Serotonin and norepinephrine reuptake inhibitors

Serotonin and norepinephrine reuptake inhibitors also known as SNRIs are a class of antidepressant medications that block the reabsorption of serotonin and norepinephrine (noradrenaline) neurotransmitters or chemical messengers in your brain, increasing their availability and potentially improving mood and relieving depression, anxiety, and chronic pain ¹, ², ³. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are effective in treating depression. Serotonin and norepinephrine reuptake inhibitors (SNRIs) also are sometimes used to treat other conditions, such as anxiety disorders and long-term pain (chronic pain), especially nerve pain (neuropathic pain). SNRIs may be helpful if you have both long-term pain and depression.

Serotonin norepinephrine reuptake inhibitors (SNRIs) differ from selective serotonin reuptake inhibitors (SSRIs) in that they also inhibit the reuptake of norepinephrine (noradrenaline), as the class name indicates, but their potency with regard to serotonin reuptake inhibition is comparable to that of the SSRIs. Despite the expectation that dual receptor activity might provide greater clinical efficacy, SNRIs as a class appear to provide similar response rates to SSRIs in the treatment of major depression in adults ⁴.

SNRIs and their brand names that doctors currently prescribe in the United States include:

• Desvenlafaxine (Khedezla®, Pristiq®) is FDA-approved to treat symptoms of major depressive disorder ⁵
• Duloxetine (Cymbalta®, Drizalma®, Irenka®). Duloxetine is also approved to treat generalized anxiety disorder (GAD) and certain types of pain, such as fibromyalgia pain and pain from diabetic neuropathy ⁶
• Levomilnacipran (Fetzima®) ⁷
• Venlafaxine (Effexor®). Venlafaxine is also approved to treat generalized anxiety disorder (GAD), social anxiety disorder (social phobia) and panic disorder ⁸, ⁹
• Milnacipran (Savella) is the only SNRI not approved in the U.S. for the treatment of major depressive disorder, but the drug is effective for depression and is approved in some other countries for major depressive disorder. In the U.S., Milnacipran is used to treat fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ¹⁰, ¹¹.

SNRIs can interact with other medications, so it’s important to inform your doctor about all the medications you are taking.

SNRIs can cause side effects, which may include nausea, dry mouth, constipation, and dizziness.

SNRIs can cause withdrawal symptoms if stopped abruptly, so it’s important to discuss tapering the medication with your doctor.

What is anxiety?

Anxiety is a common mental health condition characterized by excessive worry, fear, and apprehension that can significantly impact your daily life, often accompanied by physical symptoms like rapid heartbeat and sweating. Anxiety is a natural human emotion that can be a normal response to stress or perceived threats.  However, when anxiety becomes persistent, intense, and difficult to control, it can indicate an anxiety disorder. Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear that impair a person’s social, occupational, and personal functions.

Symptoms of Anxiety:

• Emotional or Psychological: Excessive worry, fear, restlessness, difficulty concentrating, feeling on edge, and a sense of impending doom.
• Physical: Rapid heartbeat, sweating, trembling, shortness of breath, stomach problems, and difficulty sleeping

What types of antidepressants might I be prescribed?

There are many different types of antidepressants. They are grouped according to how they work in the body. Within each group, there are several different medicines that work in a similar way ¹².

• Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant class. While they are not necessarily more effective than others, they are usually well-tolerated by most people, which means that most people find that side effects are not too troublesome. Examples of this class of antidepressants include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline.
• Serotonin and noradrenaline reuptake inhibitors (SNRIs) have fewer side effects than SSRIs and may be used for more severe depression. They include duloxetine, venlafaxine, desvenlafaxine and levomilnacipran. Serotonin and noradrenaline reuptake inhibitors (SNRIs) are similar to selective serotonin reuptake inhibitors (SSRIs). They were designed to be a more effective antidepressant than SSRIs. However, the evidence that SNRIs are more effective in treating depression is uncertain. It seems that some people respond better to SSRIs, while others respond better to SNRIs.
• Norepinephrine reuptake inhibitors (NRIs) also called noradrenaline reuptake inhibitors (NARIs) work on norepinephrine (noradrenaline) and are less likely to cause drowsiness than other classes. This class includes reboxetine.
• Tricyclic antidepressants (TCAs) are an older type of antidepressant. Tricyclic antidepressants (TCAs) are no longer usually recommended as the first-line treatment for depression because they can be more dangerous if an overdose is taken. Tricyclic antidepressants (TCAs) also cause more unpleasant side effects than SSRIs and SNRIs. Tricyclic antidepressants (TCAs) include amitriptyline, nortriptyline, clomipramine, dothiepin, doxepin, imipramine and trimipramine.
• Reversible inhibitors of monoamine oxidase A (RIMAs) are more commonly used to treat anxiety than depression. They include moclobemide.
• Noradrenergic and specific serotonergic antidepressants (NaSSAs) are a relatively new antidepressant class with fewer sexual side effects but can cause weight gain. Noradrenergic and specific serotonergic antidepressant (NaSSA) includes mirtazapine. NASSAs may be effective for some people who are unable to take SSRIs. The side effects of NASSAs are similar to those of SSRIs, but they’re thought to cause fewer sexual problems. However, they may also cause more drowsiness at first.
• Serotonin antagonists and reuptake inhibitors (SARIs). Serotonin antagonist and reuptake inhibitors (SARIs) are a class of antidepressants that work by both blocking serotonin receptors and inhibiting the reuptake of serotonin, potentially leading to increased serotonin levels in the brain. Serotonin antagonists and reuptake inhibitors (SARIs) are not usually the first choice of antidepressant, but they may be prescribed if other antidepressants have not worked or have caused side effects. SARIs are known to have fewer sexual side effects compared to some other antidepressants.
• Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants that work by blocking the enzyme monoamine oxidase (MAO), which breaks down neurotransmitters like serotonin, norepinephrine, and dopamine, thus increasing their levels in the brain and potentially improving mood. Monoamine oxidase inhibitors (MAOIs) are rarely prescribed today for depression as they can have more side effects and interactions than other types of antidepressants. MAOIs can cause side effects, such as dizziness, insomnia, and dry mouth. Monoamine oxidase inhibitors (MAOIs) include phenelzine, tranylcypromine, selegiline, isocarboxazid and moclobemide.
• ‘Atypical’ antidepressants that don’t easily fit into the classes above, and include agomelatine, vortioxetine and lithium. Agomelatine stimulate melatonin receptors to affect mood. Vortioxetine works on serotonin receptors, but in a different way to SSRIs and SNRIs. If you’ve tried several different antidepressants and seen no improvement, your doctor may offer you a medicine called lithium, in addition to your current treatment. If the level of lithium in your blood becomes too high, it can become toxic. So, you’ll need blood tests every few months to check your lithium levels while you’re taking it. You’ll also need to avoid eating a low-salt diet because this can also cause the lithium to become toxic. Ask your doctor for advice about your diet. Side effects of lithium include:
  • dry mouth
  • a metallic taste in your mouth
  • some mild shaking of your hands
  • diarrhea
  • These side effects usually pass with time once your body gets used to the medicine.

What’s the difference between SNRIs and SSRIs?

Serotonin and noradrenaline reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) are both classes of antidepressants, but they work in different ways.

Selective serotonin reuptake inhibitors (SSRIs) work by blocking only serotonin reuptake, which increases serotonin levels in your brain.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) on the other hand increase both serotonin and norepinephrine levels.

Because SNRIs and SSRIs medications work differently, they have different side effects.

Researchers originally designed SNRIs to be more effective in treating depression symptoms than SSRIs. But studies haven’t conclusively confirmed that they are, in fact, more effective.

Finding the right antidepressant

Your doctor will take into account a range of factors when deciding which antidepressant to prescribe, including:

• Your age
• Your sex
• Your main symptoms or symptoms that bother you most. Some antidepressants may do a better job helping specific symptoms, such as trouble sleeping.
• Potential side effects
• Potential interactions with any other medicines you are taking. Some antidepressants can cause problems if you take them with certain medicines and herbs.
• Are you pregnant, planning for pregnancy, or breastfeeding? If so, your doctor will help you find a way to treat your depression that’s safe for you and your baby.
• Other health conditions. Certain antidepressants can make some other conditions better or worse. Any other conditions that you have will be part of choosing your depression treatment.
• Your preferences.

You may find that one type of antidepressant is more effective than others at relieving your symptoms. It can take some time to identify which antidepressant is right for you, so it’s important to keep in touch with your doctor, especially when you first start taking an antidepressant. If the medicine is causing side effects, or isn’t working, your doctor can advise whether another type of antidepressant might be more suitable.

Each person reacts differently to a particular antidepressant. Some people may be more likely to have certain side effects. Because of this, one antidepressant may work better for you than another. When choosing an antidepressant, your doctor considers your symptoms, any health issues you have, other medicines you take, drug interactions, drug-specific precautions (e.g., kidney disease, liver disease), and what has worked for you in the past.

Genes passed down in families may play a role in how antidepressants affect you. For some people, blood tests, where available, may offer clues about how their bodies may respond to a particular antidepressant. But other things besides genetics can affect your response to medicine.

It may take several weeks or longer before an antidepressant has a full effect. It also may take several weeks or longer for initial side effects to ease up. Your doctor may recommend dose changes or a different antidepressant. With patience, you and your doctor can find a medicine that works well for you.

How long does it take SNRIs to work?

It usually takes 6 to 8 weeks to feel the full effect of SNRIs and notice an improvement in your symptoms. Talk to your doctor if you don’t feel better after this time.

How do serotonin and norepinephrine reuptake inhibitors work?

Normally serotonin and norepinephrine (noradrenaline) neurotransmitters (chemical messengers) in your brain, that play a role in mood, alertness, and other bodily functions, after their release, they’re typically reabsorbed by the sending neuron in a process called reuptake. SNRIs work by blocking the reuptake of both serotonin and norepinephrine, which increases their levels in the brain neurons ⁴, ². By blocking (inhibiting) reabsorption or reuptake of both serotonin and norepinephrine neurotransmitters (chemical messengers) in your brain, more serotonin and norepinephrine are active in your brain contributing to the therapeutic effects of SNRIs in depression and anxiety, however, the exact mechanism is not known.

The members of the serotonin norepinephrine reuptake inhibitors (SNRIs) class differ in their relative potency at serotonin and norepinephrine auto-receptors; duloxetine and desvenlafaxine demonstrate a 10-fold higher selectivity for serotonin reuptake inhibition than norepinephrine reuptake inhibition and venlafaxine has a 30-fold higher affinity for the reuptake inhibition of serotonin compared to norepinephrine. Conversely, levomilnacipran and milnacipran demonstrate a 2-fold and 3-fold greater potency for norepinephrine reuptake inhibition than serotonin reuptake inhibition, respectively ¹³, ¹⁴. Norepinephrine receptor blockade is considered important in the treatment of pain, as selective serotonin reuptake inhibitors (SSRIs) have not been proven efficacious for pain disorders. Therefore, some SNRIs, including milnacipran and duloxetine, have FDA-approved indications in the treatment of some pain disorders.

All SNRIs inhibit serotonin uptake in human platelets, which has been associated with an increased risk of bleeding adverse events. SNRIs do not have a significant affinity for histaminergic, muscarinic, alpha1-adrenergic, postsynaptic serotonin or dopamine, gamma-aminobutyric acid (GABA), or glutamate receptors in test tube study, nor do they inhibit monoamine oxidase (MAO). Duloxetine and venlafaxine at high doses weakly inhibit the reuptake of dopamine, which may contribute to effects on blood pressure

Serotonin and norepinephrine reuptake inhibitors examples

The U.S. Food and Drug Administration (FDA), has approved these SNRIs to treat depression:

• Desvenlafaxine (Khedezla®, Pristiq®) is FDA-approved to treat symptoms of major depressive disorder ⁵
• Duloxetine (Cymbalta®, Drizalma®, Irenka®). Duloxetine is also approved to treat generalized anxiety disorder (GAD) and certain types of pain, such as fibromyalgia pain and pain from diabetic neuropathy ⁶
• Levomilnacipran (Fetzima®) ⁷
• Venlafaxine (Effexor®). Venlafaxine is also approved to treat generalized anxiety disorder (GAD), social anxiety disorder (social phobia) and panic disorder ⁸, ⁹
• Milnacipran (Savella®) is the only SNRI not approved in the U.S. for the treatment of major depressive disorder, but the drug is effective for depression and is approved in some other countries for major depressive disorder. In the U.S., Milnacipran is used to treat fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ¹⁰, ¹¹.

Desvenlafaxine

Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of venlafaxine and has been marketed separately as a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant that is used to treat major depressive disorder ¹⁵. Desvenlafaxine is believed to work by blocking the reabsorption of serotonin and norepinephrine (noradrenaline) neurotransmitters or chemical messengers in your brain, increasing their availability and potentially improving mood and relieving depression, anxiety, and chronic pain ¹, ², ³. Desvenlafaxine current clinical indication is limited to treating major depressive disorder. Desvenlafaxine is also sometimes used off-label to treat hot flashes (hot flushes; sudden strong feelings of heat and sweating) in women who have experienced menopause (‘change of life’; the end of monthly menstrual periods). Desvenlafaxine may be prescribed for other uses; ask your doctor or pharmacist for more information. Because Desvenlafaxine is the major active metabolite of venlafaxine, there is little evidence to suggest that Desvenlafaxine is more effective or has a different activity or rate of adverse events as Venlafaxine.

Desvenlafaxine was approved for use in the United States in 2008 and is still used with more than 1 million prescriptions filled yearly ¹⁶.

Desvenlafaxine is available as extended-release (long-acting) tablets of 25, 50, or 100 mg in generic forms and under the brand name of Pristiq. Desvenlafaxine is usually taken once a day with or without food. The recommended Desvenlafaxine dosage in adults is 50 mg once daily; increasing the dose has not been shown to improve effectiveness. Take desvenlafaxine at 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 desvenlafaxine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow Desvenlafaxine tablets whole with plenty of water; do not split, chew, crush, or dissolve them.

Desvenlafaxine controls depression, but does not cure it. It may take several weeks before you feel the full benefit of desvenlafaxine. Continue to take desvenlafaxine even if you feel well. Do not stop taking desvenlafaxine without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking Desvenlafaxine, you may experience withdrawal symptoms such as dizziness; confusion; nausea; headache; ringing in the ears; irritability; aggressive behavior; inability to control emotions; frequent mood changes; abnormally excited, difficulty falling asleep or staying asleep, diarrhea, anxiety; extreme tiredness; unusual dreams; seizures; sweating; uncontrollable shaking of a part of the body; blurred vision; or pain, burning or tingling in the hands or feet. Tell your doctor if you experience any of these symptoms while you are decreasing your dose of desvenlafaxine or soon after you stop taking desvenlafaxine.

While believed to be better tolerated than venlafaxine, desvenlafaxine appears to have a similar spectrum and frequency of side effects.

Common side effects of desvenlafaxine may include:

• dizziness, drowsiness, anxiety
• increased sweating (diaphoresis)
• nausea, decreased appetite, constipation
• sleep problems (insomnia)
• decreased sex drive, impotence, or difficulty having an orgasm.

Desvenlafaxine may cause serious side effects. See your doctor at once if you have:

• a seizure;
• easy bruising or bleeding (nosebleeds, bleeding gums), blood in your urine or stools, coughing up blood;
• blurred vision, eye pain or swelling, or seeing halos around lights;
• cough, chest discomfort, trouble breathing;
• low blood sodium–headache, confusion, problems with thinking or memory, weakness, feeling unsteady.

Desvenlafaxine may cause some teenagers and young adults to be agitated, irritable, or display other abnormal behaviors. Desvenlafaxine may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, see your doctor right away. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive) or has tried to commit suicide.

Desvenlafaxine may cause a serious condition called serotonin syndrome if taken together with some medicines. Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea. Do not use desvenlafaxine with buspirone (Buspar®), fentanyl (Abstral®, Duragesic®), lithium (Eskalith®, Lithobid®), tryptophan, St. John’s wort, amphetamines, or some pain or migraine medicines (eg, meperidine, methadone, rizatriptan, sumatriptan, tramadol, Demerol®, Methadose®, Frova®, Imitrex®, Maxalt®, Relpax®, Ultram®, Zomig®). Check with your doctor first before using any other medicines with desvenlafaxine.

Desvenlafaxine uses

Desvenlafaxine is a FDA-approved drug to treat major depressive disorder in adults ¹⁷, ¹⁸. For healthy women who have contraindications to estrogen, doctor can use desvenlafaxine off-label to treat hot flashes during menopause ¹⁹.

What to know before taking Desvenlafaxine

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make.

People with depression or mental illness may have thoughts about suicide. Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults during short-term studies. Tell your doctor right away if you have any sudden changes in mood or behavior, or thoughts about suicide. Do not stop using desvenlafaxine without first asking your doctor.

You should know that desvenlafaxine is very similar to another serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine (Effexor). You should not take these medications together.

Do not take desvenlafaxine with a monoamine oxidase (MAO) inhibitor (eg, isocarboxazid [Marplan], linezolid (Zyvox), methylene blue, phenelzine [Nardil], selegiline [Emsam, Zelapar], tranylcypromine [Parnate]). Do not start taking desvenlafaxine within 14 days after you stop using an monoamine oxidase (MAO) inhibitor. Wait 7 days after stopping desvenlafaxine before you start taking an monoamine oxidase (MAO) inhibitor. If you take them together or do not wait the proper amount of time, you may develop confusion, agitation, restlessness, stomach or bowel symptoms, a sudden high body temperature, an extremely high blood pressure, or severe seizures.

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

• Bipolar disorder (mood disorder with mania and depression)
• Bleeding problems
• Angle-closure glaucoma. You should know that Desvenlafaxine may cause angle-closure glaucoma, a condition where the fluid is suddenly blocked and unable to flow out of the eye causing a quick, severe increase in eye pressure which may lead to a loss of vision. Talk to your doctor about having an eye examination before you start taking Desvenlafaxine. If you have nausea, eye pain, changes in vision, such as seeing colored rings around lights, and swelling or redness in or around the eye, see your doctor or get emergency medical treatment right away.
• Heart or blood vessel disease
• Hyperlipidemia (high cholesterol or triglycerides in the blood)
• Hypertension (high blood pressure)
• Hyponatremia (low sodium levels in the blood)
• Interstitial lung disease
• Mania or hypomania
• Seizures
• Stroke
• Tachycardia (fast heartbeat): Use with caution. May make these conditions worse.
• Kidney disease
• Liver disease: Use with caution. The effects may be increased because of slower removal of the medicine from the body.
• Alcohol can make the side effects from desvenlafaxine worse.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to Desvenlafaxine, venlafaxine (Effexor) or any other medicines. Also tell your doctor if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. Ask your pharmacist or check the Medication Guide for a list of the ingredients. For non-prescription products, read the label or package ingredients carefully.

Children

Appropriate studies have not been performed on the relationship of age to the effects of desvenlafaxine in the pediatric population. Safety and efficacy have not been established.

Elderly

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of desvenlafaxine in the elderly. However, elderly patients are more likely to have low blood pressure, hyponatremia (low sodium in the blood), and age-related kidney problems, which may require an adjustment in the dose for patients receiving desvenlafaxine.

Pregnancy

Some antidepressants may harm your baby if you take them during pregnancy or while you’re breastfeeding. If you are pregnant, are thinking about getting pregnant or are breastfeeding, talk to your doctor about the benefits and possible risks of antidepressants. Don’t stop taking your medicine without talking with your doctor first.

If you become pregnant while taking desvenlafaxine, see your doctor. Desvenlafaxine may cause problems in newborns following delivery if it is taken during the last months of pregnancy. Do not start or stop desvenlafaxine without asking your doctor. If you are pregnant, your name may be listed on a pregnancy registry to track the effects of desvenlafaxine on the baby.

Desvenlafaxine is a category C drug, which means that tests done on animals have shown an adverse effect on the fetus, and there are no well-controlled studies in pregnant women. Still, possible benefits may justify the use of the drug in pregnant women despite the risks.

Some neonates exposed to Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), or Selective Serotonin Reuptake Inhibitors (SSRIs) late in the third trimester had clinical findings including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. This clinical picture is consistent with either direct toxic effect of SSRIs and SNRIs, drug discontinuation syndrome, or serotonin syndrome.

To monitor maternal-fetal outcomes of pregnant women exposed to antidepressant therapy, a National Pregnancy Registry for Antidepressants has been established.

Breastfeeding

There are no adequate studies in women for determining infant risk when using Desvenlafaxine during breastfeeding. Modest doses of desvenlafaxine are excreted into breastmilk, but serum drug levels of breastfed infants are less than 10% of simultaneous maternal levels ²⁰. Total drug exposure of breastfed infants is about half of that experienced by breastfed infants whose mothers are taking venlafaxine ²¹. With the related drug venlafaxine, newborn infants of mothers who took the drug during pregnancy sometimes experienced poor neonatal adaptation as seen with other antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitor (SNRI). Similar effects may occur with desvenlafaxine. Monitor breastfed infants for excessive sedation and adequate weight gain if this drug is used during lactation, especially newborn or preterm infants.

Ten infants ranging in age from 0.9 to 12.7 months were breastfed (8 exclusively) during maternal use of desvenlafaxine in doses of 50 to 150 mg daily or an average of 1.2 mg/kg daily ²⁰. Mothers were also taking lorazepam (n = 6), quetiapine (n = 5), lamotrigine (n = 2), levonorgestrel (n = 2), domperidone (n = 1), and temazepam (n = 1). Infants were studied after an average of 9 days of exposure (range 4 to 35 days) of desvenlafaxine exposure via breastmilk ²⁰. At the time of the study, 7 of the 10 infants were at a lower growth percentile than at the time of birth. Examination by a pediatrician found that all infants were healthy and had Denver developmental scores that matched their age on the day of the study ²¹.

A woman with depressive type schizoaffective disorder was taking lurasidone 40 mg at night and desvenlafaxine 50 mg daily after giving birth. She exclusively breastfed her infant. The infant’s growth and development was good during a follow-up period of 39 days ²².

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 Desvenlafaxine, it is especially important that your doctor 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 Desvenlafaxine 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.

• Bromopride
• Isocarboxazid
• Linezolid
• Methylene Blue
• Metoclopramide
• Ozanimod
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Selegiline
• Tranylcypromine

Using Desvenlafaxine 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.

• Abciximab
• Aceclofenac
• Acemetacin
• Acenocoumarol
• Alfentanil
• Almotriptan
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Amtolmetin Guacil
• Anagrelide
• Anileridine
• Apixaban
• Ardeparin
• Argatroban
• Aripiprazole
• Aspirin
• Atomoxetine
• Bemiparin
• Benzhydrocodone
• Benzphetamine
• Betrixaban
• Bivalirudin
• Bromfenac
• Brompheniramine
• Bufexamac
• Buprenorphine
• Bupropion
• Buspirone
• Butorphanol
• Cangrelor
• Carbamazepine
• Carvedilol
• Celecoxib
• Certoparin
• Chlorpheniramine
• Choline Salicylate
• Cilostazol
• Plus many more not on this list.

The following nonprescription or herbal products may interact with desvenlafaxine:

• St. John’s wort
• Aspirin
• Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn);
• Tryptophan
• Dextromethorphan.

Be sure to let your doctor and pharmacist know that you are taking these medications before you start taking desvenlafaxine. Do not start any of these medications while taking desvenlafaxine without discussing with your doctor.

Desvenlafaxine dosage

The dose of Desvenlafaxine 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 Desvenlafaxine. 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 (extended-release tablets)

• For depression
  • Adults: 50 milligrams (mg) once a day. 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 Desvenlafaxine, 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.

Desvenlafaxine side effects

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

• constipation
• loss of appetite
• dry mouth
• dizziness
• sleepiness
• extreme tiredness
• unusual dreams
• yawning
• difficulty falling asleep or staying asleep
• sweating
• uncontrollable shaking of a part of the body
• pain, burning, numbness, or tingling in part of the body
• enlarged pupils (black circles in the centers of the eyes)
• sexual problems in males; decreased sex drive, inability to get or keep an erection, or delayed or absent ejaculation
• sexual problems in females; decreased sex drive, or delayed orgasm or unable to have an orgasm
• difficulty urinating

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

• rash
• hives
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• difficulty swallowing or breathing
• fast heartbeat
• cough
• chest, arm, back, neck, or jaw pain
• fever
• coma (loss of consciousness for a period of time)
• seizures
• fever, sweating, confusion, fast or irregular heartbeat, severe muscle stiffness or twitching, agitation, hallucinations, loss of coordination, nausea, vomiting, or diarrhea
• unusual bleeding or bruising
• nosebleeds
• small red or purple dots on the skin
• headache
• difficulty concentrating
• memory problems
• confusion
• weakness
• increased falls
• fainting

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

Duloxetine

Duloxetine also called duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that is currently used to treat major depression, generalized anxiety disorder (GAD), fibromyalgia, pain and tingling caused by diabetic neuropathy (nerve damage that can develop in people who have diabetes) in adults and excessive worry and tension that disrupts daily life and lasts for 6 months or longer) in adults and children 7 years of age and older ²³. Duloxetine is also used to treat ongoing (chronic) bone or muscle pain such as lower back pain or osteoarthritis (joint pain or stiffness that may worsen over time) in adults. Duloxetine is also sometimes used to treat chemotherapy-induced peripheral neuropathy and stress urinary incontinence (leakage of urine during physical activity such as coughing, sneezing, laughing, and exercise) in women.

Duloxetine was approved for use in the United States in 2004 and is available in delayed-release (releases the medication in the intestine to prevent break-down of the medication by stomach acids) capsules of 20, 30 and 60 mg in multiple generic forms and under the brand name Cymbalta. The recommended dosage in adults is 40 to 60 mg daily, which can be raised to 120 mg daily based upon tolerance and clinical effects. Swallow the delayed-release capsules whole; do not split, chew, or crush them. Do not open the delayed-release capsules and mix the contents with liquids or sprinkle the contents on food. Your doctor may start you on a low dose of medication and increase your dose after one week.

When duloxetine is used to treat depression, it is usually taken once or twice a day with or without food. When duloxetine is used to treat generalized anxiety disorder (GAD), the pain of diabetic neuropathy, fibromyalgia, or ongoing bone or muscle pain, it is usually taken once a day with or without food. Take duloxetine 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 duloxetine exactly as directed. Do not take more or less of it, take it more often, or take it for a longer time than prescribed by your doctor.

Duloxetine may help control your symptoms but will not cure your condition. It may take 1 to 4 weeks or longer before you feel the full benefit of duloxetine. Continue to take duloxetine even if you feel well. Do not stop taking duloxetine without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking duloxetine, you may experience withdrawal symptoms such as nausea; vomiting; diarrhea; anxiety; dizziness; tiredness; headache; pain, burning, numbness, or tingling in the hands or feet; irritability; difficulty falling asleep or staying asleep; sweating; and nightmares. Tell your doctor if you experience any of these symptoms when your dose of duloxetine is decreased.

Common side effects of duloxetine are drowsiness, dyspepsia, nausea, headache, increased sweating, increased appetite, weight gain, urinary retention and sexual dysfunction. Rare, but potentially severe adverse events include suicidal thoughts and behaviors, mania, postural hypotension, syncope and falls, serotonin syndrome, seizures, severe skin rash, hypersensitivity reactions, hyponatremia, and glaucoma.

Duloxetine special precautions

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For duloxetine, the following should be considered ²⁴:

• tell your doctor and pharmacist if you are allergic to duloxetine, any other medications, or any of the ingredients in duloxetine delayed-release capsules. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor or pharmacist if you are taking the following medications or have stopped taking them within the past two weeks: thioridazine or a monoamine oxidase (MAO) inhibitor, such as isocarboxazid (Marplan), linezolid (Zyvox); methylene blue; phenelzine (Nardil), selegiline (Emsam, Zelapar), and tranylcypromine (Parnate).
• your doctor will probably tell you not to take duloxetine. If you stop taking duloxetine, you should wait at least 5 days before you start to take an MAO inhibitor.
• some medications should not be taken with duloxetine. Other medications may cause dosing changes or extra monitoring when taken with duloxetine. Make sure you have discussed any medications you are currently taking or plan to take before starting duloxetine with your doctor and pharmacist. Before starting, stopping, or changing any medications while taking duloxetine, please get the advice of your doctor or pharmacist.
• the following nonprescription or herbal products may interact with duloxetine: St. John’s wort; tryptophan; proton pump inhibitors such as lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex); cimetidine (Tagamet); aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn). Be sure to let your doctor and pharmacist know that you are taking these medications before you start taking duloxetine. Do not start any of these medications while taking duloxetine without discussing with your doctor.
• tell your doctor if you drink or have ever drunk large amounts of alcohol or if you use or have ever used street drugs or have ever overused prescription medications. Also tell your doctor if you have a low level of sodium in your blood; glaucoma (increased pressure in the eye that may cause loss of sight); if you have recently had a heart attack; or if you have or have ever had high blood pressure; seizures; coronary artery disease (blockage or narrowing of the blood vessels that lead to the heart); bleeding problems; any type of stomach problem such as slow stomach emptying; or heart, liver, or kidney disease. If you have diabetes, be sure to talk to your doctor about how serious your condition is so your doctor can decide if duloxetine is right for you.
• tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy, or if you plan to become pregnant or are breast-feeding. If you become pregnant while taking duloxetine, call your doctor. Duloxetine may cause problems in newborns following delivery if it is taken during the last months of pregnancy.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking duloxetine.
• you should know that duloxetine may make you drowsy, dizzy, or may affect your judgment, thinking or coordination. Do not drive a car or operate machinery until you know how this medication affects you.
• ask your doctor about the safe use of alcoholic beverages while you are taking duloxetine. Alcohol can increase the risk of serious side effects from duloxetine.
• you should know that duloxetine may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking duloxetine or with an increase in dose. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• you should know that duloxetine may cause high blood pressure. You should have your blood pressure checked before starting treatment and regularly while you are taking this medication.
• you should know that duloxetine may cause angle-closure glaucoma (a condition where the fluid is suddenly blocked and unable to flow out of the eye causing a quick, severe increase in eye pressure which may lead to a loss of vision). Talk to your doctor about having an eye examination before you start taking this medication. If you have nausea, eye pain, changes in vision, such as seeing colored rings around lights, and swelling or redness in or around the eye, call your doctor or get emergency medical treatment right away.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to duloxetine or any other medicines. Also tell your doctor if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of duloxetine in children to treat anxiety in children 7 years of age and older. However, safety and efficacy have not been established in children younger than 7 years of age.

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of duloxetine in children to treat fibromyalgia in children 13 years of age and older. However, safety and efficacy have not been established in children younger than 13 years of age.

Appropriate studies have not been performed on the relationship of age to the effects of duloxetine for other indications in the pediatric population. Safety and efficacy have not been established for other indications.

Elderly

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of duloxetine in the elderly. However, elderly patients may be more sensitive to the effects of duloxetine than younger adults, and are more likely to have hyponatremia (low sodium in the blood) and increase risk for falls, which may require caution in patients receiving duloxetine ²⁵.

Pregnant women

Duloxetine is U.S. Food and Drug Administration (FDA) pregnancy category C, which means risk to fetal development cannot be ruled out. In animal reproductive studies, duloxetine demonstrated adverse effects on embryo/fetal development. Therefore, your doctor should only prescribe duloxetine if the potential benefits justify the potential risk to the fetus.

Breastfeeding Women

Duloxetine is excreted in breast milk and may produce effects in the nursing infant. Some studies show the relative infant dose of duloxetine to be 2.3%. Relative infant dose (RID) is the dose received via breast milk relative to the mother’s dose. A relative infant dose below 10% is acceptable when breastfeeding. Some sources recommend breastfeeding only if the relative infant dose is less than 5% if the mother is on psychotropic medication. Regardless, an infant breastfed by a mother receiving duloxetine requires monitoring for behavior changes, sleep disturbance, feeding changes, growth, and neurodevelopment ²⁶.

Medical problems

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

• Alcohol abuse, history of or kidney disease, severe or liver disease (including cirrhosis): Duloxetine should not be used in patients with these conditions.
• Bipolar disorder (mood disorder with mania and depression), or risk of or bleeding problems or diabetes or digestion problems or glaucoma (angle-closure) or heart or blood vessel disease or hypertension (high blood pressure) or hyponatremia (low sodium in the blood) or mania, history of or seizures, history of or urinating problems (eg, urinary retention or trouble urinating): Use duloxetine with caution. Duloxetine may make these conditions worse.
• Kidney disease: Use duloxetine with caution. The effects may be increased because of slower removal of duloxetine from the body.

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 duloxetine, 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 duloxetine 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.

• Bromopride
• Isocarboxazid
• Linezolid
• Mavorixafor
• Methylene Blue
• Metoclopramide
• Ozanimod
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Selegiline
• Thioridazine
• Tranylcypromine
• Viloxazine

Using duloxetine 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.

• Abciximab
• Abiraterone Acetate
• Abiraterone Acetate, Micronized
• Aceclofenac
• Acemetacin
• Alfentanil
• Almotriptan
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Amtolmetin Guacil
• Anagrelide
• Anileridine
• Apixaban
• Ardeparin
• Aripiprazole
• Asenapine
• Aspirin
• Atomoxetine
• Benzhydrocodone
• Benzphetamine
• Betrixaban
• Brexpiprazole
• Bromfenac
• Brompheniramine
• Bufexamac
• Buprenorphine
• Bupropion
• Buspirone
• Butorphanol
• Cangrelor
• Capmatinib
• Carbamazepine
• Carvedilol
• Celecoxib
• Certoparin
• Chlorpheniramine
• Chlorpromazine
• Choline Salicylate
• Cifenline
• Cilostazol
• Cimetidine
• Ciprofloxacin
• Citalopram
• Clomipramine
• Clonixin
• Clopidogrel
• Clozapine
• Cocaine
• Codeine
• Cyclobenzaprine
• Dacomitinib
• Deferasirox
• Desipramine
• Desvenlafaxine
• Deutetrabenazine
• Dexibuprofen
• Dexketoprofen
• Dextroamphetamine
• Dextromethorphan
• Dibenzepin
• Diclofenac
• Difenoxin
• Diflunisal
• Dihydrocodeine
• Diphenoxylate
• Dipyridamole
• Dipyrone
• Dixyrazine
• Dolasetron
• Donepezil
• Doxepin
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Droxicam
• Edoxaban
• Eletriptan
• Eliglustat
• Encainide
• Enclomiphene
• Enoxacin
• Epoprostenol
• Eptifibatide
• Escitalopram
• Ethylmorphine
• Etodolac
• Etofenamate
• Etoricoxib
• Fedratinib
• Felbinac
• Fenfluramine
• Fenoprofen
• Fentanyl
• Fepradinol
• Feprazone
• Flecainide
• Floctafenine
• Flufenamic Acid
• Fluoxetine
• Fluphenazine
• Flurbiprofen
• Fluvoxamine
• Frovatriptan
• Gepirone
• Givosiran
• Granisetron
• Haloperidol
• Hydrocodone
• Hydromorphone
• Hydroxytryptophan
• Ibuprofen
• Iloperidone
• Iloprost
• Imipramine
• Indecainide
• Indomethacin
• Iobenguane I 123
• Iobenguane I 131
• Ketobemidone
• Ketoprofen
• Ketorolac
• Lasmiditan
• Levoketoconazole
• Levomilnacipran
• Levorphanol
• Lisdexamfetamine
• Lithium
• Lofepramine
• Lofexidine
• Lorcainide
• Lorcaserin
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Melitracen
• Meloxicam
• Meperidine
• Metaxalone
• Methadone
• Methamphetamine
• Methdilazine
• Methotrexate
• Methotrimeprazine
• Methoxyphenamine
• Metopimazine
• Metoprolol
• Mexiletine
• Milnacipran
• Mirtazapine
• Morniflumate
• Morphine
• Morphine Sulfate Liposome
• Nabumetone
• Nalbuphine
• Naproxen
• Naratriptan
• Nebivolol
• Nefazodone
• Nepafenac
• Nicergoline
• Nicomorphine
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Nortriptyline
• Oliceridine
• Ondansetron
• Opipramol
• Opium
• Opium Alkaloids
• Oxaprozin
• Oxycodone
• Oxymorphone
• Oxyphenbutazone
• Pacritinib
• Palonosetron
• Papaveretum
• Parecoxib
• Paregoric
• Parnaparin
• Paroxetine
• Pentazocine
• Perazine
• Perphenazine
• Phenylbutazone
• Piketoprofen
• Pimozide
• Piperazine
• Pipotiazine
• Piritramide
• Piroxicam
• Pitolisant
• Pixantrone
• Prajmaline
• Pranoprofen
• Prasugrel
• Prochlorperazine
• Proglumetacin
• Promazine
• Promethazine
• Propafenone
• Propiomazine
• Propyphenazone
• Proquazone
• Protriptyline
• Quinidine
• Recainam
• Remifentanil
• Reviparin
• Risperidone
• Ritlecitinib
• Rivaroxaban
• Rizatriptan
• Rofecoxib
• Salicylic Acid
• Salsalate
• Selexipag
• Sertraline
• Sibutramine
• Sodium Salicylate
• St John’s Wort
• Sufentanil
• Sulfinpyrazone
• Sulindac
• Sulodexide
• Sumatriptan
• Tamoxifen
• Tapentadol
• Tenoxicam
• Thiethylperazine
• Thioproperazine
• Tianeptine
• Tiaprofenic Acid
• Ticagrelor
• Ticlopidine
• Tilidine
• Timolol
• Tirofiban
• Tolfenamic Acid
• Tolmetin
• Tolperisone
• Tolterodine
• Tramadol
• Trazodone
• Treprostinil
• Trifluoperazine
• Triflupromazine
• Trimipramine
• Tropisetron
• Tryptophan
• Valdecoxib
• Venlafaxine
• Vernakalant
• Vilazodone
• Vorapaxar
• Vortioxetine
• Warfarin
• Yohimbine
• Ziprasidone
• Zolmitriptan
• Zuclopenthixol

Duloxetine uses

Duloxetine hydrochloride is U.S. Food and Drug Administration (FDA) approved for use in the treatment of major depressive disorder, generalized anxiety disorder (GAD), fibromyalgia, chronic muscle and joint pain, and diabetic peripheral neuropathy ²⁷, ²⁸, ²⁹. Duloxetine is used off-label (non-FDA approved) for chemotherapy-induced peripheral neuropathy and stress urinary incontinence in both men and women ²⁹.

Monitoring

Your doctor should check your blood pressure and vitals before initiating duloxetine hydrochloride therapy and routinely after that. Your doctor should also monitor you for suicidal ideation, especially when starting treatment, altering the dose, and after discontinuation of therapy. Your doctor should monitor you for worsening depression, behavioral changes such as mania, and withdrawal symptoms from abrupt discontinuation. Patients should be monitored for abnormal bleeding as duloxetine may impair platelet aggregation. Caution should be exercised when using anticoagulants or antiplatelet medications along with duloxetine therapy. Laboratory workup should include monitoring serum creatinine, blood urea nitrogen(BUN), transaminase levels, blood glucose levels, and HgbA1c in diabetic patients. Sodium levels require follow-up when prescribing duloxetine in the elderly population ²⁹.

Duloxetine dosage

The dose of duloxetine 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 duloxetine. 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 (delayed-release capsules):

• For treatment of anxiety
  • Adults: At first, 60 milligrams (mg) once a day. Some patients may start at 30 mg once a day for 1 week before increasing the dose to 60 mg once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 120 mg per day.
  • Older adults: At first, 30 mg once a day for 2 weeks before increasing the dose to 60 mg once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 120 mg per day.
  • Children 7 years of age and older: At first, 30 mg once a day for 2 weeks before increasing the dose to 60 mg once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 120 mg per day.
  • Children younger than 7 years of age: Use and dose must be determined by your doctor.
• For treatment of chronic muscle pain
  • Adults: 60 milligrams (mg) once a day. Some patients may start at 30 mg once a day for 1 week before increasing the dose to 60 mg once a day.
    • Low back pain: 30 mg can be given once daily for one week and increased up to 60 mg once daily as tolerated as an adjunct therapy. Maximum dose: 60 mg/day.
    • Knee pain: 30 mg can be given once daily for one week and increased up to 60 mg once daily as tolerated as an adjunct therapy.[6]
  • Children: Use and dose must be determined by your doctor.
• For treatment of depression
  • Adults: 40 milligrams (mg) per day (given as 20 mg two times per day) to 60 mg per day (given either once a day or as 30 mg two times per day). Your doctor may increase your dose as needed. However, the dose is usually not more than 120 mg per day.
  • Children: Use and dose must be determined by your doctor.
• For treatment of diabetic peripheral neuropathy
  • Adults: 60 milligrams (mg) once a day.
  • Children: Use and dose must be determined by your doctor.
• For treatment of fibromyalgia
  • Adults: 60 milligrams (mg) once a day. Some patients may start at 30 mg once a day for 1 week before increasing the dose to 60 mg once a day.
  • Children 13 years of age and older: At first, 30 mg once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 60 mg per day.
  • Children younger than 13 years of age: Use and dose must be determined by your doctor.

If you miss a dose of duloxetine, 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.

Duloxetine side effects

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

• nausea
• vomiting
• constipation
• diarrhea
• weight changes
• heartburn
• stomach pain
• decreased appetite
• dry mouth
• increased urination
• sweating or night sweats
• dizziness
• headache
• weight changes
• tiredness
• drowsiness
• muscle pain or cramps
• sexual problems in males; decreased sex drive, inability to get or keep an erection, or delayed or absent ejaculation
• sexual problems in females; decreased sex drive, or delayed orgasm or unable to have an orgasm
• uncontrollable shaking of a part of the body

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

• unusual bruising or bleeding
• pain in the upper right part of the stomach
• swelling of the abdomen
• itching
• yellowing of the skin or eyes
• dark colored urine
• loss of appetite
• extreme tiredness or weakness
• confusion
• unsteady walking that may cause falling
• flu-like symptoms
• agitation, fever, sweating, confusion, fast or irregular heartbeat, and severe muscle stiffness or twitching, loss of coordination, nausea, vomiting, or diarrhea
• seizures
• hallucinations (seeing things or hearing voices that do not exist)
• fever
• blisters or peeling skin
• rash
• hives
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness
• difficulty urinating.

Duloxetine may cause some teenagers and young adults to be agitated, irritable, or display other abnormal behaviors. Duloxetine may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, see your doctor right away. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive) or has tried to commit suicide.

Duloxetine may decrease appetite and cause weight loss in children. Your child’s doctor will watch his or her growth carefully. See your child’s doctor if you have concerns about your child’s growth or weight while he or she is taking duloxetine. See your child’s doctor about the risks of giving duloxetine to your child.

Duloxetine may cause a serious condition called serotonin syndrome if taken together with some medicines. Do not use duloxetine with buspirone (Buspar®), fentanyl (Abstral®, Duragesic®), lithium (Eskalith®, Lithobid®), tryptophan, St. John’s wort, amphetamines, or some pain or migraine medicines (eg, meperidine, methadone, rizatriptan, sumatriptan, tramadol, Demerol®, Methadose®, Frova®, Imitrex®, Maxalt®, Relpax®, Ultram®, Zomig®). Check with your doctor first before using any other medicines with duloxetine.

Duloxetine may increase your risk for bleeding problems. Make sure your doctor knows if you are also taking other medicines that thin the blood, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) pain medicines (eg, ibuprofen, naproxen, Advil®, Aleve®, Celebrex®, or Motrin®) or warfarin (Coumadin®).

Serious skin reactions (eg, erythema multiforme, Stevens-Johnson syndrome) can occur during treatment with duloxetine. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, chills, cough, diarrhea, itching, joint or muscle pain, red irritated eyes, red skin lesions, often with a purple center, sore throat, sores, ulcers, or white spots in the mouth or on the lips, or unusual tiredness or weakness while you are using duloxetine.

Do not suddenly stop taking duloxetine without checking first with your doctor. If you have been instructed to stop taking duloxetine, ask your doctor how to slowly decrease the dose. This will decrease your chance of having withdrawal symptoms such as dizziness, nausea, headaches, vomiting, increased sweating, irritability, nightmares, trouble with sleeping, or prickling or tingling feelings.

Duloxetine may affect blood sugar levels. If you are diabetic and notice a change in the results of your blood or urine sugar tests, check with your doctor.

Duloxetine may cause blurred vision, dizziness, drowsiness, trouble with thinking, or trouble with controlling body movements, which may lead to falls, fractures, or other injuries. Make sure you know how you react to duloxetine before you drive, use machines, or do anything else that could be dangerous if you are not alert or able to see clearly. You may also feel lightheaded or you may fall or faint when getting up suddenly from a lying or sitting position, so get up slowly. If these symptoms are bothering you or keeping you from doing your daily activities, tell your doctor right away.

You will need to measure your blood pressure before starting duloxetine and while you are using it. If you notice any change to your recommended blood pressure, call your doctor right away. If you have questions about this, talk to your doctor.

Hyponatremia (low sodium in the blood) may occur with duloxetine. Check with your doctor right away if you have confusion, decreased urine output, difficulty concentrating, fast or irregular heartbeat, headaches, memory problems, nausea or vomiting, swelling of the face, ankles, or hands, trouble breathing, or unusual tiredness or weakness.

Duloxetine may cause sexual problems. Check with your doctor right away if you have decreased interest in sexual intercourse, inability to have or keep an erection, or loss in sexual ability, desire, drive, or performance.

Avoid smoking while you are using duloxetine. If you have any questions about this, check with your doctor.

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

Duloxetine overdose

Fatal outcomes have occurred with duloxetine overdoses at as low as 1000 mg. Signs and symptoms of duloxetine overdose include serotonin syndrome, seizures, coma, somnolence, syncope, tachycardia, autonomic instability, diarrhea, and vomiting. Signs of serotonin syndrome include agitation, restlessness, disorientation, diaphoresis, hyperthermia, tachycardia, nausea, vomiting, tremor, muscle rigidity, hyperreflexia, myoclonus, dilated pupils, dry mucous membranes, and increased bowel sounds. Clonus and hyperreflexia are particularly common in serotonin syndrome.

There is no antidote to duloxetine overdose. If the patient is presenting with serotonin syndrome, cyproheptadine and cooling measures may be considered. Patients with abnormal vital signs need monitoring, and severe cases may warrant ICU-level of care ³⁰, ³¹.

Levomilnacipran

Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant that is used to treat major depressive disorder ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰. Levomilnacipran is the most recently available product in the serotonin and norepinephrine reuptake inhibitor (SNRI) line. Levomilnacipran extended-release (Fetzima) was approved by the FDA in 2013 for the treatment of major depression in adults ⁴¹, ⁴², ⁴³, ⁴⁴. Additional applications for levomilnacipran are currently under investigation ⁴⁵. Levomilnacipran is the more active L-enantiomer of milnacipran ⁴⁴. Levomilnacipran has been developed solely as a extended-release formulation (once per day) ⁴⁶, ⁴¹.

Levomilnacipran comes as an extended-release (long-acting) 20 mg, 40 mg, 80 mg and 120 mg capsule to take by mouth. Levomilnacipran is usually taken once daily with or without food. The starting dose is 20 mg daily, and the usual maintenance dose is 40 to 120 mg daily. Take levomilnacipran at 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 levomilnacipran exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole; do not open, chew, or crush them.

Your doctor may start you on a low dose of levomilnacipran and gradually increase your dose, not more than once every 2 days.

Levomilnacipran controls depression but does not cure it. It may take several weeks or longer before you feel the full benefit of levomilnacipran. Continue to take levomilnacipran even if you feel well. Do not stop taking levomilnacipran without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking levomilnacipran, you may experience withdrawal symptoms such as mood changes, agitation, irritability, dizziness, ringing in the ears, shock-like sensations, anxiety, confusion, tiredness, difficulty falling asleep or staying asleep, numbness or tingling in the arms, legs, hands, or feet, headache, increased sweating, seizures, or nausea. Tell your doctor if you experience any of these symptoms when your dose of levomilnacipran is decreased.

Common side effects of levomilnacipran may include:

• nausea, vomiting, constipation
• irregular heartbeats
• sweating (diaphoresis)
• decreased sex drive, impotence, or difficulty having an orgasm.

Levomilnacipran may cause serious side effects. Serious side effects may be more likely in older adults. See your doctor at once if you have:

• blurred vision, tunnel vision, eye pain or swelling, eye redness;
• painful or difficult urination;
• easy bruising, unusual bleeding, purple or red spots under your skin;
• pounding heartbeats or fluttering in your chest;
• seizure (convulsions);
• manic episodes with racing thoughts, increased energy, decreased need for sleep, risk-taking behavior, being agitated or talkative;
• low sodium level (hyponatremia) causing headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady.

Seek medical attention right away if you have symptoms of serotonin syndrome. Serotonin syndrome also called serotonin toxicity, is a potentially life-threatening condition associated with increased serotonergic activity in your brain. Serotonin syndrome can occur when you increase the dose of certain medications or start taking a new drug. Serotonin syndrome is most often caused by combining medications that contain serotonin, such as a migraine medication and an antidepressant. Some illicit drugs and dietary supplements are associated with serotonin syndrome. Serotonin syndrome signs and symptoms can range from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures). Severe serotonin syndrome can cause death if not treated.

Levomilnacipran Uses

Levomilnacipran is FDA approved to treat Major Depressive Disorder ⁴¹, ⁴².

What to know before taking Levomilnacipran

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make.

Do not take levomilnacipran with a monoamine oxidase (MAO) inhibitor (eg, isocarboxazid [Marplan], phenelzine [Nardil], selegiline [Eldepryl], tranylcypromine [Parnate]). Do not start taking levomilnacipran during the 2 weeks after you stop a MAO inhibitor. Wait 1 week after stopping levomilnacipran before you start taking a monoamine oxidase (MAO) inhibitor. Do not use Levomilnacipran if you are using certain monoamine oxidase (MAO) inhibitor (eg, linezolid [Zyvox], methylene blue injection). If you take them together or do not wait the proper amount of time, you may develop confusion, agitation, restlessness, stomach or intestinal symptoms, a sudden high body temperature, an extremely high blood pressure, or severe seizures.

Levomilnacipran may cause some teenagers and young adults to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, tell your doctor right away. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive) or has tried to commit suicide.

Levomilnacipran may cause a serious condition called serotonin syndrome if taken together with some medicines. Do not use levomilnacipran with buspirone (Buspar), fentanyl (Abstral, Duragesic), lithium (Eskalith, Lithobid), tryptophan, St. John’s wort, amphetamines, or some pain or migraine medicines (eg, meperidine, methadone, rizatriptan, sumatriptan, tramadol, Demerol, Methadose, Frova, Imitrex, Maxalt, Relpax, Ultram, Zomi®). Check with your doctor first before taking any other medicines with levomilnacipran.

Levomilnacipran may increase your risk for bleeding problems. Make sure your doctor knows if you are also taking other medicines that thin the blood, including aspirin, nonsteroidal antiinflammatory agents, also called NSAIDs (eg, diclofenac, ibuprofen, naproxen, Advil, Aleve, Celebrex, Voltaren), or warfarin (Coumadin, Jantoven).

Tell your doctor if you also use stimulant medicine, opioid medicine, herbal products, or medicine for depression, mental illness, Parkinson’s disease, migraine headaches, serious infections, or prevention of nausea and vomiting. An interaction with levomilnacipran could cause a serious condition called serotonin syndrome.

Levomilnacipran may cause some people to become dizzy, drowsy, or less alert than they are normally. Make sure you know how you react to levomilnacipran before you drive, use machines, or do anything else that could be dangerous if you are not alert.

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

• Bipolar disorder (manic-depressive disorder)
• Bleeding problems
• Angle-closure glaucoma. You should know that Levomilnacipran may cause angle-closure glaucoma, a condition where the fluid is suddenly blocked and unable to flow out of the eye causing a quick, severe increase in eye pressure which may lead to a loss of vision. Talk to your doctor about having an eye examination before you start taking Levomilnacipran. If you have nausea, eye pain, changes in vision, such as seeing colored rings around lights, and swelling or redness in or around the eye, see your doctor or get emergency medical treatment right away.
• Heart or blood vessel disease
• Heart rhythm problems
• Hypertension (high blood pressure)
• Hyponatremia (low sodium levels in the blood). This is more common in elderly patients, those who are taking diuretic medicines, or those who have less fluid in the body due to severe diarrhea or vomiting. Check with your doctor right away if you have confusion, a headache, memory problems, trouble concentrating, weakness, or feel unsteady when standing.
• Mania
• Seizures
• Stroke
• Tachycardia (fast heart rate)
• Trouble urinating
• Urinary bladder blockage: Use with caution. May make these conditions worse.
• Kidney disease: Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to Levomilnacipran or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children

Appropriate studies have not been performed on the relationship of levomilnacipran in the pediatric population. Safety and efficacy have not been established.

Elderly

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of levomilnacipran in the elderly. However, elderly patients are more likely to have hyponatremia (low sodium in the blood) and age-related kidney problems, which may require an adjustment in the dose for patients receiving levomilnacipran.

Pregnancy

Tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking levomilnacipran, see your doctor. If you are pregnant, your name may be listed on a pregnancy registry to track the effects of levomilnacipran on the baby.

Taking levomilnacipran during pregnancy could harm the baby, but stopping levomilnacipran may not be safe for you. Do not start or stop levomilnacipran without asking your doctor.

Breastfeeding

Levomilnacipran has not been studied in nursing mothers ⁴⁷. However, the racemic form of milnacipran has low levels in breastmilk and would not be expected to cause any adverse effects in breastfed infants. Until more data become available, levomilnacipran should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant ⁴⁷. Monitor breastfed infants for agitation, irritability, poor feeding and poor weight gain ⁴⁷.

Eight lactating women who were at least 12 weeks following childbirth and weaning their infants received a single oral dose of racemic milnacipran 50 mg. The average peak milk level of milnacipran was 262 mcg/L at an average of 4 hours and the average milk level was 122 mcg/L. The relative infant dosage was estimated to be 2.8% of the weight-adjusted maternal dosage. Milnacipran was eliminated from milk with an average half-life of 7.5 hours ⁴⁸, ⁴⁹.

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 Levomilnacipran, 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 Levomilnacipran 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.

• Isocarboxazid
• Linezolid
• Methylene Blue
• Metoclopramide
• Ozanimod
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Selegiline
• Tranylcypromine

Using Levomilnacipran 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.

• Abciximab
• Aceclofenac
• Acemetacin
• Acenocoumarol
• Alfentanil
• Almotriptan
• Amifampridine
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Amtolmetin Guacil
• Anagrelide
• Anileridine
• Apixaban
• Ardeparin
• Argatroban
• Aspirin
• Bemiparin
• Benzhydrocodone
• Benzphetamine
• Betrixaban
• Bivalirudin
• Boceprevir
• Bromfenac
• Brompheniramine
• Bufexamac
• Buprenorphine
• Bupropion
• Buspirone
• Butorphanol
• Cangrelor
• Carbamazepine
• Celecoxib
• Ceritinib
• Certoparin
• Chlorpheniramine
• Choline Salicylate
• Cilostazol
• Plus many more not on this list.

Levomilnacipran Dosage

The dose of Levomilnacipran 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 Levomilnacipran. 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 (extended-release capsules)

• For depression
  • Adults: At first, 20 milligrams (mg) once a day. After 2 days, the dose will be increased to 40 mg once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 120 mg per day. In general, the higher doses of levomilnacipran (i.e., between 80 to 120 mg/day) have been more effective than the lower doses have (i.e., around 40 mg/day) ⁵⁰.
  • Children: Use is not recommended.

Missed Dose

If you miss a dose of Levomilnacipran, 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.

Levomilnacipran side effects

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

• nausea
• constipation
• excessive sweating
• vomiting
• sexual problems in males; decreased sex drive, inability to get or keep an erection, or delayed or absent ejaculation
• sexual problems in females; decreased sex drive, or delayed orgasm or unable to have an orgasm. Check with your doctor right away if you have decreased interest in sexual intercourse, delayed or inability to have an orgasm in women, inability to have or keep an erection in men, or loss in sexual ability, desire, drive, or performance. These could be symptoms of sexual dysfunction.
• decreased appetite

Some side effects can be serious. If you experience any of these symptoms, stop taking levomilnacipran and call your doctor immediately or get emergency medical treatment:

• rash
• hives
• swelling
• difficulty breathing or swallowing
• hallucinations (seeing things or hearing voices that do not exist)
• confusion
• memory problems
• difficulty concentrating
• agitation, fever, sweating, confusion, fast or irregular heartbeat, severe muscle stiffness or twitching, loss of coordination, nausea, vomiting, or diarrhea
• unsteady walking that may cause falling
• seizures
• fainting
• coma (loss of consciousness for a period of time)
• abnormal bleeding or bruising
• difficulty urinating or unable to urinate
• rapid, pounding, or irregular heartbeat

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

Milnacipran

Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant that is used to treat chronic pain caused by fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ⁵¹, ⁵², ⁵³, ⁵⁴, ¹¹, ⁵⁵, ¹³, ⁵⁶. Milnacipran was approved for use in the United States in 2009 to treat chronic pain caused by fibromyalgia ⁵⁷. Milnacipran works by increasing the amount of serotonin and norepinephrine, natural neurotransmitters that help stop the movement of pain signals in your brain.

Milnacipran (Savella) comes as a 12.5 mg, 25 mg, 50 mg, and 100 mg mg tablets to be taken by mouth. Milnacipran is initiated at 12.5 mg daily, and the dose is increased by 12.5 mg every few weeks until reaching a maximum of 50 to 100 mg, taken once or twice daily. Clinical trials indicate an average effective dose of 100 mg/day. The recommended Milnacripran dosage is 50 mg twice daily after a 7 day titration schedule.

Milnacipran should be administered in two divided doses per day. The general titration table goes as follows: day 1: 12.5 mg once, days 2-3: 25 mg/day (12.5 mg twice daily), Day 4-7: 50 mg/day (50 mg twice daily), Day 7, and after 100 mg/day (50 mg twice daily) ⁵⁸ The recommended dosage of 100 mg (50 mg twice daily) can be increased up to 200 mg/day depending on the individual patient ⁵⁸.

The first dose of milnacipran is usually taken once on day 1 of therapy. After that, it is usually taken two times a day. Milnacipran may be taken with or without food, but taking it with food will decrease the chance that milnacipran will upset your stomach. Take milnacipran 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 milnacipran exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will start you on a low dose of milnacipran and gradually increase your dose during the first week of treatment.

Milnacipran may help control the symptoms of fibromyalgia, but will not cure it. It is important that your doctor check your progress at regular visits to allow for changes in your dose and to help reduce any side effects. Blood and urine tests may be needed to check for any unwanted effects.

Do not stop taking milnacipran without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking milnacipran, you may experience withdrawal symptoms such as mood changes, irritability, agitation, dizziness, numbness or tingling in the hands or feet, anxiety, confusion, headache, tiredness, difficulty falling asleep or staying asleep, ringing in the ears, abnormal excitement, or seizures. Tell your doctor if you experience any of these symptoms when your dose of milnacipran is decreased.

Common side effects of milnacipran include nausea, vomiting, constipation, headache, sweating, increased heart rate, palpitations, testicular pain, urinary hesitancy and erectile dysfunction. When used with other serotonin reuptake inhibitors, milnacipran can be associated with serotonin syndrome. Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonin activity in your brain, often triggered by drug interactions or overdose, and characterized by a combination of mental, autonomic, and neuromuscular symptoms. Symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, lack of coordination, major changes in blood pressure and rapid heart rate. Get medical help right away if you have any of these symptoms. Severe serotonin syndrome can be life-threatening due to complications like seizures, hyperthermia (high body temperature), and organ damage. Serotonin syndrome happens most often when you take two medicines that both raise serotonin levels. This includes taking an serotonin and norepinephrine reuptake inhibitor (SNRI) with other antidepressants (selective serotonin reuptake inhibitors (SSRIs) + SNRIs), migraine medications (triptans), certain pain or headache medicines, the herbal supplement St. John’s wort or even some illicit drugs.

Milnacipran uses

Milnacipran is an selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that is US Food and Drug Administration (FDA) approved to treat chronic pain caused by fibromyalgia (a medical condition that causes chronic pain in the muscles and joints) ⁵⁹, ⁵¹, ⁵⁶. Milnacipran is initiated at 12.5 mg daily, and the dose is increased by 12.5 mg every few weeks until reaching a maximum of 50 to 100 mg, taken once or twice daily. Clinical trials indicate an average effective dose of 100 mg/day ⁵⁶. Milnacipran has been shown to improve pain and fatigue levels in patients with fibromyalgia but can cause sleep problems and depressive symptoms ⁶⁰. Milnacipran has a clinical benefit of improving 30% or more significant pain relief but not for 50% or greater ⁶¹. Milnacipran is intended to reduce pain levels, improve fibromyalgia, and ease physical activity.

Milnacipran is only approved for adults 18 years and older and is only available by prescription ⁵⁹. Milnacipran is not approved for children. It can cause suicidal thoughts and ideations in some participants. Importantly, it is not used to treat depression and psychiatric conditions, but its mechanism of action is very similar to antidepressant medications. Milnacipran should never be taken with a monoamine oxidase inhibitor (MAOI) as it could cause potentially life-threatening serotonin syndrome side effects ⁵⁹.

What to know before taking Milnacipran

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do.

Milnacipran may cause some teenagers and young adults to be agitated, irritable, or display other abnormal behaviors. Milnacipran may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, tell your doctor right away. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive) or has tried to commit suicide.

Do not take Milnacipran during 14 days after stopping a monoamine oxidase inhibitor (MAOI) (eg, isocarboxazid [Marplan], linezolid [Zyvox], methylene blue injection, phenelzine [Nardil], selegiline [Eldepryl], or tranylcypromine [Parnate]). Do not take an monoamine oxidase (MAO) inhibitor for at least 5 days after stopping Milnacipran. Talk to your doctor about this if you have questions.

Make sure your doctor knows if you are also using aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen, naproxen, Advil, Aleve, Celebrex, Motrin), or a blood thinner (eg, warfarin, Coumadin). Milnacipran may increase your risk of bleeding problems when taken together with these medicines.

Milnacipran may cause a serious condition called serotonin syndrome when taken with certain medicines such as St. John’s wort, buspirone, fentanyl, lithium, tryptophan, amphetamines, other medicines to treat depression, or some pain or migraine medicines (eg, rizatriptan [Maxalt], sumatriptan [Imitrex], tramadol [Ultram], or zolmitriptan [Zomig]. Check with your doctor first before taking any other medicines. Check with your doctor right away if you have anxiety, restlessness, a fast heartbeat, fever, sweating, muscle spasms, twitching, nausea, vomiting, diarrhea, or see or hear things that are not there.

You will also need to have your blood pressure and pulse measured before starting and while you are using Milnacipran. If you notice any change to your recommended blood pressure or pulse rate, call your doctor right away. If you have questions about this, talk to your doctor.

Check with your doctor right away if you have clay-colored stools, dark urine, decreased appetite, fever, headache, itching, loss of appetite, nausea and vomiting, skin rash, stomach pain or tenderness, swelling of the feet or lower legs, unusual tiredness or weakness, or yellow eyes or skin. These may be symptoms of a serious liver problem.

Avoid drinking alcohol while you are using Milnacipran.

Milnacipran may cause some people to become less alert than they are normally. Do not drive or do anything else that could be dangerous until you know how Milnacipran affects you.

Milnacipran may cause hyponatremia (low sodium in the blood). This is more common in elderly patients, those who are taking diuretic medicines for high blood pressure, or those who have decreased amounts of fluid in the body due to severe diarrhea or vomiting. Check with your doctor right away if you have confusion, headache, memory problems, trouble concentrating, weakness, or feel unsteady when standing.

Check with your doctor right away if you have decreased interest in sexual intercourse, delayed or inability to have and orgasm in women, inability to have or keep an erection in men, or loss in sexual ability, desire, drive, or performance. These could be symptoms of sexual dysfunction.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John’s wort) or vitamin supplements.

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

• Alcohol abuse
• Bleeding
• Depression
• Enlarged prostate
• Glaucoma, angle-closure
• Heart disease
• Heart rhythm problems (eg, tachyarrhythmia)
• Hypertension (high blood pressure)
• Hyponatremia (low sodium in the blood)
• Liver disease
• Mania
• Painful or difficult urination
• Seizures
• Urinary tract blockage: Use with caution. May make these conditions worse.
• End stage kidney disease: Use is not recommended in patients with this condition.
• Kidney disease, moderate or severe: Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to Milnacipran or any other medicines. Also tell your doctor if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children

Appropriate studies have not been performed on the relationship of age to the effects of milnacipran in the pediatric population. Safety and efficacy have not been established.

Elderly

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of milnacipran in the elderly. However, elderly patients are more likely to have hyponatremia (low sodium in the blood) and age-related kidney problems, which may require an adjustment in the dose for patients receiving milnacipran.

Pregnancy

Taking Milnacipran during pregnancy may cause serious lung problems or other complications in the baby. See your doctor right away if you become pregnant. Do not start or stop taking milnacipran during pregnancy without your doctor’s advice. If you are pregnant, your name may be listed on a pregnancy registry to track the effects of milnacipran on the baby.

Breastfeeding

Amounts of milnacipran in breastmilk are low and would not be expected to cause any adverse effects in breastfed infants ⁶². However, until more data become available, milnacipran should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant ⁶².

Eight lactating women who were at least 12 weeks following childbirth and weaning their infants received a single oral dose of milnacipran 50 mg. The average peak milk level of milnacipran was 262 mcg/L at an average of 4 hours and the average milk level was 122 mcg/L. The average relative infant dosage was estimated to be 2.8% of the weight-adjusted maternal dosage or 5% using the peak milk levels. Milnacipran was eliminated from milk with an average half-life of 7.5 hours ⁴⁸, ⁵⁹.

Galactorrhea (inappropriate lactation or milk production from the breast unrelated to pregnancy or lactation) is reported by the manufacturer to be a side effect of milnacipran ⁵⁹. One woman who was being treated for depression took an intentional overdose of 950 mg of milnacipran orally. From day 5 to day 15 after the overdose, the patient noted a flow of milk from her left breast. The galactorrhea resolved without treatment ⁶³.

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 Milnacipran, 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 Milnacipran 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.

• Isocarboxazid
• Linezolid
• Methylene Blue
• Metoclopramide
• Ozanimod
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Selegiline
• Tranylcypromine

Using Milnacipran 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.

• Abciximab
• Aceclofenac
• Acemetacin
• Acenocoumarol
• Alfentanil
• Almotriptan
• Amifampridine
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Amtolmetin Guacil
• Anagrelide
• Anileridine
• Apixaban
• Ardeparin
• Argatroban
• Aspirin
• Avitriptan
• Azathioprine
• Bemiparin
• Benperidol
• Benzhydrocodone
• Benzphetamine
• Betrixaban
• Bivalirudin
• Bromfenac
• Brompheniramine
• Bufexamac
• Buprenorphine
• Bupropion
• Buspirone
• Butorphanol
• Cangrelor
• Carbamazepine
• Celecoxib
• Certoparin
• Chlorpheniramine
• Choline Salicylate
• Plus many more not on this list.

Milnacipran Dosage

The dose of Milnacipran 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 Milnacipran. 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 treatment of fibromyalgia
  • Adults: At first, 12.5 milligrams (mg) once a day on Day 1. 12.5 mg 2 times a day on Days 2 to 3. 25 mg 2 times a day on Days 4 to 7. 50 mg 2 times a day after Day 7. Your doctor may adjust your dose as needed. However, the dose is usually not more than 200 mg per day.
  • Children: Use and dose must be determined by your doctor.

Missed Dose

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

Milnacipran Side Effects

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

• nausea
• vomiting
• constipation
• stomach pain
• weight loss
• dry mouth
• feeling of extreme facial warmth and/or redness
• headache
• blurred vision
• extreme tiredness
• lack of energy
• loss of appetite
• sexual problems in males; decreased sex drive, inability to get or keep an erection, or delayed or absent ejaculation
• sexual problems in females; decreased sex drive, or delayed orgasm or unable to have an orgasm
• pain or swelling of the testicles
• difficulty urinating
• rash
• itching

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

• fever, sweating, confusion, fast or irregular heartbeat, severe muscle stiffness or twitching, nausea, vomiting, or diarrhea
• hallucinations (seeing things or hearing voices that do not exist)
• confusion
• difficulty concentrating
• memory problems
• sweating or fever
• diarrhea
• dizziness
• uncontrollable shaking of a part of the body
• severe muscle stiffness
• weakness
• unsteady walking that may cause falling
• seizures
• fainting
• coma (loss of consciousness for a period of time)
• fast or irregular heartbeat
• difficulty breathing
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• dark colored urine
• unusual bleeding or bruising
• nosebleeds
• tiny red spots directly under the skin

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

Venlafaxine

Venlafaxine is an antidepressant often used to treat depression, anxiety and panic attacks. Venlafaxine is in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SNRIs). Venlafaxine works by increasing the amounts of serotonin and norepinephrine, natural substances in the brain that help maintain mental balance.

Venlafaxine helps many people recover from depression, and has fewer unwanted effects than older antidepressants.

Venlafaxine comes as tablets and capsules which are available only on prescription.

The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS (central nervous system). Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine, are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and O-desmethylvenlafaxine have no significant affinity for muscarinic, histaminergic, or adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs.

Key facts

• It usually takes 4 to 6 weeks for venlafaxine to work.
• Side effects such as feeling sick, headaches, sweating, and dry mouth are common. They are usually mild and go away after a couple of weeks.
• Venlafaxine can cause withdrawal symptoms. Don’t stop taking it without talking to your doctor.
• Venlafaxine has lots of different brand names including Effexor, Effexor XR and Efexor XL.

How and when to take venlafaxine

• Take venlafaxine once or twice a day as recommended by your doctor. It’s best to take venlafaxine with food so it doesn’t make you feel sick.

How should venlafaxine be used?

Venlafaxine comes as a tablet or extended-release capsule to take by mouth. The tablet is usually taken two or three times a day with food. The extended-release capsule is usually taken once daily in the morning or evening with food. Take venlafaxine 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 venlafaxine exactly as directed. Do not take more or less of it or take it more often or for a longer period of time than prescribed by your doctor.

Swallow the extended-release capsule whole; do not split, chew, or crush it, or place it in water. If you cannot swallow the extended-release capsule, you may carefully open the capsule and sprinkle the entire contents on a spoonful of applesauce. Swallow (without chewing) this mixture immediately after preparation and then drink a glass of water to make sure that you have swallowed all of the medication.

Your doctor will probably start you on a low dose of venlafaxine and gradually increase your dose, not more often than once every 4 to 7 days. Tell your doctor how you are feeling during your treatment so that your doctor can adjust your dose properly.

Venlafaxine controls depression but does not cure it. It may take 6 to 8 weeks or longer for you to feel the full benefit of this medication. Continue to take venlafaxine even if you feel well. Do not stop taking venlafaxine without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking venlafaxine, you may experience withdrawal symptoms such as agitation; anxiety; confusion; sad mood; irritability; frenzied or abnormal excitement; lack of coordination; trouble falling asleep or staying asleep; nightmares; nausea; vomiting; loss of appetite; diarrhea; dry mouth; sweating; ringing in the ears; seizures; or burning, tingling, numbness, or electric shock-like feelings in any part of the body. Tell your doctor if you experience any of these symptoms while you are decreasing your dose of venlafaxine or soon after you stop taking venlafaxine.

Pregnancy and breastfeeding

It’s important for you and your baby that you stay well during your pregnancy. If you become pregnant while taking venlafaxine speak to your doctor. Do not stop taking your medicine unless your doctor tells you to.

Venlafaxine has been linked to a very small increased risk of problems for your unborn baby. However if your depression is not treated during pregnancy this can also increase the chance of problems.

You may need to take venlafaxine during pregnancy if you need it to remain well. Your doctor can explain the risks and the benefits, and will help you decide which treatment is best for you and your baby.

Who can and can’t take venlafaxine

Venlafaxine can be taken by adults for depression, anxiety and panic attacks.

Check with your doctor before starting to take venlafaxine if you:

• have had an allergic reaction to venlafaxine or any other medicines in the past
• have a heart problem – as venlafaxine can speed up or change your heartbeat
• are trying to become pregnant, are already pregnant or you are breastfeeding
• have an eye problem called glaucoma because venlafaxine can increase the pressure in your eye

If you have diabetes, venlafaxine can make it more difficult to keep your blood sugar stable. Monitor your blood sugar more often for the first few weeks of treatment with venlafaxine and adjust your diabetes treatment if necessary.

Venlafaxine special precautions

Before taking venlafaxine:

• tell your doctor and pharmacist if you are allergic to venlafaxine, any other medications, or any of the ingredients in venlafaxine tablets or extended-release capsules. Ask your pharmacist for a list of the ingredients.

• tell your doctor if you are taking a monoamine oxidase (MAO) inhibitor, such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate), or if you have stopped taking one of these medications within the past 14 days. Your doctor will probably tell you that you should not take venlafaxine. If you stop taking venlafaxine, your doctor will tell you that you should wait at least 7 days before you start to take an MAO inhibitor.

• tell your doctor and pharmacist what other prescription and nonprescription medications, and vitamins you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin); amiodarone (Cordarone, Pacerone); other antidepressants; cimetidine (Tagamet); clozapine (Clozaril); diuretics (‘water pills’); duloxetine (Cymbalta); haloperidol (Haldol); imipramine (Tofranil); indinavir (Crixivan); ketoconazole (Nizoral); linezolid (Zyvox); lithium; medications for anxiety, mental illness, pain, seizures, or weight loss; medications for migraine such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig); methadone (Dolophine); methylene blue; phentermine (Adipex P, Ionamin); ritonavir (Norvir); sedatives; selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft); sibutramine (Meridia); sleeping pills; tramadol (Ultram); and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.

• tell your doctor what nutritional supplements and herbal products you are taking, especially St. John’s wort and tryptophan.

• tell your doctor if you have ever used illegal drugs or overused prescription medications. Also tell your doctor if you have recently had a heart attack and if you have or have ever had high blood pressure, high blood cholesterol seizures, or heart, kidney, liver, or thyroid disease.

• tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy, or if you plan to become pregnant or are breast-feeding. If you become pregnant while taking venlafaxine, call your doctor. Venlafaxine may cause problems in newborns following delivery if it is taken during the last months of pregnancy.

• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking venlafaxine.

• 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.

• remember that alcohol can add to the drowsiness caused by this medication.

• you should know that venlafaxine may cause angle-closure glaucoma (a condition where the fluid is suddenly blocked and unable to flow out of the eye causing a quick, severe increase in eye pressure which may lead to a loss of vision). Talk to your doctor about having an eye examination before you start taking this medication. If you have nausea, eye pain, changes in vision, such as seeing colored rings around lights, and swelling or redness in or around the eye, call your doctor or get emergency medical treatment right away.

Cautions with other medicines

Some medicines and venlafaxine can interfere with each other and increase the chances of you having side effects.

Tell your doctor if you’re taking these medicines before you start venlafaxine:

• any medicines that affect your heartbeat – as venlafaxine can speed up or change your heartbeat
• any other medicines for depression. Some rarely used antidepressants can interact with venlafaxine to cause very high blood pressure even when they have been stopped for a few weeks.

Mixing venlafaxine with herbal remedies and supplements

Don’t take the herbal remedy for depression, St John’s wort, while you are being treated with venlafaxine as it will increase your risk of side effects.

Tell your doctor or pharmacist if you are taking any other medicines, including herbal remedies, vitamins or supplements.

What is venlafaxine used for?

Venlafaxine is used to treat depression and it is also sometimes used to treat anxiety and panic attacks. Venlafaxine extended-release (long-acting) capsules are also used to treat generalized anxiety disorder (GAD; excessive worrying that is difficult to control), social anxiety disorder (extreme fear of interacting with others or performing in front of others that interferes with normal life), and panic disorder (sudden, unexpected attacks of extreme fear and worry about these attacks).

Venlafaxine dosage

The usual starting dose of venlafaxine is 75mg a day. This might be gradually increased to a maximum dose of 375mg.

If you have problems with your liver or kidneys your doctor might prescribe a lower dose.

Venlafaxine tablets and capsules can be either immediate release or extended release. How you take them depends on the type you’ve been prescribed.

Immediate release tablets release the venlafaxine into your system as soon as you swallow them. You will usually take 37.5mg immediate release tablets twice a day, once in the morning and once in the evening.

Extended release tablets and capsules are released into your system gradually. You will usually take 75mg extended release tablets or capsules once a day. You can choose to take them at any time as long as you stick to the same time every day. If you have trouble sleeping, it’s best to take it in the morning.

Dose adjustments for discontinuation: A gradual reduction in the dose is recommended whenever possible. In clinical studies, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals.

Adult Dose for Depression

Use: Treatment of major depressive disorder

Immediate release:

• Initial dose: 37.5 mg orally twice a day or 25 mg orally 3 times a day
• Maintenance dose: May increase in daily increments of up to 75 mg orally at intervals of no less than 4 days
• Maximum dose: (moderately depressed outpatients): 225 mg orally per day
• Maximum dose (severely depressed inpatients): 375 mg orally per day

Comments:

• Daily dosage may be divided in 2 or 3 doses/day

Extended release:

• Initial dose: 75 mg orally once a day
• Maintenance dose: May increase in daily increments of up to 75 mg orally at intervals of no less than 4 days
• Maximum dose (moderately depressed outpatients): 225 mg orally per day
• Maximum dose (severely depressed inpatients): 375 mg orally per day

Adult Dose for Anxiety

Uses:

• Treatment of Generalized Anxiety Disorder (GAD)
• Treatment of Social Anxiety Disorder

Extended release:

• Initial dose: 75 mg orally once a day
• Maintenance dose: May increase in daily increments of 75 mg orally at intervals of no less than 4 days
• Maximum dose: 225 mg orally per day

Adult Dose for Panic Disorder

Use: Treatment of Panic Disorder, with or without agoraphobia

Extended release:

• Initial dose: 37.5 mg orally once a day
• Maintenance dose: May increase dose in daily increments of 75 mg orally at intervals of no less than 7 days
• Maximum dose: 225 mg orally per day

Renal Dose Adjustments

• Mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min): Dosage should be reduced by 25% to 50%

Liver Dose Adjustments

• Mild to moderate hepatic impairment: Dosage should be reduced 50%.
• Cirrhosis: Dosage should be reduced by at least 50%.

What should I do if I forget a dose?

If you occasionally forget to take a dose, don’t worry. Take your next dose at the usual time. Never take 2 doses at the same time to make up for a forgotten one.

If you forget doses often, it may help to set an alarm to remind you. You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.

What if I take too much?

Ask your doctor for advice straight away. An overdose can lead to potentially serious symptoms such as:

• feeling sleepy
• vomiting
• a racing heart
• seizures

Venlafaxine side effects

Like all medicines, venlafaxine can cause side effects in some people, but many people have no side effects or only minor ones. Some of the common side effects of venlafaxine will gradually improve as your body gets used to it.

Common side effects

These side effects happen in more than 1 in 100 people. Keep taking the medicine, but tell your doctor or pharmacist if these side effects bother you or don’t go away:

• feeling sick
• headaches
• sweating
• dry mouth
• trouble sleeping
• dizziness
• feeling sleepy
• constipation

Call your doctor if any of the following symptoms are severe or do not go away:

• drowsiness
• weakness or tiredness
• dizziness
• headache
• nightmares
• nausea
• vomiting
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• burping
• dry mouth
• change in ability to taste food
• loss of appetite
• weight loss
• uncontrollable shaking of a part of the body
• pain, burning, numbness, or tingling in part of the body
• muscle tightness
• twitching
• yawning
• sweating
• hot flashes or flushing
• frequent urination
• difficulty urinating
• sore throat, chills, or other signs of infection
• ringing in the ears
• changes in sexual desire or ability
• enlarged pupils (black circles in the middle of the eyes)

Some side effects can be serious.

Serious side effects happen uncommonly (in less than 1 in 100 people), but some people may have serious side effects when taking venlafaxine.

Tell a doctor straight away if you develop:

• headaches, trouble focusing, memory problems, not thinking clearly, weakness, seizures, or losing your balance – these can be signs of low sodium levels
• thoughts about harming yourself or ending your life
• chest pain or pressure, shortness of breath, or a fast or irregular heart beat
• severe dizziness or passing out
• feelings of euphoria, excessive enthusiasm or excitement, or a feeling of restlessness that means you can’t sit or stand still
• unexplained muscle pain or weakness
• yellow skin or eyes – this can be a sign of liver problems
• any changes in your eyesight, like blurred vision or dilated pupils
• putting on or losing weight without trying to
• changes in your periods such as heavy bleeding, spotting, or bleeding between periods

Or, if you get any signs of abnormal bleeding including:

• vomiting blood or dark vomit, coughing up blood, blood in your pee, black or red poo – these can be signs of bleeding from the gut
• bleeding from the gums or bruises that appear without a reason or that get bigger
• any bleeding that is very bad or that you cannot stop

Serious allergic reaction

In rare cases, it’s possible to have a serious allergic reaction to venlafaxine. A serious allergic reaction is an emergency. Contact a doctor straight away if you think you or someone around you is having a serious allergic reaction.

The warning signs of a serious allergic reaction are:

• getting a skin rash that may include itchy, red, swollen, blistered or peeling skin
• wheezing
• tightness in the chest or throat
• having trouble breathing or talking
• swelling of the mouth, face, lips, tongue, or throat

If you experience any of the following symptoms or those listed in the IMPORTANT WARNING or SPECIAL PRECAUTIONS sections, call your doctor immediately:

• rash
• hives
• itching
• difficulty breathing or swallowing
• chest pain
• fast, pounding, or irregular heartbeat
• seizures
• unusual bruising or bleeding
• small purple spots on the skin
• eye pain or redness
• fever, sweating, confusion, fast or irregular heartbeat, and severe muscle stiffness
• fever
• problems with coordination
• hallucinations (seeing things or hearing voices that do not exist)
• coma (loss of consciousness for a period of time)

Venlafaxine may slow growth and weight gain in children. If your child is taking venlafaxine, your child’s doctor will watch your child’s growth carefully. Talk to your child’s doctor about the risks of giving venlafaxine to your child.

These are not all the side effects of venlafaxine. For a full list see the leaflet inside your medicines packet. Call your doctor if you have any unusual problems while you are taking venlafaxine.

Serotonin and norepinephrine reuptake inhibitors uses

The U.S. Food and Drug Administration (FDA), has approved these SNRIs to treat depression:

• Desvenlafaxine (Pristiq) ⁵
• Duloxetine (Cymbalta, Drizalma Sprinkle). Duloxetine is also approved to treat generalized anxiety disorder (GAD) and certain types of pain, such as fibromyalgia pain and pain from diabetic neuropathy ⁶
• Levomilnacipran (Fetzima) ⁷
• Venlafaxine (Effexor XR). Venlafaxine is also approved to treat generalized anxiety disorder (GAD), social anxiety disorder (social phobia) and panic disorder ⁸, ⁹
• Milnacipran (Savella) is the only SNRI not approved in the U.S. for the treatment of major depressive disorder, but the drug is effective for depression and is approved in some other countries for major depressive disorder. In the U.S., Milnacipran is used to treat fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ¹⁰, ¹¹.

Drug interactions may occur with duloxetine, desvenlafaxine, and venlafaxine due to metabolism by CYP isoenzymes. Milnacipran and levomilnacipran have minimal CYP450 metabolism, and clinically relevant interactions related to CYP metabolism are not expected.

Duloxetine should not be used in patients with liver impairment or risk factors for liver impairment (e.g., alcoholism). Milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine can be used in patients with hepatic impairment; however, dosage adjustments for venlafaxine and desvenlafaxine are required.

Drug-specific dosage adjustments are required for desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine in the presence of renal dysfunction and are based upon the severity of the kidney impairment.

Major depressive disorder

Given the absence of differences in efficacy or tolerability between drug classes, the SNRIs are not preferentially recommended over SSRIs in the treatment of major depressive disorder (clinical depression) ⁶⁴, ⁶⁵, ⁶⁶.

Choice of antidepressant for each patient is based on several factors such as tolerability, drug interactions, prior history of response, and efficacy in the selected indication ⁶⁷, ⁶⁸, ⁶⁶.

SNRIs have not been approved for use in pediatric populations for the treatment of depression; however, guidelines from the American Academy of Child and Adolescent Psychiatry (AACAP) recommend the use of antidepressants when nonpharmacologic treatment is insufficient or illness severity is high. Data specific to SNRIs in the treatment of pediatric depression are limited. Therefore, SNRIs are generally reserved for use in pediatric patients with documented antidepressant treatment failure or intolerability to an SSRI ⁶⁹, ⁷⁰.

According to the manufacturer of duloxetine, efficacy was not established in two 10-week controlled trials with 800 pediatric patients 7 years and older with major depressive disorder ⁶.

Fibromyalgia

Duloxetine and milnacipran have proven efficacy and safety in the treatment of fibromyalgia in adults. Duloxetine is the only SNRI approved for the treatment of fibromyalgia in adolescents 13 years and older ⁶.

In adults, the overall benefit is modest (i.e., benefit for pain, sleep, fatigue, depression, and health-related quality of life in randomized controlled trials was significant, but the effect size was small for pain and not substantial for the other efficacy parameters) ⁷¹.

Duloxetine and milnacipran are similar in efficacy to pregabalin, an anticonvulsant with FDA approval for the treatment of fibromyalgia; however, pregabalin is superior to milnacipran for sleep outcomes ⁷².

Off-label uses

Doctors sometimes prescribe SNRIs for other conditions. This is considered an off-label, or non-FDA-approved, use of the medication. Examples of off-label uses include:

• Anxiety disorders.
• Hot flashes and night sweats associated with menopause.
• Peripheral neuropathy due to chemotherapy.
• Urinary incontinence.
• Attention-deficit and hyperactivity disorder (ADHD).
• Obsessive-compulsive disorder (OCD).
• Migraine prevention.

Anxiety disorder

Due to their efficacy and safety profile, venlafaxine and duloxetine are considered first-line treatment options for generalized anxiety disorder (GAD) in adults ⁷³.

Duloxetine is approved for generalized anxiety disorder (GAD) in children 7 years and older ⁶, ⁷⁴.

Other uses

Duloxetine has shown effectiveness in treating pain associated with diabetic peripheral neuropathy and was the first drug specifically approved for diabetic peripheral neuropathy in adults.

Duloxetine is beneficial for treating chronic musculoskeletal pain in adults. Efficacy was established in patients with chronic low back pain and chronic pain due to osteoarthritis.

Duloxetine is recommended for the off-label treatment of stress urinary incontinence in women because it increases detrusor muscle tone.

Venlafaxine and desvenlafaxine are used off-label in the treatment of vasomotor symptoms (hot flushes) associated with menopause or breast cancer; these drugs are effective alternatives for women who cannot use, or do not wish to use, hormonal therapy for vasomotor symptom control.

What to know before taking SNRI

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are safe for most people. But sometimes SNRI can slightly raise your blood pressure, lower electrolyte levels such as sodium (hyponatremia) and worsen liver conditions. You should know that SNRIs may cause angle-closure glaucoma, a form of glaucoma that happens when the iris bulges blocking the fluid outflow inside your eye and causing a quick, severe increase in eye pressure which may lead to a loss of vision. Talk to your doctor about having an eye examination before you start taking SNRI. If you have nausea, eye pain, changes in vision, such as seeing colored rings around lights, and swelling or redness in or around the eye, call your doctor or get emergency medical treatment right away. Most of these safety issues can be monitored by your doctor while you’re taking SNRI.

Talk with your doctor about safety issues before you take an SNRI, including:

• Medicine interactions. Tell your doctor about any other prescription or nonprescription medicines, herbs or other supplements you’re taking. Some antidepressants can cause dangerous reactions when taken with certain medicines or herbal products. For example, SNRIs may slightly raise your risk of bleeding, especially when you’re taking other medicines that also raise the risk of bleeding. These other medicines can include ibuprofen (Advil, Motrin IB, others), aspirin, warfarin (Jantoven) and other blood thinners.
• Serotonin syndrome (serotonin toxicity). Rarely, antidepressants can cause dangerously high levels of serotonin in the body. This is called serotonin syndrome or serotonin toxicity. Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonin activity in your brain, often triggered by drug interactions or overdose, and characterized by a combination of mental, autonomic, and neuromuscular symptoms. Symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, lack of coordination, major changes in blood pressure and rapid heart rate. Get medical help right away if you have any of these symptoms. Severe serotonin syndrome can be life-threatening due to complications like seizures, hyperthermia (high body temperature), and organ damage. Serotonin syndrome happens most often when you take two medicines that both raise serotonin levels. This includes taking an SNRI with other antidepressants (selective serotonin reuptake inhibitors (SSRIs) + SNRIs), migraine medications (triptans), certain pain or headache medicines, the herbal supplement St. John’s wort or even some illicit drugs.
• Antidepressants and pregnancy. Some antidepressants may harm your baby if you take them during pregnancy or while you’re breastfeeding. If you are pregnant, are thinking about getting pregnant or are breastfeeding, talk to your doctor about the benefits and possible risks of antidepressants. Don’t stop taking your medicine without talking with your doctor first.

Increased risk of suicide

Most antidepressants are generally safe, but the U.S. Food and Drug Administration (FDA) says that all antidepressants must carry boxed warnings, the strictest warnings for prescriptions. In some cases, children, teenagers and young adults under age 25 may have an increase in suicidal thoughts or behavior when taking antidepressants. This may be more likely in the first few weeks after starting the medicine or when the dose is changed. There has been no evidence that this increase in suicidal thoughts or behaviors has resulted in completed suicides. In 2004, the U.S. Food and Drug Administration (FDA) issued a “black-box” warning regarding a potential increase in suicidality in adolescents receiving antidepressant treatment for depression that was later expanded to include both young adults and a broader range of antidepressants.

Anyone taking an antidepressant should be watched closely for worsening depression or unusual behavior. If you or someone you know has suicidal thoughts when taking an antidepressant, call your doctor right away or get emergency help. Keep in mind that depression that’s not treated is a more concerning risk factor for suicide. And antidepressants may lessen suicide risk in the long run by improving mood for many people ⁷⁵.

Bipolar disorder

The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, the antidepressant should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Hypersensitivity and cross-sensitivity issues

Allergic reactions may occur with the use of any SNRI. Because some SNRIs are available as both a racemic compound (e.g., milnacipran) and a single enantiomer of the racemic compound (e.g., levomilnacipran), cross-sensitivity should be expected. Similarly, cross-sensitivity is possible between desvenlafaxine and venlafaxine, since venlafaxine is the parent compound of desvenlafaxine. Levomilnacipran and milnacipran are contraindicated in patients exhibiting hypersensitivity to the related drug; desvenlafaxine and venlafaxine are contraindicated in patients who have demonstrated a hypersensitivity to the related drug.

Breastfeeding

Small concentrations of SNRIs have been measured in breast milk, with uncertain consequences for the infant. The benefits of drug treatment to the mother need to be weighed against the potential risk of infant drug exposure. There are reports of agitation, irritability, poor feeding, and poor weight gain following exposure to serotonergic antidepressants through breast milk. Any infant exposed to an SNRI through breast-feeding should be monitored for these adverse effects.

Pregnancy

The American Psychiatric Association guidelines state that treatment of depression during early pregnancy requires careful risk-benefit assessment, in collaboration with the patient and potentially a neonatal specialist. Use of serotonergic antidepressants, including SNRIs, during the third trimester has been associated with neonatal complications, including prolonged hospitalization, respiratory support, and tube feeding. In addition, exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia; this potential has been reported for venlafaxine. Data indicate exposure to SNRIs, particularly in the month before obstetric delivery, may be associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Treatment with any SNRI during pregnancy should be individualized.

Alcohol and antidepressants

Talk to your doctor about drinking alcohol while taking an antidepressant. You should be careful about drinking until you know how the medicine affects you. The effects of alcohol can combine with the effects of the antidepressant and cause problems. Regular heavy drinking can make it harder to treat depression. Certain kinds of medicine can lead to seizures for heavy drinkers.

Liver impairment

SNRI use has been associated with elevated hepatic enzymes. Duloxetine is not recommended in patients with any degree of hepatic impairment. Avoidance of duloxetine is recommended in patients with substantial alcohol use, alcoholism, hepatic necrosis, and/or chronic liver disease. Dosage adjustments of venlafaxine and desvenlafaxine are recommended in patients with hepatic impairment. Milnacipran can be used cautiously in patients with hepatic impairment. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative option in patients with hepatic disease.

Stopping treatment with SNRIs

Talk with your doctor before you stop taking an SNRI. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are not considered habit-forming. But stopping antidepressant treatment suddenly or missing several doses may cause some symptoms. This is sometimes called discontinuation syndrome or antidepressant discontinuation syndrome. A discontinuation syndrome can occur when SNRIs are abruptly halted. This syndrome is characterized by dizziness, weakness, nausea, headache, lethargy, insomnia, anxiety, poor concentration, paresthesias (tactile sensations), and increased gastrointestinal motility. Symptoms occur most frequently and severely with shorter-acting agents (e.g., immediate-release venlafaxine). A slow, individualized taper is advisable, particularly after chronic use, to minimize discontinuation symptoms. If your doctor recommended you take a lower dosage of your medicine and you’re experiencing symptoms of antidepressant discontinuation syndrome, talk with your doctor. You may need to take a higher dosage before weaning your body from the medicine completely.

If you decided to stop taking your antidepressant medicine on your own, talk to your doctor about why you stopped. For example, was the medicine causing an unpleasant side effect? Did it cost too much? Your doctor can help by altering your dosage or suggesting another antidepressant.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) discontinuation symptoms can include:

• Dizziness.
• Headache.
• Flu-like symptoms, such as tiredness, chills and muscle aches.
• Irritability and restlessness.
• Upset stomach.
• Insomnia or sleep disturbances, such as nightmares.
• Diarrhea.

These symptoms may be more likely to happen with venlafaxine or desvenlafaxine, though they can happen when any SNRI is stopped suddenly. Work with your doctor to slowly and safely lower your dose over time so you can stop the medicine safely.

Drug Interactions

Monoamine oxidase inhibitors (MAOIs)

SNRIs are contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) or within 2 weeks of their discontinuation due to the risk of serotonin syndrome. Medications with monoamine oxidase inhibitors (MAOIs) activity, such as linezolid or intravenous methylene blue, are also contraindicated for use with SNRIs because of an increased risk of serotonin syndrome or serotonin toxicity. Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonin activity in your central nervous system (brain and spinal cord), often triggered by combining medications that increase serotonin levels, such as certain antidepressants (SSRIs, SNRIs), migraine medications (triptans), or even some illicit drugs or supplements or overdose. Serotonin syndrome causes signs and symptoms that can range from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures). Severe serotonin syndrome can cause death if not treated.

Serotonin syndrome symptoms usually occur within several hours of taking a new drug or increasing the dose of a drug you’re already taking.

Serotonin syndrome signs and symptoms include:

• Agitation or restlessness
• Insomnia
• Confusion
• Rapid heart rate and high blood pressure
• Dilated pupils
• Loss of muscle coordination or twitching muscles
• High blood pressure
• Muscle rigidity
• Heavy sweating
• Diarrhea
• Headache
• Shivering
• Goose bumps

Severe serotonin syndrome can be life-threatening. Signs include:

• High fever
• Tremor
• Seizures
• Irregular heartbeat
• Unconsciousness.

If you suspect you might have serotonin syndrome after starting a new drug or increasing the dose of a drug you’re already taking, call your doctor right away or go to the emergency room. If you have severe or rapidly worsening symptoms, seek emergency treatment immediately.

SSRIs, SNRIs and other serotonergic drugs

Any use of an SNRI with other serotonergic agents increases the likelihood of serotonergic adverse effects and should be monitored closely. Drugs that have serotonergic properties include opiates, triptans, most antidepressants, amphetamines, St. John’s wort, tramadol, lithium, buspirone, and others.

Antithrombotic drugs (antiplatelet and anticoagulant therapies)

Anticoagulants (blood thinners), antiplatelet drugs (e.g., aspirin), and nonsteroidal anti-inflammatory drugs (NSAIDs) should be administered with caution to any patient taking an SNRI. Platelet aggregation may be impaired by SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.

Drugs that inhibit CYP2D6 or CYP1A2

Levomilnacipran and milnacipran are not metabolized to any significant extent by CYP450 isoenzymes and are not inducers or inhibitors of any of these isoenzymes. Venlafaxine is metabolized by CYP2D6, and CYP2D6 inhibitors may increase venlafaxine concentrations. A dose-related CYP2D6 inhibitory effect has been observed with desvenlafaxine; therefore, the dose of primary CYP2D6 substrates should be reduced by up to one-half if coadministered with desvenlafaxine 400 mg/day. Duloxetine is metabolized by CYP1A2 and CYP2D6; inhibitors of CYP1A2 and CYP2D6 may increase duloxetine concentrations.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) Dosage

Dosages fluctuated depending on the SNRI used due to varying potencies of the drug in question as well as multiple strengths for each drug.

• Venlafaxine: The starting dose is 75 mg daily, and the usual maintenance dose is 225 to 375 mg daily.
• Desvenlafaxine: The starting dose is 25 to 50 mg daily; the usual maintenance dose is 50 mg daily.
• Duloxetine: The starting dose is 30 mg daily, and the usual maintenance dose is 60 mg daily.
• Milnacipran: The starting dose is 12.5 mg daily, and the usual maintenance dose is 100 mg daily.
• Levomilnacipran: The starting dose is 20 mg daily, and the usual maintenance dose is 40 to 120 mg daily.

Serotonin and norepinephrine reuptake inhibitors side effects

All serotonin and norepinephrine reuptake inhibitors (SNRIs) work in much the same way and generally can cause the same kinds of side effects. Some people may not have any side effects. Side effects that do occur are usually mild and go away after the first few weeks of treatment. Taking medicine with food may lessen upset stomach, a common side effect. If you can’t handle the side effects of one SNRI, you may have fewer side effects with a different one, as each SNRI has a different chemical makeup.

The most common possible side effects of serotonin and norepinephrine reuptake inhibitors (SNRIs) include:

• Upset stomach.
• Dry mouth.
• Dizziness.
• Headache.
• Sweating.

Other possible side effects of serotonin and norepinephrine reuptake inhibitors (SNRIs) may include:

• Tiredness.
• Constipation.
• Trouble sleeping.
• Less sexual desire or trouble reaching orgasm.
• Loss of appetite.

The benefits of antidepressants typically outweigh the possible side effects when depression is severe. Which antidepressant is best for you depends on several factors, such as your symptoms and any other health conditions you may have.

Ask your doctor or pharmacist about the most common possible side effects for your specific medicine. Read the patient medication guide that comes with the prescription.

Gastrointestinal adverse reactions

Gastrointestinal (GI) side effects are the most common adverse reactions in patients receiving SNRI treatment. Nausea is the most common adverse reaction with any SNRI. It is most often transient and of mild to moderate intensity. Other less frequently reported gastrointestinal effects include dry mouth (xerostomia), constipation, and vomiting. One review noted that venlafaxine, one of the SNRIs, was associated with a higher risk for nausea when compared to agents in the SSRI class ⁶, ¹⁰, ⁸, ⁹, ⁵, ⁶⁸, ⁷.

Central nervous system adverse reactions

Headache, dizziness, drowsiness, and insomnia are the most common centrally-mediated adverse reactions, but are rarely severe and usually do not lead to treatment discontinuation.

Bleeding disorder

Monitor patients taking an SNRI for signs and symptoms of bleeding. Impaired platelet aggregation may occur during treatment with SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. In published observational studies, pregnant patients taking SSRIs, particularly in the month prior to obstetric delivery, were at an increased risk of postpartum hemorrhage; this effect is also possible with the SNRIs. A postmarketing study showed a higher incidence of postpartum hemorrhage in mothers taking the SNRI duloxetine. Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase the risk of these bleeding complications. Patients should be instructed to promptly report any bleeding events to their health care provider.

Blood pressure changes

All SNRIs have been associated with sustained elevation of blood pressure, most notably venlafaxine. Blood pressure should be monitored closely when initiating therapy or increasing SNRI dosages, and routinely thereafter. Orthostatic hypotension has also been reported, particularly in the elderly.

Low blood sodium (hyponatremia)

SNRIs may cause hyponatremia (low blood sodium level) as a result of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion; serum sodium levels less than 110 mmol/L have been reported. Elderly patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume-depleted (e.g., hypovolemia) appear to be at greatest risk. The syndrome of inappropriate antidiuretic hormone (SIADH) is reversible upon discontinuation of the causative SNRI.

Skin and hypersensitivity reactions

Hyperhidrosis (increased sweating) is the most common adverse dermatologic effect associated with SNRIs. Severe reactions, including anaphylactoid reactions, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have been reported rarely with the various SNRIs. The SNRI should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other cause can be identified.

Sexual dysfunction

Sexual dysfunction is commonly reported with the use of serotonergic agents such as SNRIs and may result in treatment discontinuation in some patients. In men, these symptoms may include ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Women may experience decreased libido and delayed or absent orgasm. Clinicians should discuss sexual function with patients prior to initiating treatment and throughout treatment to identify any changes in sexual function and determine if they are medication-related or attributed to the underlying psychiatric disorder. Patients should also be provided with management strategies and treatment options for symptoms of sexual dysfunction.

Angle-closure glaucoma

Closed-angle glaucoma has occurred in patients with untreated anatomically narrow angles during treatment with antidepressants. Duloxetine is contraindicated in patients with uncontrolled angle-closure glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

Liver toxicity

Elevated liver function tests (LFTs) have been reported with all SNRIs and appear to be dose-related. Hepatitis and hepatic failure have occurred during administration of some SNRIs; fatalities have been reported. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative to consider in patients with hepatic disease.

Neonatal abstinence syndrome

Symptoms consistent with a neonatal discontinuation syndrome (e.g., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting) have been reported in infants exposed to SNRIs in utero, particularly during the third trimester. SNRIs should be used in pregnancy only where the benefit to the mother clearly outweighs any potential risk to the fetus. Consider the risks of untreated depression during pregnancy as well as the potential risks to the fetus from exposure to the drug. If clinically feasible, and taking the drug half-life into consideration, tapering of the antidepressant prior to delivery may be considered.

SNRI Poisoning

Clinical features include:

• Tachycardia
• Hypertension
• Electrocardiogram (ECG) changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia
• Changes in the level of consciousness (ranging from somnolence to coma)
• Mydriasis
• Serotonin syndrome
• Rhabdomyolysis
• Liver necrosis
• Death

SNRI Poisoning management:

• In case of acute overdose with SNRI, the clinician should ensure an adequate airway, breathing, and circulation.
• For serotonin syndrome, specific treatment such as with cyproheptadine may be considered.
• Treat prolonged QRS intervals with sodium bicarbonate
• Prolonged QTc leading to Torsades de pointes: Administer magnesium sulfate 2 g IV.
• Consider extracorporeal life support in severe poisoning with venlafaxine ⁷⁶.

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