Sirolimus should be taken consistently with or without food.

Children dose for Organ Transplant

Use: As an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplant.

For children with low to moderate immunologic risk

Greater than or equal to 13 years of age

Dosing by body weight:

• Less than 40 kg:
  • Loading dose: 3 mg/m² on day 1
  • Maintenance dose: 1 mg/m² once daily
• Greater than or equal to 40 kg:
  • Loading dose: 6 mg orally on day 1
  • Maintenance dose: 2 mg orally once daily

Sirolimus Dose Adjustments

Sirolimus dosages should be adjusted to maintain trough concentrations within the desired range based on risk and concomitant therapy. Maximum daily dose: 40 mg. The dosage should be adjusted at intervals of 7 to 14 days to account for the long half-life of sirolimus. In general, dose proportionality may be assumed. The new sirolimus dose equals current dose multiplied by (target concentration/current concentration).

If a large dose increase is required, consider loading dose calculated as:

• Loading dose equals (new maintenance dose minus current maintenance dose) multiplied by 3.
• Maximum dose in one day: 40 mg

If the required dose is greater than 40 mg (due to loading dose), then the dose should be divided over 2 days. Serum concentrations should not be used as the sole basis for dosage adjustment. Clinical signs/symptoms, tissue biopsy, and laboratory parameters should also be monitored.

Sirolimus narrow therapeutic index

• Sirolimus should be considered a narrow therapeutic index drug as small differences in dose or blood concentrations may lead to serious therapeutic failures or adverse drug reactions ²⁰⁾, ²¹⁾.
• Recommendations:
  • Generic substitution should be done cautiously, if at all, as current bioequivalence standards are generally insufficient for narrow therapeutic index drugs.
  • Additional and/or more frequent monitoring should be done to ensure receipt of an effective dose while avoiding unnecessary toxicities.

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population has not been established.

Safety and efficacy have not been established in patients less than 13 years old, or in pediatric (less than 18 years) renal transplant patients considered at high-immunologic risk.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Sirolimus side effects

Common side effects of sirolimus may include:

• fever, cold symptoms such as stuffy nose, sneezing, sore throat
• mouth sores
• nausea, stomach pain, diarrhea
• headache, muscle aches
• chest pain
• dizziness
• acne.

See your doctor if any of these symptoms are severe or do not go away.

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them or those listed in the IMPORTANT WARNING section, see your doctor immediately:

• unusual bleeding or bruising
• redness, oozing, or slow healing of a skin wound
• cough
• a new skin lesion, or a mole that has changed in size or color
• swollen, red, cracked, scaly skin
• hives
• rash
• itching
• sudden chest pain or discomfort, cough, feeling short of breath
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet
• hoarseness
• tenderness around the transplanted kidney
• signs of infection–fever, chills, painful mouth sores, skin sores, cold or flu symptoms, pain or burning when you urinate.

Sirolimus may cause a serious brain infection that can lead to disability or death. See your doctor right away if you have any change in your mental state, decreased vision, weakness on one side of your body, or problems with speech or walking. These symptoms may start gradually and get worse quickly.

Get emergency medical help if you have signs of an allergic reaction such as hives, rash, or peeling skin; wheezing, difficulty breathing, chest pain or tightness; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Sirolimus may cause other side effects. See your doctor if you have any unusual problems while taking sirolimus.

Sirolimus overdose

Tacrolimus

Tacrolimus also known as Prograf, Astagraf XL, Envarsus XR or FK 506 is an immunosupressant or a drug that weakens your body’s immune system in order to help keep it from “rejecting” a transplanted organ that is used along with other medications to prevent rejection (attack of a transplanted organ by the immune system of a person receiving the organ) in people who have received a heart, kidney, liver, or lung transplant ¹⁾, ²⁾. Tacrolimus works by decreasing the activity of your immune system to prevent it from attacking the transplanted organ. Tacrolimus is also sometimes used to treat fistulizing Crohn’s disease (a condition in which the body attacks the lining of the digestive tract, causing pain, diarrhea, weight loss, fever, and the formation of abnormal tunnels connecting the digestive tract to other organs or the skin).

Tacrolimus should be used only by physicians with experience in immunosuppressive therapy and its complications.

Tacrolimus was approved for use in the United States in 1994 and rapidly became an important part of the primary regimen of immunosuppression after allogenic transplantation ³⁾. Tacrolimus current indications are for prevention of organ rejection after transplantation. It is also used off label as therapy of active and recalcitrant forms of autoimmune diseases ⁴⁾.

Tacrolimus comes as a capsule of 0.5, 1 and 5 mg, granules for oral suspension (to be mixed with liquid), an extended-release (long acting) capsule, and an extended-release tablet to take by mouth. Tacrolimus is also available as a solution for intravenous administration (5 mg/mL). Tacrolimus is also available in topical forms for ophthalmologic and dermatologic conditions, as eye drops, creams ointments and lotions. The immediate-release capsules (Prograf) and oral suspension (Prograf) are usually taken twice a day (12 hours apart). You may take the immediate-release capsules and oral suspension either with or without food, but be sure to take it the same way each time. The extended-release capsules (Astagraf XL) or extended-release tablets (Envarsus XR) are usually taken every morning on an empty stomach at least 1 hour before breakfast or at least 2 hours after breakfast. Take tacrolimus at the same time(s) every day. Because of variability in individual pharmacokinetics of tacrolimus, the maintenance dose varies greatly and proper dosing requires monitoring for drug levels, which is also important because of its many dose dependent side effects and drug-drug interactions. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tacrolimus exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are taking the granules for oral suspension, you will need to mix it with room temperature water before use. Place 1 to 2 tablespoons (15 to 30 milliliters) of water into a cup containing the granules. Mix the contents and then immediately take the mixture by mouth from the cup or with an oral syringe; do not save the mixture for a later time. The granules will not completely dissolve. If any of the mixture remains, add 1 to 2 tablespoons (15 to 30 milliliters) of water to the mixture and immediately take it.

Swallow the extended-release capsules and extended-release tablets whole with water; do not split, chew, or crush them. Do not open or crush the immediate-release capsules,

Your doctor will monitor you carefully and adjust your dose as needed. Talk to your doctor often about how you are feeling during your treatment. Ask your doctor if you have any questions about how much tacrolimus you should take.

Different tacrolimus products release the medication differently in your body and cannot be used interchangeably. Only take the tacrolimus product prescribed by your doctor and do not switch to a different tacrolimus product unless your doctor says that you should.

Tacrolimus can only prevent rejection of your transplant as long as you are taking the medication. Continue to take tacrolimus even if you feel well. Do not stop taking tacrolimus without talking to your doctor.

Oral and parenteral tacrolimus common side effects include headache, dizziness, paresthesias, neuropathy, hypertension, nephropathy, diabetes, acne, hirsutism and opportunistic infections. Less common but potentially severe adverse events include diabetes, renal failure, hyperkalemia, hypertension, severe neuropathy, blood dyscrasias, microangiopathy and anaphylactic reactions. Talk to your doctor about the risks of using tacrolimus to treat your condition.

Figure 1. Tacrolimus chemical structure

Tacrolimus special precautions

Before taking tacrolimus:

• Tacrolimus increases the risk of development of lymphoma and other cancers, particularly of the skin, due to immunosuppression. This may lead to hospitalization or death.
• Tacrolimus increases your risk to bacterial, viral, fungal, and protozoal infections, including opportunistic infections.
• Patients should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.
• Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
• tell your doctor and pharmacist if you are allergic to tacrolimus, any other medications, or any of the other ingredients in tacrolimus products. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you more carefully for side effects.
• tell your doctor if you are taking or have recently stopped taking cyclosporine (Gengraf, Neoral, Sandimmune). If you were taking cyclosporine, your doctor will probably tell you not to start taking tacrolimus until 24 hours after you took your last dose of cyclosporine. If you stop taking tacrolimus, your doctor will also tell you to wait 24 hours before starting to take cyclosporine.
  The following nonprescription or herbal products may interact with tacrolimus: antacids containing magnesium and aluminum hydroxide (Maalox), cimetidine, lansoprazole (Prevacid 24 HR), omeprazole (Prilosec OTC, Zegerid OTC), St. John’s wort, or Schisandra sphenanthera extracts. Be sure to let your doctor and pharmacist know that you are taking any of these medications before you start taking tacrolimus. Do not start these medications while taking tacrolimus without discussing with your healthcare provider.
• tell your doctor if you have or have ever had long QT syndrome (an inherited condition in which a person is more likely to have QT prolongation, an irregular heart rhythm that can lead to fainting, loss of consciousness, seizures, or sudden death) low or high levels of potassium or low levels of calcium or magnesium in your blood, an irregular heartbeat, high cholesterol levels, high blood pressure, cystic fibrosis (an inborn disease that causes the body to produce thick, sticky mucus that may clog the pancreas, the lungs, and other parts of the body), heart, kidney, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you or your partner are able to become pregnant, use effective birth control before and during treatment with tacrolimus. If you become pregnant while taking tacrolimus, call your doctor. Tacrolimus may harm the fetus.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tacrolimus.
• you should know that taking tacrolimus may increase the risk that you will develop skin cancer. Protect yourself from skin cancer by avoiding unnecessary or prolonged exposure to sunlight or ultraviolet light (tanning beds) and wearing protective clothing, sunglasses, and sunscreen with a high skin protection factor (SPF).
• do not drink alcoholic beverages while you are taking tacrolimus extended-release capsules or extended-release tablets. Alcohol can make the side effects from tacrolimus worse.
  you should know that tacrolimus may cause high blood pressure. Your doctor will monitor your blood pressure carefully, and may prescribe medication to treat high blood pressure if it develops.
• you should know that there is a risk that you will develop diabetes during your treatment with tacrolimus. African American and Hispanic patients who have had kidney transplants have an especially high risk of developing diabetes during their treatment with tacrolimus. Tell your doctor if you or anyone in your family has or has ever had diabetes. If you experience any of the following symptoms, call your doctor immediately: excessive thirst; excessive hunger; frequent urination; blurred vision or confusion.
• do not have any vaccinations without talking to your doctor.

Breastfeeding women

Limited data indicate that amounts of systemically administered tacrolimus are low in breastmilk and probably do not adversely affect the breastfed infant ⁵⁾. United States and European experts and guidelines consider tacrolimus to be probably safe to use during breastfeeding ⁶⁾, ⁷⁾, ⁸⁾, ⁹⁾, ¹⁰⁾, ¹¹⁾, ¹²⁾, ¹³⁾, ¹⁴⁾. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.

Topical tacrolimus presents a low risk to the nursing infant because it is poorly absorbed after topical application and peak blood concentrations are less than 2 mcg/L in most patients. Ensure that the infant’s skin does not come into direct contact with the areas of skin that have been treated. Current guidelines allow topical tacrolimus to be applied to the nipples just after nursing, with the nipples cleaned gently before nursing ¹⁵⁾, ¹⁶⁾. Only water-miscible cream or gel products should be applied to the breast or nipple because ointments may expose the infant to high levels of mineral paraffins via licking, so pimecrolimus cream may be preferable to tacrolimus ointment for nipple application ¹⁷⁾.

Tacrolimus contraindications

Contraindications to tacrolimus include:

• Hypersensitivity
• Polyoxyl 60 hydrogenated castor oil (HCO-60) or other components of the formulation.

Tacrolimus drug interactions

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective. Tacrolimus can harm your kidneys, especially if you also use certain medicines for infections, cancer, osteoporosis, organ transplant rejection, bowel disorders, high blood pressure, or pain or arthritis (including Advil, Motrin, and Aleve).

Tell your doctor about all your current medicines. Many drugs can affect tacrolimus, especially:

• amiodarone
• cisplatin
• cyclosporine
• sirolimus
• antibiotic, antifungal, or antiviral medicines
• heart or blood pressure medication, such as a diuretic or “water pill.”

This list is not complete and many other drugs may affect tacrolimus.

Tacrolimus mechanism of action

Tacrolimus is a macrolide antibiotic which also has profound immunosuppressive properties, particularly affecting T cells and the cellular immune response. Tacrolimus acts as a calcineurin inhibitor which is responsible for activating an important signal transduction molecule in the pathway of T cell activation. Inhibition of this pathway results in a decrease in maturation of T lymphocytes and reduction in lymphokine production, including interlukin-2 (IL-2) ¹⁸⁾, ¹⁹⁾. The molecular action of tacrolimus is depicted in Figure 2. Tacrolimus binds to the immunophilin FKBP-12. The resulting molecular complex inhibits the phosphorylation activity of calcineurin therefore preventing the translocation of nuclear factor of activated T cells (NFAT) into the nucleus and the transcription of NFAT-dependent genes. Inhibition of nuclear factor of activated T cells (NFAT) activation thereby suppresses T-cell stimulation and prevents cell-mediated rejection.

Data from in vitro studies suggest that calcineurin is activated by the influx of calcium ions secondary to T-cell receptor binding at the cell surface ²⁰⁾. Calmodulin activity is also essential for calcineurin action. Once activated, calcineurin dephosphorylates nuclear factor of activated T cells (NFAT) triggering its translocation into the nucleus and the transcription of NFAT-dependent genes including cytokines which promote T-cell proliferation.

Following oral administration, tacrolimus acts systemically to inhibit the signaling phosphatase calcineurin ²¹⁾. By complexing calcineurin with the FK506-binding protein (FKBP12), tacrolimus prevents calcineurin from binding to activated calmodulin and enables the translocation of nuclear factor of activated T cells (NFAT) transcription factors from the cytoplasm to the nucleus ²²⁾. The lack of NFAT translocation prevents the transcription of NFAT-regulated proinflammatory cytokine genes in T-cells ²³⁾, subsequently blocking T-cell function. Interestingly, the use of calcineurin inhibitors does not appear to affect T-cell production, differentiation, or migration to patient skin, as T cells can be readily detected in the skin of kidney transplant recipients receiving ciclosporine and tacrolimus-based immunosuppression regimens ²⁴⁾.

Studies comparing the action of calcineurin inhibitors have found that tacrolimus has a 100-fold greater in vitro inhibitory activity against T lymphocytes when compared to cyclosporine ²⁵⁾. Furthermore, tacrolimus has been shown to inhibit the transformation of precursor T-helper cells into antigen-conditioned T cells in animal models whereas cyclosporine failed to exert this effect ²⁶⁾.

Figure 2. Tacrolimus mechanism of action

Tacrolimus uses

Tacrolimus use is in combination with one or, most commonly, two other immunosuppressive medications. Tacrolimus has an application as an agent for the prevention or treatment of certain autoimmune diseases.

In solid organ transplantation, Tacrolimus serves as the treatment of organ rejection in kidney, liver, and heart allogeneic transplants. There is also an off-label indication for the prevention of rejection in lung transplant patients.

Other off-label indications include:

• Crohn disease
• Graft-versus-host disease (GVHD)
• Myasthenia gravis
• Rheumatoid arthritis

Tacrolimus indications also include topical use in moderate to severe atopic dermatitis, as well as other off-label dermatologic disease states ²⁸⁾.

Tacrolimus administration advice

• Tacrolimus should not be used simultaneously with cyclosporine. Tacrolimus may be initiated at least 24 hours after stopping cyclosporine; however, dosing should be delayed if cyclosporine blood levels are elevated.
• Dosing should be titrated based on clinical assessments of rejection and tolerability, and to maintain recommended trough concentration ranges.
• Patients should not eat grapefruit or drink grapefruit juice with Tacrolimus.

Extended release (ER):

• Should be taken once daily in the morning, preferably on an empty stomach at least 1 hour before or 2 hours after a meal; do not take with an alcoholic beverage; do not chew, divide, or crush.
• Take a missed dose as soon as possible but not more than 14 hours after the scheduled time. Beyond the 14-hour timeframe, the patient should wait until the usual scheduled time the following morning to take the next scheduled dose. Do not take 2 doses at the same time.

General advice:

• The capsule formulation and the oral suspension of Tacrolimus are not interchangeable or substitutable with other tacrolimus extended-release products because the rate of absorption following the administration of an extended-release product is not equivalent to that of an immediate-release product. Under-or overexposure to Tacrolimus may result in graft rejection or other serious adverse reactions.
• The capsule formulation should not be used without supervision of a physician with experience in immunosuppressive therapy.
• Therapeutic drug monitoring is recommended for all patients receiving Tacrolimus.

Tacrolimus dosage

Tacrolimus can administration can be by oral, sublingual, topical, or intravenous (IV) route. Oral tacrolimus is available in immediate-release (IR) and extended-release (ER: XR and XL) formulations. The various formulations have different pharmacokinetic parameters and are not interchangeable ²⁹⁾. Doses should be titrated to target trough concentrations.

Adult Dosing of Post-Organ Transplant Rejection Prevention

Liver Transplant:

• Oral Tacrolimus ³⁰⁾:
  • Immediate-release (IR): Initially 0.1 to 0.15 mg/kg/day in two divided doses in combination
  • Extended-release (ER: XR and XL): 0.1 to 0.2 mg/kg once daily in combination with corticosteroid. Please note that the XL formulation is not approved for liver transplants in the US due to increased mortality in female liver transplants receiving the XL formulation.
• Intravenous (IV) Tacrolimus: Initially 0.03 to 0.05 mg/kg/day as a continuous infusion

Heart Transplant: In combination with an antimetabolite

• Oral Tacrolimus: Immediate-release (IR) Initially 0.075 mg/kg/day in two divided doses, given every 12 hours
• Intravenous (IV) Tacrolimus: Initially 0.01 mg/kg/day as a continuous infusion

Kidney Transplant: Use in combination with an antimetabolite agent

• Oral Tacrolimus:
  • Immediate-release (IR): Initially, 0.2 mg/kg/day in combination with azathioprine or 0.1 mg/kg/day combined with mycophenolate mofetil.
  • Extended-release (ER):
    • XL tacrolimus: 0.15 to 0.2 mg/kg/day with basiliximab induction; 0.2mg/kg/day without basiliximab induction.
    • XR tacrolimus: Initially 0.14 mg/kg/day
• Intravenous (IV) Tacrolimus: 0.03 to 0.05 mg/kg/day as a continuous infusion

IV tacrolimus use is not common due to increased kidney injury adverse effects ³¹⁾, ³²⁾.

Tacrolimus can be administered with or without food but may occur with food in the presence of gastrointestinal intolerance. Immediate-release (IR) doses should be 12 hours apart. Dose rounding should be to a whole number that is feasible with the available strengths. For example, immediate-release (IR) tacrolimus comes in 0.5 mg, 1mg, and 5 mg strengths ³³⁾.

When converting from Immediate-release (IR) to Extended-release (ER) formulations, use the following factors ³⁴⁾, ³⁵⁾:

• Immediate-release (IR) to XL: 1 to 1
• Immediate-release (IR) to XR: 1 to 0.8

Sublingual to oral conversion rates have varied from 1 to 1 to 1 to 3, but 1 to 2 has recently been the most commonly suggested in studies. There has been no optimally established dosing ³⁶⁾, ³⁷⁾.

Adult dose Kidney Transplant

Immediate-release (IR) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Immediate-release (IR) in combination with azathioprine: Initial dose: 0.1 mg/kg orally every 12 hours; initiate within 24 hours of surgery but delay until renal function has recovered
• Immediate-release (IR) in combination with mycophenolate mofetil (MMF)/interleukin-2 (IL-2) receptor antagonist: Initial dose: 0.05 mg/kg orally every 12 hours; initiate within 24 hours of surgery, but delay until renal function has recovered

Comments:

Should be taken consistently either with or without food because the presence and composition of food decreases the bioavailability.

Extended-release (ER) Tacrolimus

Use: Prevention of organ rejection in patients receiving a kidney transplant with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction

• Extended-release (ER) with Basiliximab Induction, mycophenolate mofetil (MMF) and Corticosteroids: Initial dose: 0.15 to 0.2 mg/kg/day orally as a single dose. Give first dose prior to or within 48 hours of transplant completion. May delay initiation until renal function has recovered.
• Extended-release (ER) with mycophenolate mofetil (MMF) and Corticosteroids, but Without Basiliximab Induction: Pre-operative dose: 0.1 mg/kg/day orally as a single dose within 12 hours prior to reperfusion; Post-operative dose: 0.2 mg/kg/day orally as a single dose. Give first post-operative dose within 12 hours after reperfusion but not less than 4 hours after the pre-operative dose.

Comments:

• Extended-release capsules are not interchangeable or substitutable with immediate-release capsules.
• Concomitant use with cyclosporine is not recommended.
• If switching from tacrolimus infusion, administer 8 to 12 hours after discontinuing infusion.

Intravenous (IV) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

Intravenous (IV) Tacrolimus initial dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion

Comments:

• Adult patients should receive doses at the lower end of the dosing range.
• IV administration should be reserved only for initiation in patients unable to take oral therapy.
• Convert to oral therapy as soon as it can be tolerated, usually within 2 to 3 days.

Adult dose Liver Transplant

Immediate-release (IR) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Immediate-release (IR) initial dose: 0.05 to 0.075 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery.

Comments:

Should be taken consistently either with or without food because the presence and composition of food decreases the bioavailability.

Intravenous (IV) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Intravenous (IV) Tacrolimus initial dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion

Comments:

• Adult patients should receive doses at the lower end of the dosing range.
• IV administration should be reserved only for initiation in patients unable to take oral therapy.
• Convert to oral therapy as soon as it can be tolerated, usually within 2 to 3 days.

Adult dose Heart Transplant

Immediate-release (IR) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Immediate-release (IR) initial dose: 0.0375 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery.

Comments:

Should be taken consistently either with or without food because the presence and composition of food decreases the bioavailability.

Intravenous (IV) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Intravenous (IV) Tacrolimus initial dose: 0.01 mg/kg/day as a continuous IV infusion

Comments:

• Adult patients should receive doses at the lower end of the dosing range.
• IV administration should be reserved only for initiation in patients unable to take oral therapy.
• Convert to oral therapy as soon as it can be tolerated, usually within 2 to 3 days.

Children dose Liver Transplant

Immediate-release (IR) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Immediate-release (IR) initial dose: 0.075 to 0.1 mg/kg orally every 12 hours

Comments:

Should be taken consistently either with or without food because the presence and composition of food decreases the bioavailability.

Intravenous (IV) Tacrolimus

Use: Prevention of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Intravenous (IV) Tacrolimus initial dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion

Comments:

• Children without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.
• IV administration should be reserved only for initiation in patients unable to take oral therapy.
• Convert to oral therapy as soon as it can be tolerated, usually within 2 to 3 days.

Liver impairment Dose Adjustments

Severe liver impairment (Child-Pugh 10 or greater): May require lower tacrolimus doses.

Liver transplant:

• Patients experiencing post-transplant liver impairment may be associated with an increased risk of developing renal insufficiency related to high blood levels of this drug. Monitor closely and consider dose adjustments.

Kidney impairment Dose Adjustments

Kidney transplant

• Immediate-release (IR) initial dose: 0.15 mg/kg orally every 12 hours; initiate within 24 hours of surgery but delay until renal function has recovered
• Immediate-release (IR) in combination with mycophenolate mofetil (MMF)/interleukin-2 (IL-2) receptor antagonist: Initial dose 0.05 mg/kg orally every 12 hours; initiate within 24 hours of surgery, but delay until renal function has recovered

Liver transplant

• Immediate-release (IR) initial dose: 0.075 to 0.1 mg/kg orally every 12 hours

Comments:

Should be taken consistently either with or without food because the presence and composition of food decreases the bioavailability.

Use:

Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

Heart transplant

• Immediate-release (IR) initial dose: 0.15 mg/kg orally every 12 hours

Comments:

Should be taken consistently either with or without food because the presence and composition of food decreases the bioavailability.

Use:

Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

• Intravenous (IV) Tacrolimus initial dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion

Comments:

• Children in general need higher doses compared to adults; the higher dose requirements may decrease as the child grows older.
• Children without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.
• IV administration should be reserved only for initiation in patients unable to take oral therapy.
• Convert to oral therapy as soon as it can be tolerated, usually within 2 to 3 days.

Use:

Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF).

Tacrolimus monitoring

Tacrolimus is a narrow therapeutic index drug. Therapeutic monitoring of tacrolimus in transplant patients is a valuable tool in adjusting drug levels ³⁸⁾, ³⁹⁾. Since tacrolimus use is typically in combination with other immunosuppressants, target levels usually decrease as post-transplant time increases to minimize calcineurin inhibitor-mediated nephrotoxicity and adverse effects ⁴⁰⁾. Whole blood concentrations should be used, drawn typically within 30 minutes before the next dose. Therapeutic levels range from 5 to 20 mcg/mL, though 5 to 15 mcg/mL is often employed to alleviate toxicity while preventing rejection.

Additional monitoring parameters include renal function, hepatic function, serum electrolytes (magnesium, phosphorus, potassium), glucose, and blood pressure. Parameters should initially be measured two to three times a week post-operatively, gradually decreasing as time passes, achieving target levels, and patient stabilization.

The following are recommendations for tacrolimus level ranges per British Columbia Transplant Guidelines (http://www.transplant.bc.ca/health-professionals/transplant-resources/transplant-clinical-guidelines). However, target levels vary by institution, induction protocols, and patient needs.

Adult and Children Kidney/Pancreas Transplant

• Less than 1 month: 8 to 12 ng/mL
• From 1 to 3 months: 6 to 9 ng/mL
• Greater than 3 months: 4 to 8 ng/mL

Adult Liver Transplant

• Less than 1 month: 6 to 9 ng/mL
• From 1 to 3 months: 4 to 8 ng/mL
• Greater than 3 months: 4 to 6 ng/mL
• More than 12 months: 3 to 5 ng/mL

Adult Heart Transplant

• Less than 3 months: 9 to 12 ng/mL
• From 3 to 6 months: 8 to 9 ng/mL
• From 6 to 12 months: 6 to 8 ng/mL
• Over 12 months: 4 to 8 ng/mL

Adult Lung Transplant

• From 0 to 3 months: 10 to 12 ng/mL
• From 4 to 12 months: 8 to 10 ng/mL
• More than 12 months: 6 to 8 ng/mL
• Due to the metabolism pathway of tacrolimus, many drug-drug interactions exist. If starting medications that inhibit or induce the metabolism of tacrolimus, added monitoring is suggested to prevent a supra or sub-therapeutic level.

What should I do if I forget a dose?

If the immediate-release capsule or oral suspension dose is missed, take it as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If the extended-release capsule dose is missed, take the dose if it is within 14 hours after missing the dose. However, if it is more than 14 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If the extended-release tablet dose is missed, take the dose it if it is within 15 hours after missing the dose. However, if it is more than 15 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Tacrolimus side effects

Tacrolimus may cause side effects. See your doctor if any of these symptoms are severe or do not go away:

• headache
• diarrhea
• constipation
• nausea
• vomiting
• heartburn
• stomach pain
• difficulty falling asleep or staying asleep
• dizziness
• weakness
• back or joint pain
• burning, numbness, pain, or tingling in the hands or feet

Some side effects can be serious. If you experience any of the following symptoms, or those mentioned in the IMPORTANT WARNING section, see your doctor immediately:

• decreased urination
• pain or burning on urination
• shortness of breath, hives, rash, or itching
• pale skin, shortness of breath, or fast heartbeat
• tiredness; weight gain; swelling of the arms, hands, feet, ankles, or lower legs; or shortness of breath
• unusual bleeding or bruising
• seizures, vision changes, headache, confusion, or uncontrollable shaking of a part of the body
• coma (loss of consciousness for a period of time)
• pinpoint-sized purple dots under the skin, bruising, fever, tiredness, sleepiness, confusion, yellowing of skin or eyes (jaundice), or decreased urination

Additional serious adverse effects include, but are not limited to ⁴¹⁾, ⁴²⁾:

• Cardiovascular: Angina pectoris, cardiac arrhythmias, hypertension
• Central nervous system: Abnormal dreams, headaches, insomnia, tremors
• Dermatologic: Acne vulgaris, alopecia, pruritis, rash
• Endocrine and metabolic: Decreased serum bicarbonate, decreased serum iron, new-onset diabetes mellitus after transplant (NODAT), hypercalcemia, hyperkalemia, hyperlipidemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypervolemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, metabolic acidosis, weight gain
• Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea
• Genitourinary: Urinary tract infection
• Liver: Abnormal hepatic function tests
• Infection: Bacterial infection, BK virus, candidiasis, cytomegalovirus, Epstein-Barr infection, herpes simplex infection, herpes zoster infection, other opportunistic infection
• Neuromuscular and skeletal: Arthralgia, muscle cramps
• Ophthalmic: Blurred vision, visual disturbance
• Otic: Otalgia, otitis media, tinnitus
• Kidney: Acute renal failure, increased blood urea nitrogen (BUN), increase serum creatinine (SCr), renal failure syndrome, renal tubular necrosis, decreased GFR, nephrotoxicity

Tacrolimus may cause other side effects. Call your doctor if you have any unusual problems while you are taking tacrolimus.

Tacrolimus overdose

Tacrolimus overdose symptoms may include:

• hives
• sleepiness
• nausea, vomiting, and diarrhea
• uncontrollable shaking of a part of the body, headache, confusion, imbalance, and extreme tiredness
• swelling of arms or legs
• fever or other signs of infection

Tacrolimus overdose and toxicity commonly presents as acute renal failure. Close monitoring of serum creatinine, GFR, and urine output is necessary for patients on tacrolimus.

Tacrolimus toxicity may also present as the development of adverse effects such as tremors, electrolyte disturbances, headaches, and increased SCr.

No antidote exists currently to counter Tacrolimus toxicity ⁴³⁾. Hemodialysis does not remove tacrolimus ⁴⁴⁾.

Cyclosporine

Cyclosporine also known as cyclosporin, ciclosporin A, cyclosporin A, Neoral, Gengraf or Sandimmune is a powerful immunosuppressant or a drug that weakens your body’s immune system in order to help keep it from “rejecting” a transplanted organ or bone marrow transplants ¹⁾. Organ rejection happens when your immune system treats the new organ as an invader and attacks it. Cyclosporine is currently used to prevent organ rejection after a kidney, heart, or liver transplantation. Cyclosporine is also used to treat severe, active rheumatoid arthritis in patients for whom classical slow-acting antirheumatic agents (including methotrexate) are inappropriate or ineffective. Cyclosporine is used to treat severe psoriasis in whom conventional therapy is ineffective or inappropriate and the disease has caused a significant interference with the quality of life. Cyclosporine is also sometimes used to treat Crohn’s disease (a condition in which the body attacks the lining of the digestive tract, causing pain, diarrhea, weight loss, and fever). Furthermore, cyclosporine is also used to treat severe atopic dermatitis when other treatment is ineffective or inappropriate. Careful monitoring of all cyclosporine-treated patients is mandatory. Cyclosporine should only be used by medical practitioners who are experienced in the use of immunosuppressive therapy (see “IMPORTANT WARNING”).

Cyclosporine was introduced into use in the United States in the early 1980s and rapidly became part of the primary treatment regimen of immunosuppression after allogenic, solid organ transplantation.

Cyclosporine and cyclosporine (modified) both come as capsules of 25 and 100 mg under the brand name of Sandimmune and a Cyclosporine (modified) solution with absorbed microemulsion formulation of 25 and 100 mg under the brand name of Neoral. Cyclosporine is also available in solution for intravenous use. Because of variable absorption, the usual maintenance dose of cyclosporine varies greatly and proper dosing requires monitoring for drug levels, which is also important because of its many dose dependent side effects and drug-drug interactions.

Cyclosporine is usually taken by mouth once a day. Cyclosporine (modified) is usually taken twice a day. It is important to take both types of cyclosporine on a regular schedule. Take cyclosporine or cyclosporine (modified) at the same time(s) each day, and allow the same amount of time between doses and meals every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take cyclosporine or cyclosporine (modified) exactly as directed. Do not take more or less of the medication or take it more often than prescribed by your doctor.

Your blood urea nitrogen (BUN), creatinine ratio, magnesium levels, and blood pressure require monitoring while on Cyclosporine therapy. Uric acid monitoring is debatable. Therapeutic monitoring of cyclosporine in transplant patients is a valuable tool in adjusting drug dosage to prevent acute rejection, nephrotoxicity, and predictable dose-dependent adverse reactions.

Your doctor will probably adjust your dose of cyclosporine or cyclosporine (modified) during your treatment. If you are taking either type of cyclosporine to prevent transplant rejection, your doctor will probably start you on a high dose of the medication and gradually decrease your dose. If you are taking cyclosporine (modified) to treat rheumatoid arthritis or psoriasis, your doctor will probably start you on a low dose of the medication and gradually increase your dose. Your doctor may also decrease your dose if you experience side effects of the medication. Tell your doctor how you are feeling during your treatment.

Cyclosporine (modified) helps control the symptoms of psoriasis and rheumatoid arthritis, but does not cure these conditions. If you are taking cyclosporine (modified) to treat psoriasis, it may take 2 weeks or longer for your symptoms to begin to improve, and 12 to 16 weeks for you to feel the full benefit of the medication. If you are taking cyclosporine (modified) to treat rheumatoid arthritis, it may take 4 to 8 weeks for your symptoms to improve. Continue to take cyclosporine (modified) even if you feel well. Do not stop taking cyclosporine (modified) without talking to your doctor. Your doctor may decrease your dose gradually.

You may notice an unusual smell when you open a blister card of cyclosporine capsules. This is normal and does not mean that the medication is damaged or unsafe to use.

Cyclosporine (modified) oral solution may gel or become lumpy if it is exposed to temperatures below 68 °F (20 °C). You can use the solution even if it has gelled, or you can turn the solution back to a liquid by allowing it to warm to room temperature (77 °F [25 °C]).

Cyclosporine and cyclosporine (modified) oral solution must be mixed with a liquid before use. Cyclosporine (modified) oral solution may be mixed with room temperature (77 °F [25 °C]) orange juice or apple juice but should not be mixed with milk. Cyclosporine oral solution may be mixed with milk, chocolate milk, or orange juice. You should choose one drink from the appropriate list and try to always mix your medication with that drink.

Cyclosporine common side effects of cyclosporine include headache, dizziness, paresthesias (pins and needles sensation), nerve damage (neuropathy), tremor, high blood pressure (hypertension), high blood cholesterol (hyperlipidemia), kidney damage (nephropathy), acne, hirsutism (unwanted excessive hair growth on a woman’s face, chest and back) and excessive growth of the gums (gum hyperplasia). Uncommon but potentially severe adverse events include kidney damage (nephrotoxicity), microangiopathic hemolytic anemia, neurotoxicity, serious and opportunistic infections, increase risk of cancer and anaphylactic reactions. Nephrotoxicity is one of the serious adverse effects that limit the therapeutic uses of cyclosporine A. Several reports have discussed the mechanisms by which cyclosporine A induces nephrotoxicity ²⁾, ³⁾.

Oral and parenteral cyclosporine should be prescribed only by physicians experienced in immunosuppressive therapy and management of its complications.

Figure 1. Cyclosporine A chemical structure

Cyclosporine special precautions

Before taking cyclosporine:

• tell your doctor and pharmacist if you are allergic to cyclosporine, cyclosporine (modified), any other medications, or any of the inactive ingredients in cyclosporine or cyclosporine (modified) capsules or solution. Ask your pharmacist for a list of the inactive ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking, or plan to take. Your doctor may need to change the doses of your medications or monitor you more carefully for side effects.
• if you are taking sirolimus (Rapamune), take it 4 hours after you take cyclosporine or cyclosporine (modified).
• The following nonprescription or herbal products may interact with cyclosporine: nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn), and St. John’s wort. Be sure to let your doctor and pharmacist know that you are taking these medications before you start taking cyclosporine. Do not start any of these medications while taking cyclosporine without talking to your healthcare provider.
• Avoid drinking grapefruit juice or eating grapefruit while taking cyclosporine or cyclosporine (modified).
• tell your doctor if you have or have ever had any of the conditions mentioned in the IMPORTANT WARNING section or any of the following: low cholesterol, low levels of magnesium in your blood, high levels of potassium or uric acid in your blood, any condition that makes it difficult for your body to absorb nutrients, or liver disease.
• tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking either type of cyclosporine, call your doctor. Both types of cyclosporine may increase the risk that your baby will be born too early.
• tell your doctor if you are breast-feeding or planning to breast-feed.
• you should know that cyclosporine may make you drowsy, dizzy, or confused. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that cyclosporine capsules and oral solution contain alcohol. Ask your doctor about the safe use of alcoholic beverages while you are taking cyclosporine.
• do not have vaccinations without talking to your doctor.

Drugs that can decrease cyclosporin A levels include rifampicin, rifabutin, isoniazid, barbiturates, phenytoin, carbamazepine, intravenous trimethoprim, intravenous sulfadimidine, imipenem, cephalosporins, terbinafine, ciprofloxacin, ticlopidine, octreotide, and nefazodone. Conversely, drugs that can increase cyclosporine A levels include verapamil, diltiazem, amlodipine, nicardipine, ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, azithromycin, saquinavir, indinavir, nelfinavir, ritonavir, methylprednisolone.

Your doctor may tell you to limit the amount of potassium in your diet. Follow these instructions carefully. Talk to your doctor about the amount of potassium-rich foods such as bananas, prunes, raisins, and orange juice you may have in your diet. Many salt substitutes contain potassium, so talk to your doctor about using them during your treatment.

Non-MODIFIED and MODIFIED formulations

• The non-modified formulation should be administered with corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.
• The non-modified formulation has decreased bioavailability in comparison to the modified formulation.
• The absorption of cyclosporine during chronic administration of the non-modified formulation is erratic. Patients taking this formulation over a prolonged time should be monitored at intervals for cyclosporine blood concentrations and dose adjustments should be made to avoid toxicity due to high concentrations and possible organ rejection due to low absorption of the drug. This is especially important in liver transplants.
• The non-modified formulation and the modified formulation are not bioequivalent and cannot be used interchangeably without physician supervision.
• The modified formulation has increased bioavailability in comparison to the non-modified formulation. For a given trough concentration, cyclosporine exposure will be greater with the modified formulation than with the non-modified formulation. If a patient who is receiving exceptionally high doses of the non-modified formulation is converted to the modified formulation, caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking the modified formulation to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations.

Cyclosporine mechanism of action

Cyclosporine is a cyclic polypeptide of 11 amino acids produced by a fungal species called Tolypocladium inflatum, which has profound immunosuppressive properties, particularly affecting T cells (T lymphocytes), cell-mediated immune response and humoral immunity ⁴⁾, ⁵⁾, ⁶⁾. Cyclosporine works to suppress cell-mediated immune reactions.

The mechanism of action of cyclosporine is as calcineurin inhibitor, a cytochrome P450 3A4 inhibitor, and a P-glycoprotein inhibitor ⁷⁾. Cyclosporine A acts by blocking T cell infiltration, activation, and the subsequent release of inflammatory cytokines as illustrated in Figure 2 ⁸⁾, ⁹⁾, ¹⁰⁾. In addition, cyclosporine A has an antiapoptotic and protective action on human conjunctival epithelial cells, unlike corticosteroids ¹¹⁾, ¹²⁾.

Cyclosporine is in an inactive form (prodrug) at first ¹³⁾. Because cyclosporine is a lipophilic peptide, it can easily pass through the cell membrane where cyclosporine gets combined with cyclophilin, which is a cytosolic protein. The cyclosporine/cyclophilin complexes inhibit the production of interleukins (IL), including interlukin-2 (IL-2), which is essential for the self-activation of T lymphocytes (T cells) and their differentiation via calcineurin inhibition. Calcineurin is accepted to be the target molecule that cyclosporine/cyclophilin complexes attach. What affects the signal production that calcineurin T cells trigger is an enzyme which is in bond with calmodulin and calcium and has serine/threonine phosphatase quality. Dephosphorylation, kinase activity, phosphatase activity, and protein expression can be included among the calcineurin activities. Dephosphorylation occurs in the target molecules within the cell as a result of cyclosporine/cyclophilin bonding with calcineurin, and as a result, inhibition of the IL-2 gene and other cytokine genes occur. Therefore, IL-2 production is blocked, and proliferation signals
of T cells disappear ¹⁴⁾, ¹⁵⁾.

Cyclosporin A is effective due to specific and reversible inhibition of immunocompetent lymphocytes in the G0 and G1-phase of the cell cycle ¹⁶⁾. The T-helper cell is the primary target, although it may also suppress T-suppressor cells. The B-lymphocyte (B cell) co-operation is essential for activation of B-lymphocyte; the latter also gets inhibited. In addition, research has demonstrated that Cyclosporin had an inhibiting effect on CD4+ CD25+ Tregs, which might block the host immune tolerance potentiality.

Cyclosporine metabolism is via liver CYP450 3A 4/5 and is metabolized into a pair of hydroxylated derivatives (AM1 and AM9) and one N-methylated derivative (AM4N) ¹⁷⁾.

Figure 2. Cyclosporine A mechanism of action

Footnotes: (A) Inhibits intrinsic mitochondrial pathway and caspase activation with an antiapoptotic and protective action on human conjunctival epithelial cells ¹⁸⁾, ¹⁹⁾ (B) Inhibits nuclear factor κB (NFκB) activation and the subsequent release of proinflammatory cytokines through modulating proteasome activity ²⁰⁾, ²¹⁾ (C) Binds with cyclophilin to form a calcineurin complex and inhibits dephosphorylation of nuclear factor of activated T cells and the subsequent release of interleukin 2 (IL-2) ²²⁾ (D) Induces T cell apoptosis by regulating Fas/Fas ligand expression, caspase activation, and mitochondrial permeability transition pore (MPTP) opening.

Abbreviations: CsA = cyclosporine A; CyP = cyclophilin; Iĸßα = nuclear factor of ĸ light polypeptide gene enhancer in ß-cell inhibitor alpha; IL-2 = interleukin 2; MPTP = mitochondrial permeability transition pore; NFAT = nuclear factor of activated T cells; NFkB = nuclear factor of kB; P = phosphorylated.

Cyclosporine uses

Cyclosporine is a potent immunosuppressive agent used to treat organ rejection post-transplant. Cyclosporine also has uses in certain other autoimmune diseases ²⁴⁾, ²⁵⁾, ²⁶⁾, ²⁷⁾, ²⁸⁾.

U.S. Food and Drug Administration (FDA) approved indications ²⁹⁾:

• Solid organ transplantation,Cyclosporine is used to treat organ rejection in kidney, liver, and heart allogeneic transplants.
• In patients with rheumatoid arthritis, Cyclosporine is indicated when the disease has not adequately responded to methotrexate.
• For psoriasis, indications include the treatment of adult, nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis who have not responded to at least one systemic therapy.
• In patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig disease), cyclosporin is approved to treat amyotrophic lateral sclerosis (ALS) and its variants.
• In nephrotic syndrome, Cyclosporin is indicated to treat focal segmental glomerulosclerosis not responding to corticosteroids.
• In individuals with graft vs. host disease (GVHD), Cyclosporin prevents and treats the disease.
• In the case of uveitis, cyclosporin is indicated for refractory posterior uveitis and Behcet disease.

Non-FDA approved indications ³⁰⁾:

• Allergic conjunctivitis, keratoconjunctivitis, Langerhans cells histiocytosis, ocular graft vs. host disease, autoimmune hepatitis, Duchenne muscular dystrophy, ulcerative colitis, pure red cell aplasia, and Henoch Schönlein purpura nephritis.

To take oral cyclosporine, follow these steps:

1. Fill a glass (not plastic) cup with the drink you have chosen.
2. Remove the protective cover from the top of the dosing syringe that came with your medication.
3. Place the tip of the syringe into the bottle of solution and pull back on the plunger to fill the syringe with the amount of solution your doctor has prescribed.
4. Hold the syringe over the liquid in your glass and press down on the plunger to place the medication in the glass.
5. Stir the mixture well.
6. Drink all of the liquid in the glass right away.
7. Pour a little more of the drink you have chosen into the glass, swirl the glass around to rinse, and drink the liquid.
8. Dry the outside of the syringe with a clean towel and replace the protective cover. Do not wash the syringe with water. If you do need to wash the syringe, be sure that it is completely dry before you use it to measure another dose.

Cyclosporine dosage

Adult Dosing for Organ Transplant

• Oral cyclosporine
  
  • Four to 12 hours pre-transplant: 14 to 18 mg/kg by mouth for one dose.
  • One to two weeks post-transplant: 5 to 15 mg/kg per day by mouth divided twice a day.
  • Reduce the dose by 5% per week until 5 to 10 mg/kg per day by mouth divided twice per day.
• Intravenous (IV) cyclosporine (maximum concentration 2.5 mg/dL)
  • Four to 12 hours pre-transplant IV: 5 to 6 mg/kg IV for one dose over 2 to 6 hours.
  • Post-transplant until the patient can tolerate oral therapy: 2 to 10 mg/kg IV once per day.
  • Adjust dosage according to trough levels.

Cyclosporine dosage for focal segmental glomerulosclerosis

• Oral 3 mg/kg/day every 12 hours.

Cyclosporine dosage for Rheumatoid arthritis

• Oral (modified), initially: 2.5 mg/kg per day every 12 hrs, increase 0.5 to 0.75 mg/kg per day after eight weeks if the response has not been effective. Maximum dose: 4 mg/kg per day.

Cyclosporine dosage for Psoriasis

• Oral (modified), initially: 2.5 mg/kg per day every 12 hours, increase 0.5 mg/kg per day after four weeks if the response has not been effective. Maximum dose: 4 mg/kg per day.

The ideal therapeutic range of cyclosporine in whole blood is as follows ³¹⁾:

• Kidney transplant: 200 to 400 ng/ml in the first week after transplantation; 125 to 275 ng/ml in the second week to the sixth-month post-transplantation; 100 to 150 ng/ml in the seventh to the twelfth-month post-transplantation; and 75 to 160 ng/ml one year after transplantation (residual concentration predose).
• Heart transplant: 250 to 350 ng/mL in the first six months; 100 to 200 ng/mL six months to one year after transplantation (residual concentration predose).
• Liver transplant: 250 to 350 ng/mL for the first six months; 100 to 200 ng/mL six months to one year after transplantation (residual concentration predose).

The range between effective cyclosporine concentrations and the concentrations associated with serious toxicity is fairly narrow. Sub-optimal doses or concentrations can lead to therapeutic failure or severe toxicity. Cyclosporine is subject to therapeutic monitoring based on pharmacokinetics measures. The medication has low-to-moderate within-subject variability.

Adult dose for Organ Transplant

Uses: For the prevention of organ rejection in kidney, liver, and heart allogeneic transplants with corticosteroids and in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Modified and non-modified cyclosporine formulations are not bioequivalent and cannot be used interchangeably without physician supervision.

Oral cyclosporine (modified with absorbed microemulsion formulation)

• Note: The dose is dependent upon type of transplant and formulation; refer to local protocol for specific dosing.
• Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.

Newly transplanted patients:

• Kidney transplantation: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
• Liver transplantation: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
• Heart transplantation: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses

Comment:

• The initial dose of cyclosporin A varies depending on the transplanted organ and the other immunosuppressive agents included in the protocol.
• In newly transplanted patients, the initial oral dose is the same as the initial oral dose of the non-modified formulation.
• Titrate the dose based on rejection and tolerability.
• Lower doses of the modified formulation may be sufficient as maintenance therapy.
• Adjunct therapy with corticosteroids is recommended initially. Consult local protocol and/or manufacturer product information.

Oral cyclosporine

Note: The dosing presented here is to be used as a guideline only. Local protocol should be consulted for specific dosing. Dosing in clinical practice may be very different than the manufacturer labeling. Non-modified formulations have decreased bioavailability in comparison to modified absorbed microemulsion formulations. Modified and non-modified formulations are not bioequivalent and cannot be used interchangeably without physician supervision.

Manufacturer recommendation:

• Initial dose: 15 mg/kg orally 4 to 12 hours prior to transplantation; although a single dose of 14 to 18 mg/kg was used in most clinical trials, most clinicians favor the lower end of the scale; lower initial doses are usually used for renal transplantation in the ranges of 10 to 14 mg/kg/day
• Maintenance dose: The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day; some clinicians prefer to reduce the maintenance dose to 3 mg/kg/day in some renal transplant patients without an apparent rise in rejection rate

Cyclosporine Parenteral formulation

Note: Local protocol should be consulted for dosing recommendations.

Manufacturer suggested dosing:

• Initial dose: 5 to 6 mg/kg/day IV (or one-third of the oral dose) as a single dose infused over 2 to 6 hours given 4 to 12 hours prior to transplantation
• Maintenance dose: 5 to 6 mg/kg/day IV continued postoperatively until the patient can tolerate capsules or oral solution

Comments:

• Due to the risk of anaphylaxis, the IV formulation should be reserved for patients who are unable to take the oral formulation.
• Adjunct steroid therapy should be used with cyclosporine.

Adult dose for Rheumatoid Arthritis

Use: For severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate; ciclosporin A can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.

Oral cyclosporine (modified with absorbed microemulsion formulation)

• Initial dose: 1.25 mg/kg orally 2 times a day; onset of action usually occurs between 4 and 8 weeks
• Titration: If insufficient benefit is seen and tolerability is good at the initial dose (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks
• Maximum dose: 4 mg/kg/day orally in 2 divided doses; if no benefit is seen by 16 weeks, therapy should be discontinued

Comments:

• Salicylates, nonsteroidal anti-inflammatory agents, and oral corticosteroids may be continued concomitantly with cyclosporine.
• Dose decreases by 25% to 50% should be made at any time to control adverse events (e.g., hypertension, elevations in serum creatinine 30% above pretreatment level), or significant laboratory abnormalities.
• Most patients can be treated with the modified formulation at doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week.

Adult dose for Psoriasis

Use: For nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated.

Oral cyclosporine (modified with absorbed microemulsion formulation)

• Initial dose: 1.25 mg/kg orally 2 times a day for at least 4 weeks
• Titration: If insufficient benefit is seen at 4 weeks and tolerability is good at the initial dose, the dose may be increased by 0.5 mg/kg/day at 2-week intervals based on patient response.
• Maximum dose: 4 mg/kg/day in 2 divided doses
• Note: Doses below 2.5 mg/kg/day may also be effective.

Comments:

• Dose decreases by 25% to 50% should be made at any time for adverse events (e.g., hypertension, elevations in serum creatinine greater than or equal to 25% above pretreatment level), or significant laboratory abnormalities. Discontinue therapy if dose reduction is not effective.
• Improvement is usually seen in 2 weeks; stabilization may take 12 to 16 weeks.
• Discontinue therapy if a satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the maximum tolerated dose.
• When a patient appears stable the dose should be lowered, and the patient treated with the lowest dose that maintains an adequate response (not necessarily a complete response).
• Doses at the lower end of the recommended range are effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be effective.
• Most patients will experience relapse of their psoriasis upon cessation of therapy.
• Long term experience in psoriasis patients is limited; therefore, therapy beyond one year is not recommended. Alternating with other forms of therapy should be considered in the long-term management of psoriasis.

Children dose for Organ Transplant

Uses: For the prevention of organ rejection in kidney, liver, and heart allogeneic transplants with corticosteroids and in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Modified and non-modified cyclosporine formulations are not bioequivalent and cannot be used interchangeably without physician supervision.

The same dose and dosing regimen may be used in children as in adults although in several studies, children have required and tolerated higher doses than adults. Consult the manufacturer product information/and or local protocol.

Oral cyclosporine (modified with absorbed microemulsion formulation)

1 year and older:

• Note: The dose is dependent upon type of transplant and formulation; refer to local protocol for specific dosing.
• Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.

Newly transplanted patients:

• Kidney transplantation: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
• Liver transplantation: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
• Heart transplantation: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses

Comments:

• The initial dose of cyclosporine varies depending on the transplanted organ and the other immunosuppressive agents included in the protocol.
• In newly transplanted patients, the initial oral dose is the same as the initial oral dose of the non-modified formulation.
• Titrate the dose based on rejection and tolerability.
• Lower doses of the modified formulation may be sufficient as maintenance therapy.
• Adjunct therapy with adrenal corticosteroids is recommended initially. Consult local protocol and/or manufacturer product information.

Oral cyclosporine

Uses: For the prevention of organ rejection in kidney, liver, and heart allogeneic transplants concomitantly with corticosteroids and in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents

6 months and older: The dosing presented here is to be used as a guideline only. Local protocol should be consulted for specific dosing. Dosing in clinical practice may be very different than the manufacturer labeling. Non-modified formulations have decreased bioavailability in comparison to modified formulations. Modified and non-modified formulations are not bioequivalent and cannot be used interchangeably without physician supervision.

Manufacturer recommendation:

• Initial dose: 15 mg/kg orally 4 to 12 hours prior to transplantation; although a single dose of 14 to 18 mg/kg was used in most clinical trials, most clinicians favor the lower end of the scale; lower initial doses are usually used for renal transplantation in the ranges of 10 to 14 mg/kg/day
• Maintenance dose: The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day; some clinicians prefer to reduce the maintenance dose to 3 mg/kg/day in some renal transplant patients without an apparent rise in rejection rate

Cyclosporine Parenteral formulation

6 months and older: Local protocol should be consulted for dosing recommendations.

Manufacturer suggested dosing:

• Initial dose: 5 to 6 mg/kg/day IV (or one-third of the oral dose) as a single dose infused over 2 to 6 hours given 4 to 12 hours prior to transplantation
• Maintenance dose: 5 to 6 mg/kg/day IV continued postoperatively until the patient can tolerate capsules or oral solution

Comments:

• Due to the risk of anaphylaxis, the IV formulation should be reserved for patients who are unable to take the oral formulation.
• Adjunct steroid therapy should be used with cyclosporin A.

Kidney disease dose adjustments

• Rheumatoid arthritis or psoriasis patients with abnormal kidney function: Cyclosporin A is Contraindicated
• Careful monitoring of blood or plasma concentrations of cyclosporine A is necessary to avoid exacerbation of kidney impairment.

Liver disease dose adjustments

• Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range
• Due to decreased plasma clearance of Cyclosporin A in patients with liver disease, plasma or blood concentrations should be monitored closely and dose adjustments made as necessary.

What should I do if I forget a dose?

If you forget to take a dose, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Cyclosporine side effects

Cyclosporine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• diarrhea
• heartburn
• gas
• increased hair growth on the face, arms, or back
• growth of extra tissue on the gums
• acne
• flushing
• uncontrollable shaking of a part of your body
• burning or tingling in the hands, arms, feet, or legs
• muscle or joint pain
• cramps
• pain or pressure in the face
• ear problems
• breast enlargement in men
• depression
• difficulty falling asleep or staying asleep

Some side effects can be serious. If you experience any of the following symptoms, or those listed in the IMPORTANT WARNING section, see your doctor immediately:

• unusual bleeding or bruising
• pale skin
• yellowing of the skin or eyes (jaundice), nausea, vomiting, loss of appetite, extreme tiredness, flu-like symptoms, pain in the upper right part of the stomach, dark urine, or light-colored bowel movements
• seizures
• loss of consciousness
• changes in behavior or mood
• difficulty controlling body movements
• loss of balance or coordination, or unsteadiness
• weakness or the inability to move on one side of the body
• changes in vision
• confusion
• purple blotches on the skin
• rash, itching, or hives
• Kidney damage: Decreases glomerular filtration rate (GFR) due to an increased tone of the glomerular afferent arterioles. Serum creatinine concentration rises and decreases creatinine clearance. The undesirable effects correlate with the duration of treatment and dose of Cyclosporine A.
• Neurotoxicity: There have been reports of convulsions, especially in combination with high dose methylprednisolone, encephalopathy, anxiety, headache, and fever.
• Cancer. There is an increased risk of developing skin and lymphoproliferative cancers in cyclosporine-treated psoriasis patients. Increase in the occurrence of malignant lymphomas.
• Increase the level of inflammatory cytokines such as TNF-alfa.
• Increase the risk of infection risk ³²⁾, ³³⁾, ³⁴⁾.

Cyclosporine may cause other side effects. Talk to your doctor if you experience unusual problems while taking cyclosporine.

Cyclosporine overdose

Cyclosporine overdose symptoms may include:

• vomiting
• drowsiness
• headache
• fast heart beat
• yellowing of the skin or eyes
• swelling of the arms, hands, feet, ankles, or lower legs.

In the event of Cyclosporin overdose, establishing a patent airway is a priority. There is a need to watch for signs of respiratory insufficiency and provide ventilation assistance if needed. Also, the healthcare provider needs to monitor for shock and treat if necessary. They should anticipate seizures and treat if necessary, and initiate supportive and symptomatic treatment. When overdosage occurs in patients prescribed cyclosporine A therapy, the healthcare provider may withhold the drug for a few days or initiate alternate-day therapy until the patient stabilizes ³⁵⁾.

Hemodialysis only eliminates 1% of the Cyclosporin dose. Monitoring serum Cyclosporin A levels is mandatory, and patients may need multiple dose adjustments during the treatment period. The central venous catheter (CVC) line is not used to infuse cyclosporine A and can be safely used to collect blood samples for serum cyclosporin A levels. The procedure can be performed immediately after interrupting the infusion if using the appropriate technique for discarding 5 mL of blood.

Azathioprine

Azathioprine also known as Imuran or Azasan is an immunosuppressant or a drug that weakens your body’s immune system in order to help keep it from “rejecting” a transplanted organ such as a kidney ¹⁾. Organ rejection happens when your immune system treats the new organ as an invader and attacks it. Azathioprine is used with other medications to prevent transplant rejection (attack of the transplanted organ by your immune system) in people who received kidney transplants. Azathioprine is also used as a disease-modifying antirheumatic drug (DMARD) or immunomodulator to treat autoimmune conditions such as severe rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function), Crohn’s disease, ulcerative colitis and autoimmune hepatitis when other medications and treatments have not helped ²⁾, ³⁾.

Azathioprine was introduced into use in the early 1960s and represented a major breakthrough in the development of organ rejection therapy, allowing for more widespread and successful use of kidney, heart and liver transplantation. Azathioprine was approved for use in the United States in 1968 and is still widely used in organ transplantation and in treatment of  autoimmune conditions.

Azathioprine comes as a tablet 50, 75 and 100 mg to be taken by mouth; a parenteral formulation is also available. Azathioprine is usually taken once or twice a day after meals. The usual Azathioprine dose is 1 to 3 mg/kg of body weight or 50 to 150 mg daily and it is typically given long term. Take azathioprine at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take azathioprine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are taking azathioprine to treat rheumatoid arthritis, your doctor may start you on a low dose and gradually increase your dose after 6-8 weeks and then not more than once every 4 weeks. Your doctor may gradually decrease your dose when your condition is controlled. If you are taking azathioprine to prevent kidney transplant rejection, your doctor may start you on a high dose and decrease your dose gradually as your body adjusts to the transplant.

Azathioprine controls rheumatoid arthritis but does not cure it. It may take up to 12 weeks before you feel the full benefit of azathioprine. Azathioprine prevents transplant rejection only as long as you are taking the medication. Continue to take azathioprine even if you feel well. Do not stop taking azathioprine without talking to your doctor.

Azathioprine usually requires 6 to 8 weeks to work. The recommendation is to consider stopping Azathioprine if there is no improvement in 3 months ⁴⁾. Checking thiopurine S-methyltransferase (TPMT) activity is suggested before starting azathioprine. Thiopurine S-methyltransferase (TPMT) deficiency is a condition characterized by significantly reduced activity of thiopurine S-methyltransferase (TPMT) enzyme that helps the body process drugs called thiopurines, which include 6-thioguanine, 6-mercaptopurine, and azathioprine ⁵⁾. A potential complication of treatment with thiopurine drugs is damage to the bone marrow (hematopoietic toxicity). Although this complication can occur in anyone who takes these drugs, people with thiopurine S-methyltransferase (TPMT) deficiency are at highest risk. Bone marrow normally makes several types of blood cells, including red blood cells, which carry oxygen; white blood cells, which help protect the body from infection; and platelets, which are involved in blood clotting. Damage to the bone marrow results in myelosuppression, a condition in which the bone marrow is unable to make enough of these cells. A shortage of red blood cells (anemia) can cause pale skin (pallor), weakness, shortness of breath, and extreme tiredness (fatigue). Low numbers of white blood cells (neutropenia) can lead to frequent and potentially life-threatening infections. A shortage of platelets (thrombocytopenia) can cause easy bruising and bleeding.

Many doctors recommend that patients’ TPMT activity levels be tested before Azathioprine is prescribed. In people who are found to have reduced TPMT enzyme activity, thiopurine drugs may be given at a significantly lower dose or different medications can be used to reduce the risk of hematopoietic toxicity. Misclassification of TMPT phenotype can occur by prior blood transfusion ⁶⁾.

TPMT deficiency does not appear to cause any health problems other than those associated with thiopurine drug treatment ⁷⁾.

Azathioprine common side effects include nausea, abdominal upset, rash, aphthous ulcers and dose related bone marrow suppression. Long term use of azathioprine is associated with an increased risk of certain types of cancer, especially skin cancer and lymphoma and possibly liver carcinoma.

Azathioprine special precautions

Before taking azathioprine:

• tell your doctor and pharmacist if you are allergic to azathioprine, any other medications, or any of the ingredients in azathioprine tablets. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications mentioned in the IMPORTANT WARNING section and any of the following: allopurinol (Zyloprim); aminosalicylates such as mesalamine (Apriso, Asacol, Pentasa, others), olsalazine (Dipentum), and sulfasalazine (Azulfidine); and anticoagulants (‘blood thinners’) such as warfarin (Coumadin). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have any type of infection, or if you have or have ever had kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use birth control to be sure you or your partner will not become pregnant while you are taking azathioprine. Call your doctor if you or your partner become pregnant while you are taking azathioprine. Azathioprine may harm the fetus.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking azathioprine.
• do not have any vaccinations during or after your treatment without talking to your doctor.

Test patient for hepatitis B and C and Tuberculin Skin Test (Mantoux Test) for diagnosis of silent (latent) tuberculosis (TB) infection. A pregnancy test before azathioprine treatment initiation is also a recommendation ⁸⁾.

Azathioprine contraindications

Azathioprine contraindications include ⁹⁾, ¹⁰⁾, ¹¹⁾, ¹²⁾, ¹³⁾:

• Hypersensitivity
• Pregnancy or plan for pregnancy: Contraception recommended. azathioprine can increase the risk of spontaneous miscarriage, low birth weight, and preterm delivery. Although data in systemic lupus erythematosus (SLE) and renal transplant patients showed safety in pregnancy. In some specific conditions like SLE and antiphospholipid antibody syndrome, the benefits of taking immunosuppressive medications are more than harms in keeping the mother safe.
• Breastfeeding as mercaptopurine (6-MP) was present in breast-milk of women who take azathioprine
• Unknown thiopurine S-methyltransferase (TPMT) status or deficient thiopurine S-methyltransferase (TPMT) activity due to the high risk of myelosuppression ¹⁴⁾
• Known malignancy
• Clinically active infection

Azathioprine relative contraindications ¹⁵⁾:

• Allopurinol intake concomitantly with azathioprine due to severe myelosuppression
• Cyclophosphamide or chlorambucil treatment in the past.

Azathioprine drug interactions

Tell your doctor about all your current medicines. Many drugs can affect azathioprine, especially:

• Allopurinol
• Febuxostat
• Ribavirin.

This list is not complete and many other drugs may affect azathioprine. This includes prescription and over-the-counter medicines, vitamins, and herbal products.

How does azathioprine work?

Azathioprine is a purine analog and prodrug (a pharmacologically inactive medication that metabolizes inside the body and converts into a pharmacologically active drug compound) that converts to its active metabolites, mercaptopurine (6-MP) and thioguanine (6-TGN), by the action of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT) enzymes ¹⁶⁾. Azathioprine then blocks purine synthesis thus inhibiting DNA, RNA and subsequent protein synthesis ¹⁷⁾. Azathioprine metabolites are incorporated into the replicating DNA and halt cell division. Azathioprine metabolites inhibit the maturation of T cells (T  lymphocytes) and blocks delayed hypersensitivity reactions; it also has antiinflammatory activity.

Azathioprine works by decreasing the activity of the body’s immune system so it will not attack the transplanted organ or the joints.

Azathioprine is absorbed rapidly through the gastrointestinal system and does not penetrate the blood-brain barrier. Azathioprine undergoes metabolism in the liver, and excretion is via the kidneys, which increases its toxicity in kidney failure ¹⁸⁾.

Azathioprine uses

Azathioprine (Imuran or Azasan) is approved by the U.S. Food and Drug Administration (FDA) for the symptomatic treatment of active rheumatoid arthritis as a corticosteroid sparing agent. Azathioprine also has approval as add-on therapy for the prevention of kidney transplant rejection ¹⁹⁾, ²⁰⁾.

Azathioprine (Imuran or Azasan) is also used off-label for the treatment of inflammatory bowel disease (Crohn’s disease & ulcerative colitis) ²¹⁾, Churg-Strauss syndrome, autoimmune hepatitis (for maintenance treatment along with steroids) ²²⁾, ²³⁾, chronic immune thrombocytopenic purpura (rare autoimmune disorder that causes you to have low platelet levels) as second-line agent) ²⁴⁾, lupus glomerulonephritis ²⁵⁾, fibrotic connective tissue disease-associated interstitial lung disease ²⁶⁾, multiple sclerosis, severe myasthenia gravis, recurrent pericarditis ²⁷⁾, psoriasis, non-infectious uveitis ²⁸⁾, relapsing polychondritis (a very rare autoimmune disease characterized by a relapsing inflammation of the cartilaginous tissues such as joints, ears, nose, intervertebral discs, larynx, trachea and cartilaginous bronchi) ²⁹⁾, dermatomyositis/polymyositis, erythema multiforme, severe and refractory atopic dermatitis, chronic actinic dermatitis, pyoderma gangrenosum, Behcet disease, cutaneous vasculitis, pityriasis rubra pilaris, lichen planus, bullous pemphigoid, and pemphigus vulgaris ³⁰⁾, ³¹⁾. Azathioprine or mercaptopurine (6-MP) are treatment options in children with Crohn’s disease as a maintenance treatment ³²⁾. Azathioprine is also used to treat ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum) and Crohn’s disease.

Azathioprine dosage

The starting dose for azathioprine is 2 to 2.5 mg/kg of body weight per day, except for patients with TPMT or NUDT15 gene mutation, in which the starting dose is lower than normal ³³⁾. Azathioprine dose adjustments are necessary for liver and kidney disease ³⁴⁾.

Azathioprine tablets may be administered after meals to decrease gastrointestinal adverse effects. Administration can be by intravenous (IV) push over 5 minutes, at a concentration not exceeding 5 mg/ml. Azathioprine can be further diluted with normal saline or dextrose 5% in water and administered by intermittent infusion over 30 to 60 minutes. However, it may also be infused over 5 minutes up to over 8 hours.

Adult dose for kidney transplant

Use: Adjunctive therapy for prevention of rejection in renal homotransplantation.

• Initial dose: Azathioprine 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
• Maintenance dose: Azathioprine 1 to 3 mg/kg orally or IV once a day

Comments:

• In a minority of cases, Azathioprine therapy has been started 1 to 3 days before transplantation
• Azathioprine dose should not be increased to toxic levels because of threatened rejection

Adult dose for rheumatoid arthritis

• Initial dose: 1 mg/kg (50 to 100 mg) orally or IV per day given in 1 to 2 divided doses
• Maintenance dose: Lowest effective dose
• Maximum dose: 2.5 mg/kg orally or IV per day
• Duration: At least 12 weeks

Comments:

• Azathioprine dose may be increased by 0.5 mg/kg/day (or approximately 25 mg/day), after 6 to 8 weeks of starting treatment and thereafter at 4 week intervals if necessary.
• Gradual dose reduction is recommended to reduce the risk of toxicities.
• Therapeutic response occurs after several weeks of therapy, usually 6 to 8 weeks. Patients not improved after 12 weeks can be considered refractory.
• Azathioprine may be continued long-term in patients with clinical response.

Adult dose for Acute Crohn’s disease

• Azathioprine dose 1.5 to 4 mg/kg per day for 10 days up to 52 weeks

Adult dose for Maintenance Crohn’s disease

• Azathioprine dose 1.5 to 4 mg/kg per day for 10 days up to 52 weeks

Adult dose for Ulcerative Colitis

Study (n=9)

• IV: Azathioprine dose 20 to 40 mg/kg via IV infusion over 36 hours or 40 mg/kg as three 8-hour infusions over 3 days followed by oral azathioprine
• Oral: Azathioprine dose 2 mg/kg orally per day beginning the day after completion of the IV loading dose

Study (n=12)

• Azathioprine dose 50 mg per day for 2 weeks, then 2 to 2.5 mg/kg per day plus mesalamine 500 mg orally 3 times a day; these drugs were started immediately after signs of remission was achieved (mean: 14.5 days) with cyclosporine IV (4 mg/kg/day)

Adult dose for Chronic Inflammatory Demyelinating Polyradiculoneuropathy

• Study (n=14): Azathioprine dose 2 to 3 mg/kg orally once a day for 9 months

Adult dose for Atopic Dermatitis

• Study (n=37): Azathioprine dose 2.5 mg/kg orally once a day, in the morning, for 3 months

Adult dose for Sarcoidosis

Study (n=11)

• Initial dose: Azathioprine dose 2 mg/kg per day in combination with prednisolone 0.6 to 0.8 mg/kg per day, with prednisolone reduced to 0.1 mg/kg within 2 to 3 months
• Maintenance dose: Azathioprine dose 2 mg/kg per day with prednisolone 0.1 mg/kg per day for 21 to 22 months

Adult dose for Uveitis

Study (n=14)

• Treatment of choroidal neovascularization: Azathioprine dose 1 to 1.5 mg/kg orally per day, in combination with prednisolone and cyclosporine

Adult dose for Multiple Sclerosis

Study (n=6)

Patients refractory to interferon beta-1b:

• Initial dose: Azathioprine should be titrated up to 1.5 mg/kg per day over 1 month, followed by 50 mg increments in 6-month intervals, concomitantly with 8 million international units subcutaneous interferon beta-1b on alternate days
• Maintenance dose: Azathioprine dose 2 mg/kg per day

Adult dose for Systemic Lupus Erythematosus (SLE)

Studies: Azathioprine dose 1 to 3 mg/kg actual body weight/day orally or IV once a day

Study (n=55)

• Diffuse proliferative lupus glomerulonephritis: Sequential therapy starting with prednisone (1 mg/kg/day) for 8 to 10 weeks, gradually tapering to maintenance dosage of 5 to 10 mg/day, together with oral cyclophosphamide (1 to 2 mg/kg/day) for 6 to 9 months followed by azathioprine 50 to 100 mg/day

Adult dose for Chronic Active Hepatitis

Study (n=72)

• Autoimmune hepatitis: Azathioprine dose 1 to 2 mg/kg per day, concomitantly with prednisolone (5 to 15 mg/day) for a minimum of 1 year (average 5 years)

Adult dose for Takayasu’s Arteritis

Study (n=15): Azathioprine dose2 mg/kg actual body weight/day for 1 year in combination with prednisolone taper

Children dose for Atopic Dermatitis

Study (n=37)

• Greater than 17 years: Azathioprine dose 2.5 mg/kg orally once a day, in the morning, for 3 months

Children dose for Organ Transplant (Rejection Prevention)

• Initial dose: Azathioprine dose 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
• Maintenance dose: Azathioprine dose 1 to 3 mg/kg orally or IV once a day

Children dose for Eczema

Study (n=91)

• Greater than 6 years: Azathioprine dose 2.5 to 3.5 mg/kg per day in patients with normal levels of thiopurine methyltransferase

Children dose for Systemic Lupus Erythematosus (SLE)

Case Study (n=67)

Lupus Nephritis:

• Greater than 5 years: Azathioprine dose 2 to 3 mg/kg per day (maximum dose: 150 mg/day)
• Dose should be titrated to maintain a total white blood cell count between 3 and 4 x 10(3) cells/mL.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Azathioprine side effects

Azathioprine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away.

Azathioprine common side effects include the following ³⁵⁾, ³⁶⁾, ³⁷⁾, ³⁸⁾, ³⁹⁾, ⁴⁰⁾, ⁴¹⁾, ⁴²⁾, ⁴³⁾, ⁴⁴⁾, ⁴⁵⁾, ⁴⁶⁾:

• Nausea; is the most frequent side effect
  • Dose-dependent.
  • Early-onset nausea usually resolves without dose alteration
• Fever
• Fatigue
• Joint aches and pain (arthralgias) and muscle aches & pain (myalgia)
• Bone marrow suppression causing pancytopenia, thrombocytopenia, leukopenia – there are reports of dose-dependent, life-threatening cases.
  • This complication correlates with the thioguanine (6-TGN) level
  • There is a higher risk of myelosuppression in patients who take allopurinol or angiotensin-converting enzyme inhibitors (ACEIs) and in kidney disease
  • An increase in the mean corpuscular volume of the red blood cells is also an expected side effect
• Rash
• Liver injury: Liver injury correlates with a 6-mercaptopurine (6-MP) level of more than 5700 pmol/8 x 10⁸ red blood cell.
  • Liver injury categorizes into two groups.
    • Acute idiosyncratic liver injury happens in the early course and resolves with stopping the medication.
    • Nodular regenerative hyperplasia occurs in inflammatory bowel disease and organ transplant patients several years after therapy.
• Infections (7.4%): Concomitant use of azathioprine and steroids will increase the risk of Pneumocystis pneumonia (PCP, a serious infection caused by the fungus Pneumocystis jirovecii) in leukopenic patients.
• Hypersensitivity: symptoms including fever, chills, arthralgia/myalgia, liver abnormalities, erythema nodosum
• Kidney damage

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, see your doctor immediately.

• • rash
  • fever
  • weakness
  • muscle pain

Complete blood count (CBC) and liver function test (LFT) monitoring weekly are recommended initially for the first 4 to 8 weeks. Complete blood count (CBC) and liver function test (LFT) should get checked every three months for the rest of the treatment once the maintenance dose is achieved. However, it is advisable to check CBC and LFT more frequently in patients with kidney or liver diseases or elderly patients on high dosages of azathioprine or low TPMT activity. If labs show leukopenia (WBC less than 3 x 10⁹/L), thrombocytopenia (platelet less than 120 x 10⁹/L), or transaminitis (liver biochemistry more than half of the normal upper limit), the medication should be stopped ⁴⁷⁾.

If patients have abdominal pain or severe nausea/vomiting, serum amylase is required to rule out pancreatitis. Lymph node and skin examination should be performed biannually ⁴⁸⁾. If a generalized wart occurs, the azathioprine dose should be reduced or switched to another agent.

Some studies suggested monitoring the level of azathioprine metabolites (e.g., 6-TGN and 6-MP) to avoid specific complications ⁴⁹⁾.

Azathioprine rare side effects include ⁵⁰⁾, ⁵¹⁾, ⁵²⁾, ⁵³⁾, ⁵⁴⁾, ⁵⁵⁾, ⁵⁶⁾, ⁵⁷⁾:

• Diarrhea
• Carcer: cutaneous hyperkeratosis and nonmelanoma skin cancer (squamous cell carcinoma [SCC]) in myasthenia gravis (most likely due to increased risk of photosensitivity), solid-organ transplant and IBD patients/ lymphoma in transplant and inflammatory bowel disease (IBD) patients
• Pancreatitis (3.3%): more in females with Crohn disease
  • Dose-dependent
  • Usually happens in the first six weeks
  • In the case of pancreatitis, discontinue azathioprine
• Alopecia including telogen effluvium, anagen effluvium, and plica neuropathica
• Macrocytic anemia
• Sweet syndrome (acute febrile neutrophilic dermatosis)
• Pneumonitis: in inflammatory bowel disease (IBD) and kidney transplant patients
• Upper airway edema
• Tremor: in organ transplant and Crohn patient: dose-dependent

In cases of hepatic sinusoidal obstruction syndrome, azathioprine must be discontinued permanently. If severely leukopenic, thrombocytopenic, or infected, azathioprine treatment should stop.

Azathioprine may cause other side effects. Call your doctor if you have any unusual problems while you are taking azathioprine.

Azathioprine overdose

Azathioprine overdose symptoms may include the following:

• nausea
• vomiting
• diarrhea
• sore throat, fever, chills, and other signs of infection

Azathioprine overdose symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity and bone marrow suppression (myelosuppression) ⁵⁸⁾. Azathioprine overdose usually happens when more than 1.5 times of daily dose is taken by the patient.

In the acute azathioprine overdose setting, activated charcoal may help with decreasing the symptoms within two hours of ingestion ⁵⁹⁾. No specific antidote is known for azathioprine. In severe cases of azathioprine overdose, dialysis is permissible as azathioprine is dialysable.

Tiagabine

Tiagabine also called Gabitril is an anti-epileptic medication or anticonvulsant that is used in combination with other medications to treat partial seizures (a type of epilepsy) in adults and children who are at least 12 years old ¹⁾, ²⁾, ³⁾. Tiagabine is occasionally used off-label to treat anxiety disorders and neuropathic pain.

It is not known exactly how Tiagabine (Gabitril) works, but it increases the amount of natural chemical in your brain called gamma aminobutyric acid (GABA) that prevent seizure activity ⁴⁾, ⁵⁾.

Tiagabine is available in tablets of 2, 4, 12 and 16 mg to be taken by mouth. Tiagabine usually is taken with food two to four times a day. However, for the first week of treatment you will only take tiagabine once a day. The recommended initial dose in adults is 4 mg once daily, increasing by 4 to 8 mg at weekly intervals based upon clinical response, but not exceeding 56 mg daily. Your doctor will slowly increase your dose (not more often than once each week) until you reach the dose of tiagabine you are to take regularly. To help you remember to take tiagabine, take it around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tiagabine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Continue to take tiagabine even if you feel well. Do not stop taking tiagabine without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. Abruptly stopping this medication can cause seizures. Your doctor will probably decrease your dose gradually.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with tiagabine and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions.

Tiagabine most common side effects are dose related and include dizziness, somnolence, impaired concentration, nervousness, nausea, weakness and tremor.

Tiagabine may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Drinking alcohol with Tiagabine can cause side effects.

Tiagabine special precautions

Before taking tiagabine:

• tell your doctor and pharmacist if you are allergic to tiagabine or any other medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: amiodarone (Cordarone, Pacerone);anticonvulsants such as carbamazepine (Tegretol), ethosuximide (Zarontin), gabapentin (Neurontin), lamotrigine (Lamictal), phenobarbital (Luminal, Solfoton), phenytoin (Dilantin, Phenytek), primidone (Mysoline), and valproic acid (Depakene, Depakote); anticholinesterases such as neostigmine (Prostigmin), physostigmine (Antilirium), and pyridostigmine (Mestinon, Regonol); antidepressants; antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral); chloroquine sulfate (Aralen); clarithromycin (Biaxin, in Prevpac); contrast dyes used during radiology procedures (CAT scans, X-rays); cyclosporine (Neoral, Sandimmune); dexamethasone (Decadron, Dexpak); diazepam (Valium); dicloxacillin; diltiazem (Cardizem, Dilacor, Tiazac, others); erythromycin (E.E.S., E-Mycin, Erythrocin); furosemide (Lasix); griseofulvin (Fulvicin-U/F, Grifulvin V, Gris-PEG); isoniazid (INH, Laniazid, Nydrazid); imipenem-cilastatin (Primaxin); lovastatin (Altocor, Mevacor, in Advicor); medications to treat HIV infection including delavirdine (Rescriptor), efavirenz (Sustiva), nevirapine (Viramune), and ritonavir (Norvir, in Kaletra); medications that may make you drowsy such as cough, cold, and allergy products, medications for anxiety, muscle relaxants, pain medications, sedatives, sleeping pills, or tranquilizers; medications for mental illness; methocarbamol (Robaxin); mycophenolate mofetil (CellCept); penicillins; phenylbutazone (no longer available in the US);propranolol (Inderal, Inderide); quinidine (Quinidex); quinolones such as cinoxacin (Cinobac) (no longer available in the US), ciprofloxacin (Cipro), enoxacin (Penetrex) (no longer available in the US), gatifloxacin (Tequin), levofloxacin (Levaquin), lomefloxacin (Maxequin), nalidixic acid (NegGram) (no longer available in the US), norfloxacin (Noroxin), ofloxacin (Floxin), sparfloxacin (Zagam) and trovafloxacin/alatrofloxacin combination (Trovan) (no longer available in the US); rifabutin (Mycobutin ); rifampin (Rifadin, Rifamate, Rimactane, others); stimulants such as caffeine-containing products and decongestants; tacrolimus (Prograf); triazolam (Halcion); troleandomycin (TAO); verapamil (Calan, Covera, Isoptin, Verelan); warfarin (Coumadin); or zafirlukast (Accolate).
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have or have ever had a severe rash caused by taking a medication; status epilepticus (seizures following one another without a break); or eye or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking tiagabine, call your doctor immediately.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tiagabine.
• you should know that tiagabine may make you drowsy and may affect your ability to think clearly. Do not drive a car or operate machinery until you know how this drug will affect you.
• remember that alcohol may add to the drowsiness caused by this medication. Ask your doctor about the safe use of alcoholic beverages while you are taking tiagabine.
• you should know that seizures, including status epilepticus, have occurred in people without epilepsy who take tiagabine. These seizures usually occurred soon after beginning treatment with tiagabine or near the time of a dose increase, but also have also occurred at other times during treatment.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking tiagabine for the treatment of epilepsy, mental illness, or other conditions. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as tiagabine to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as tiagabine, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Breastfeeding women

Because there is very limited published experience with tiagabine during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant ⁶⁾. Doctors and mothers are advised to monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsant or psychotropic drugs.

No adverse effects were reported in 10 newborns who were 4 to 23 days old who were breastfed during maternal intake of levetiracetam 1000 to 3000 mg daily. One mother was also taking tiagabine 30 mg daily, clobazam 45 mg daily and oxcarbazepine 600 mg daily ⁷⁾.

Drug interactions

Taking Tiagabine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking tiagabine with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• medicine to treat a psychiatric disorder
• diet pills, stimulants, or ADHD medication
• narcotic medicine
• other seizure medicines–carbamazepine, phenytoin, phenobarbital, primidone, valproate.

This list is not complete. Other drugs may interact with tiagabine, including prescription and over-the-counter medicines, vitamins, and herbal products.

How does tiagabine work?

Tiagabine (Gabitril) is a selective gamma aminobutyric acid (GABA) reuptake inhibitor that selectively and specifically inhibits the uptake of gamma aminobutyric acid (GABA) into astrocytes and neurones, by the transporter GAT-1, and therefore increases the extracellular concentration of GABA in the brain, which decreases the spread of abnormal neuronal impulses that contribute to seizures ⁸⁾, ⁹⁾, ¹⁰⁾, ¹¹⁾, ¹²⁾, ¹³⁾, ¹⁴⁾, ¹⁵⁾.

Tiagabine has been shown to be effective both as single drug therapy and in combination with other anticonvulsants for partial seizures.

Tiagabine uses

Tiagabine was approved for use in epilepsy in the United States in 1997 and is currently used predominantly as add-on therapy with other major anticonvulsants for partial seizures. Tiagabine is also used off-label to treat anxiety disorders and neuropathic pain (nerve pain) ¹⁶⁾, ¹⁷⁾. Tiagabine has also been investigated for its effect on alcohol withdrawal symptoms ¹⁸⁾, ¹⁹⁾, anxiety disorders ²⁰⁾, ²¹⁾, ²²⁾ and depression ²³⁾.

Tiagabine dosage

The recommended initial tiagabine dose in adults is 4 mg once daily, increasing by 4 to 8 mg at weekly intervals based upon clinical response, but not exceeding 56 mg daily. Your doctor will slowly increase your dose (not more often than once each week) until you reach the dose of tiagabine you are to take regularly. To help you remember to take tiagabine, take it around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tiagabine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Tiagabine is often given in combination with other medications. Your dose of tiagabine may need to be changed if you start or stop using other seizure medicines.

Follow your doctor’s dosing instructions very carefully.

Take tiagabine with food.

Your doctor will need to check your progress while you are using tiagabine. To make sure you are taking a safe dose of tiagabine, your blood may need to be tested on a regular basis.

Use tiagabine regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Wear a medical alert tag or carry an ID card stating that you take tiagabine. Any medical care provider who treats you should know that you take seizure medication.

Do not stop using tiagabine suddenly, even if you feel fine. Stopping suddenly may cause increased seizures. Follow your doctor’s instructions about tapering your dose.

Store at room temperature away from moisture, heat, and light.

Adult dose for epilepsy

Use: As add-on therapy in the treatment of partial seizures

• Initial dose: Tiagabine 4 mg orally once a day; modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated
• Titration: The total daily Tiagabine dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day; the total daily dose should be given in divided doses 2 to 4 times a day
• Maximum dose: 56 mg/day (in 2 to 4 divided doses)

Comments:

• Tiagabine should be taken with food.
• Do not use a loading dose.
• Rapid escalation and/or large dose increments should not be used.
• If a scheduled dose is missed, the patient should not make up for the missed dose by increasing the next dose; if several doses are missed, retitration may be required.
• Dosage adjustment may be needed whenever a change in the patient enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent.

Adult dose for partial seizures

Use: Use as add-on therapy in the treatment of partial seizures

• Initial dose: Tiagabine 4 mg orally once a day; modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated
• Titration: The total daily Tiagabine dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day; the total daily dose should be given in divided doses 2 to 4 times a day
• Maximum dose: 56 mg/day (in 2 to 4 divided doses)

Comments:

• Tiagabine should be taken with food.
• Do not use a loading dose.
• Rapid escalation and/or large dose increments should not be used.
• If a scheduled dose is missed, the patient should not make up for the missed dose by increasing the next dose; if several doses are missed, retitration may be required.
• Dosage adjustment may be needed whenever a change in the patient enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent.

Children dose for partial seizures

Use: Use as add-on therapy in children 12 years and older in the treatment of partial seizures

• Initial dose: Tiagabine 4 mg orally once a day; modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated
• Titration: The total daily Tiagabine dose may be increased by 4 mg at the beginning of Week 2; thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day (in divided doses 2 to 4 times a day); doses above 32 mg/day have been tolerated in a small number of adolescent patients for a relatively short duration.

Comments:

• Tiagabine should be taken with food.
• Do not use a loading dose.
• Rapid escalation and/or large dose increments should not be used.
• If a scheduled dose is missed, the patient should not make up for the missed dose by increasing the next dose; if several doses are missed, retitration may be required.
• Dosage adjustment may be needed whenever a change in the patient enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. If you have missed more than one dose, call your doctor for instructions about re-starting your medication.

Tiagabine side effects

Tiagabine may cause side effects. See your doctor if any of these symptoms are severe or do not go away:

• dizziness or lightheadedness
• drowsiness
• lack of energy or weakness
• wobbliness, unsteadiness, or incoordination causing difficulty walking
• depression
• hostility or anger
• irritability
• confusion
• difficulty concentrating or paying attention
• abnormal thinking
• speech or language problems
• increased appetite
• nausea
• stomach pain
• nervousness
• difficulty falling asleep or staying asleep
• itching
• bruising
• painful or frequent urination

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them, see your doctor immediately:

• rash
• sores on the inside of your mouth, nose, eyes or throat
• flu-like symptoms
• changes in vision
• severe weakness
• shaking hands you cannot control
• numbness, pain, burning, or tingling in the hands or feet
• seizures, including status epilepticus

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Tiagabine overdose

Tiagabine overdose symptoms may include:

• tiredness
• weakness
• wobbliness, unsteadiness, or incoordination causing difficulty walking
• shaking hands you cannot control
• confusion
• speech or language problems
• agitation
• anger or hostility
• depression
• vomiting
• loss of consciousness
• abnormal, uncontrollable muscle contractions
• temporary inability to move (paralysis)
• seizures, including status epilepticus.

In the case of Tiagabine overdose seek emergency medical attention or call your local emergency services number.

Vigabatrin

Vigabatrin marketed under the brand name Sabril or Vigadrone is an antiepileptic or anticonvulsant medication used to treat refractory complex partial seizures and infantile spasms (a type of seizure that babies and children can have) ¹⁾. Vigabatrin is thought to work by decreasing abnormal electrical activity in your brain and calming it. Vigabatrin does this by increasing the amount of an inhibitory neurotransmitter (chemical messenger) called GABA (gamma aminobutyric acid) in your brain. Vigabatrin acts as a competitive inhibitor of GABA transaminase (GABA-T) enzyme, which helps to break down GABA (gamma-aminobutyric acid) when it is not needed. Vigabatrin works by blocking the GABA transaminase (GABA-T) enzyme to increase the amount of GABA in your central nervous system (brain and spinal cord) and may increase GABAergic, neuroinhibitory activity.

Vigabatrin has been shown to be effective in reducing seizure activity as add on therapy in patients with refractory partial onset seizures. Vigabatrin was first approved in the United Kingdom in 1989 as an add-on therapy of adult patients with refractory complex partial seizures and as a treatment for patients with infantile spasms ²⁾, ³⁾. However, due to the increased incidence of peripheral vision loss in patients on vigabatrin, health experts raised concerns about Vigabatrin safety in 1997 despite its effectiveness. Finally, in 2009, after a series of studies, the US Food and Drug Administration (FDA) approved vigabatrin for the treatment of infantile spasms as a single drug (monotherapy) and refractory complex partial seizures as an add-on therapy (adjunctive therapy) to other anti-epileptic drugs ⁴⁾, ⁵⁾. Given Vigabatrin’s potential risks of permanent vision loss or blindness, the approval comes with “IMPORTANT WARNING” ⁶⁾. Vigabatrin can damage the vision of anyone who takes it. Some people can have severe loss particularly to their ability to see to the side when they look straight ahead (peripheral vision). With severe vision loss, you may only be able to see things straight in front of you sometimes called “tunnel vision”. You may also have blurry vision. If this happens, it will not get better. Your healthcare provider should monitor your vision periodically and check for signs and symptoms of anemia.

Because of the risk of vision loss, Vigabatrin is used to treat complex partial seizures only in people who do not respond well enough to several other medicines. Current Vigabatrin indications include as add-on therapy (adjunctive therapy) in patients with refractory complex partial seizures and as a single drug for infantile spasms in children ages 1 month to 2 years ⁷⁾, ⁸⁾.

Vigabatrin is available in tablets of 500 mg to be taken by mouth and as a powder to be mixed with water for oral solution and are used in combination with other medications to control certain types of seizures in adults and children 10 years of age or older whose seizures were not controlled by several other medications. The typical initial Vigabatrin dose is 500 mg twice daily with or without food, with subsequent increases to a recommended average dose of 3000 mg daily in adults and 2000 mg in children 10 to 16 years of age. Vigabatrin powder is used to control infantile spasms in babies 1 month to 2 years of age. Doses for children with infantile spasms are weight based.

Take vigabatrin at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take vigabatrin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will probably start you on a low dose of vigabatrin and gradually increase your dose, not more often than once every 3 days for babies receiving the powder mixed with water and once a week for adults taking tablets.

Vigabatrin may help control your condition but will not cure it. Continue to take vigabatrin even if you feel well. Do not stop taking vigabatrin without talking to your doctor. If you suddenly stop taking vigabatrin, your seizures may happen more often. Your doctor will probably decrease your dose gradually, not more often than once every 3-4 days for babies receiving the powder mixed with water and once a week for adults taking tablets. Tell your doctor immediately if your seizures happen more often while you are stopping vigabatrin.

If you are taking the powder, you must mix it with cold or room temperature water immediately before taking it. Do not mix the powder with any other liquid or food. The doctor will tell you how many packets of vigabatrin powder to use and how much water to mix it with. The doctor will also tell you how much of the mixture to take for each dose. Do not use a household spoon to measure your dose. Use the oral syringe that came with the medication. Carefully read the manufacturer’s instructions that describe how to mix and take a dose of vigabatrin. Be sure to ask your pharmacist or doctor if you have any questions about how to mix or take this medication.

Talk to the doctor about what to do if your baby vomits, spits up, or only takes part of the dose of vigabatrin.

Vigabatrin side effects may include fatigue, somnolence, nystagmus, tremor, blurred vision, memory impairment, mood changes, confusion and weight gain. Rare, but severe adverse events include visual loss, visual field constriction and retinal dysfunction, for which reason vigabatrin is available only through a restricted program that requires prospective ophthalmologic monitoring. Vigabatrin has been linked to a fatal case of Reye syndrome in a child with severe developmental delay.

Vigabatrin special precautions

Before taking vigabatrin:

• tell your doctor and pharmacist if you are allergic to vigabatrin, any other medications, or any of the ingredients in vigabatrin tablets or powder. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention either of the following: clonazepam (Klonopin) or phenytoin (Dilantin, Phenytek). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with vigabatrin, so be sure to tell your doctor about all the medications you are taking, even those that do not appear here.
• tell your doctor if you have or have ever had kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking vigabatrin, call your doctor.
• you should know that vigabatrin may make you drowsy or tired. Do not drive a car or operate machinery until you know how this medication affects you. If your vision is damaged by vigabatrin, talk with your doctor about whether or not you can drive safely.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking vigabatrin. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants like vigabatrin to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as 1 week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as vigabatrin, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling asleep or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); thinking about or trying to hurt yourself or end your life; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.
• you should know that in some babies that have taken vigabatrin there were changes in pictures of the brain taken by magnetic resonance imaging (MRI). These changes were not seen in older children or adults. Usually these changes went away when treatment was stopped. It is not known if these changes are harmful.

Pregnant Women

Vigabatrin is considered as pregnancy category C medicine. Due to its potential to cause permanent vision loss, Vigabatrin should start with caution after carefully evaluating risk-benefit analysis.

Researchers conducted a study to determine the possible teratogenicity of vigabatrin. It involved the injection of either a low dose (350 mg/kg) or a high dose (450 mg/kg) of vigabatrin intraperitoneally in pregnant mice. This intervention resulted in a fetal loss in the high-dose group and severe intrauterine growth restriction. Folate and B12 levels fell to half in both treatment groups. This outcome raises concern for neural tube defects making pregnancy a possible contraindication to vigabatrin ⁹⁾. There are no specific contraindications listed in the manufacturer labels.

Breastfeeding Women

Small amount of Vigabatrin is present in milk for dose up to 2000 mg ¹⁰⁾. Until more information is available, vigabatrin therapy should be used with caution in breastfeeding women ¹¹⁾. However, vigabatrin is approved for use in infants in one month and older and amounts in milk are far less than the approved infant dosage. Vigabatrin would not be expected to cause any adverse effects in breastfed infants.

Two nursing mothers were each receiving vigabatrin 1000 mg twice daily. One was also taking slow-release carbamazepine 200 mg twice daily. Milk samples were collected once predose and 3 and 6 hours after the dose at either 6 or 8 days postpartum. In both mothers, the inactive R-isomer was excreted into milk in higher concentrations than the active S-isomer. In the 2 mothers, average concentrations of the R-isomer were 1.7 mg/L in the predose sample, 2.1 mg/L at 3 hours and 3.1 mg/L at 6 hours after the dose. Average concentrations of the S-isomer were 0.4 mg/L in the predose sample, 0.4 mg/L at 3 hours and 0.8 mg/L at 6 hours after the dose. Using peak values, the authors estimated that the maximum dosage that the infant would receive in the mothers would be 2 to 3.6% of the weight-adjusted maternal dosage for the R-isomer and 0.6 to 0.96% of the maternal dosage for the S-isomer ¹²⁾.

Children

The clearance of vigabatrin is 5.1 and 5.8 L/hr for children (3 to 9 years of age) and adolescents (10 to 16 years of age), respectively. The clearance is about 7 L/hr for adults. It is recommended to use the lowest dose that can help achieve therapeutic objectives ¹³⁾.

Elderly Patients

As per the manufacturer label, renal clearance of vigabatrin in healthy geriatric patients (age 65 years or older) was 36% less compared to healthy adults.

Liver Impairment

Given that vigabatrin is almost eliminated by kidneys (80 to 95%) without undergoing liver metabolism, dose adjustment is not necessary for patients with liver failure ¹⁴⁾.

Kidney Impairment

Caution is necessary while administering vigabatrin in patients with renal impairment since it is a drug that is eliminated by the kidneys without undergoing any prior metabolism. Creatinine clearance (CrCl) is inversely proportional to the serum concentration of vigabatrin ¹⁵⁾, ¹⁶⁾. Therefore:

• In patients with mild renal failure (CrCl 50 to 80 mL/min), the dose of vigabatrin should be reduced by 25%.
• For moderate renal failure (CrCl 30 to 50 mL/min) a further reduction to 50% is necessary.
• If renal failure is severe (CrCl 10 to 30 mL/min), the dose must be reduced by three-fourth.

Vigabatrin Contraindications

Researchers conducted a study to determine the possible teratogenicity of vigabatrin. It involved the injection of either a low dose (350 mg/kg) or a high dose (450 mg/kg) of vigabatrin intraperitoneally in pregnant mice. This intervention resulted in a fetal loss in the high-dose group and severe intrauterine growth restriction. Folate and B12 levels fell to half in both treatment groups. This outcome raises concern for neural tube defects making pregnancy a possible contraindication to vigabatrin ¹⁷⁾. There are no specific contraindications listed in the manufacturer labels.

How does vigabatrin work?

Vigabatrin acts an irreversible inhibitor of gamma-amino-butyric acid transaminase (GABA-T) enzyme, an enzyme that break down GABA (gamma-aminobutyric acid) when it is not needed ¹⁸⁾. Vigabatrin helps to increase the amount of GABA, a neuro-inhibitory transmitter, in your central nervous system (brain and spinal cord) and increasing GABAergic, neuroinhibitory activity.

Vigabatrin is structurally the same as GABA (gamma-aminobutyric acid) with an extra vinyl group. Given this fact, Vigabatrin acts as a substrate for gamma-amino-butyric acid transaminase (GABA-T) enzyme, setting GABA free in the synaptic cleft ¹⁹⁾. The concentration of GABA, a neuro-inhibitory transmitter, increases in the brain, terminating seizure activity. Apart from inhibiting GABA-T, vigabatrin also prevents neuronal uptake of GABA and stimulates its release into the synapse. Some studies show that vigabatrin enhances the action of the inhibitory neurotransmitter glutamine, which researchers believe adds to its anticonvulsant effect ²⁰⁾, ²¹⁾.

Vigabatrin uses

Because of the risk of vision loss, Vigabatrin is used to treat complex partial seizures only in people who do not respond well enough to several other medicines.

Vigabatrin is used along with other treatments to treat adults and children 2 years and older with complex partial seizures if:

• the complex partial seizures do not respond well enough to several other treatments, and
• you and your healthcare provider decide the possible benefit of taking this medication is more important than the risk of vision loss.

Vigabatrin should not be the first medicine used to treat complex partial seizures.

Vigabatrin is also used to treat babies 1 month to 2 years of age who have infantile spasms if you and your healthcare provider decide the possible benefits of taking this medication are more important than the possible risk of vision loss.

Vigabatrin dosage

Vigabatrin administration is via oral powder and tablets for adults and older children and a solution for infants and younger children. Tablets and sachets of powder are available in a dose of 500 mg. The solution requires dissolving 500 mg powder of vigabatrin (available form in the market) in 10 ml water to achieve a 50 mg/ml concentration. The dose is then calculated for the weight in kg and is administered in two divided doses daily.

The FDA recommends an initial dose of 50 mg/kg/day for infantile spasms and can be increased to a maximum of 150 mg/kg/day over three days if not achieving adequate control of spasms ²²⁾.

To treat refractory complex partial seizures, the initial dose is 250 mg twice daily for children aged 10 to 16 years weighing 25 to 60 kg, followed by a maintenance dose of 1000 mg twice daily. In patients older than 16 years and weighing more than 60 kg, the maintenance dose could be increased to 3000 mg/day. The FDA has not approved an appropriate dose for children younger than ten years – the dosing can be extrapolated from that of adults depending on how well the seizures are controlled ²³⁾.