Minoxidil

Minoxidil liquid to be applied to your scalp is used to stimulate hair growth and to slow hair loss and Minoxidil tablet to be taken by mouth is used with other medications to treat high blood pressure not responding to maximum doses of 3 different antihypertensive medications also called resistant hypertension. In some countries, Minoxidil is available in other formulations such as foam or gel. Minoxidil liquid to be applied to your scalp is most effective for people under 40 years of age whose hair loss is recent. Minoxidil liquid to be applied to your scalp has no effect on receding hairlines. Minoxidil liquid to be applied to your scalp does not cure baldness; most new hair is lost within a few months after Minoxidil is stopped. In United States, Minoxidil Foam or Minoxidil Solution is available without a prescription. Furthermore, Minoxidil is marketed in an oral tablet formulation and as a topical agent in foam and solution formulations for both male and female patients.

Minoxidil is in a class of medications called vasodilators (medicines that open blood vessels). Minoxidil works by relaxing the blood vessels so that blood can flow more easily through your body. Minoxidil was originally marketed in a tablet form for the treatment of high blood pressure (hypertension). When Minoxidil tablet was used to treat high blood pressure (hypertension) one of the side effects of Minoxidil was unwanted hair growth. This side effect promoted researchers to produce Minoxidil topical solution for treating hair loss.

Topical Minoxidil is used in the treatment of male pattern hair loss in men (MPHL), and female pattern hair loss in women (FPHL) commonly known as androgenetic alopecia (androgenic alopecia). Topical Minoxidil is occasionally useful for other forms of hair loss (alopecia), including alopecia areata, and after hair replacement surgery or chemotherapy. Minoxidil effectiveness may be enhanced by concurrent use of a topical retinoid (medications derived from vitamin A formulated as a cream, lotion, foam, emulsion, or gel).

Minoxidil is marketed as Rogaine Topical Solution (5%) and Headway Topical Solution (2% and 5%). Minoxidil 5% solution is probably more effective but it may result in greater irritation than Minoxidil 2% solution. Minoxidil Topical Solution is applied to the affected area of the scalp once or twice daily for a minimum of 6 months. If it is found to be effective, it may be continued long term.

Follow the directions on your package or prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use minoxidil exactly as directed. Do not use more or less of it or use it more often than directed by your doctor.

Exceeding the recommended dosage does not produce greater or faster hair growth and may cause increased side effects. You must use Minoxidil Topical Solution for at least 4 months, and possibly for up to 1 year, before you see any effect.

Three special applicators are provided: a metered-spray applicator for large scalp areas, an extender spray applicator (used with the metered-spray applicator) for small areas or under the hair, and a rub-on applicator.

Remove the outer and inner caps from the bottle, choose an applicator, and screw it tightly onto the bottle.

To use the extender spray applicator, first assemble the metered-spray applicator and then follow the instructions provided to attach the extender spray applicator. Pump the metered-spray or extender spray applicator six times for each dose. Try not to inhale the mist. Place the large cap on the metered-spray bottle or the small cap on the extender spray nozzle when not in use.

To use the rub-on applicator, hold the bottle upright and squeeze it until the upper chamber of the applicator is filled to the black line. Then turn the bottle upside down and rub on the medication. Place the large cap on the bottle when not in use. If you use your fingertips to apply the medication, wash them thoroughly afterwards.

Apply Minoxidil Topical Solution to dry hair and scalp only. Do not apply it to other body areas, and keep it away from your eyes and sensitive skin. If it accidentally comes in contact with these areas, wash them with lots of cool water; call your doctor if they become irritated.

Do not apply minoxidil to a sunburned or irritated scalp.

Minoxidil side effects include local irritation most often resulting in itching or stinging. Contact allergy to minoxidil or propylene glycol (the main component of Minoxidil solution) occurs rarely, and results in dermatitis.

Unwanted hair growth might occur (hypertrichosis), for example if Minoxidil solution is dripped onto the forehead.

Internal effects are not likely as there is minimal absorption into your body. However, hair growth in distant sites such as your arms, chest and lower back has occasionally been reported when Minoxidil 5% solution has been used.

Hypotension (low blood pressure) is a rare occurrence in patients using topical minoxidil. Nonetheless, some clinicians advise consistent monitoring of blood pressure, heart rate, and electrocardiographic changes for patients undergoing topical minoxidil therapy. Clinicians should conduct thorough assessments to eliminate secondary causes of hypertension, such as renal artery stenosis, primary aldosteronism, pheochromocytoma, and Cushing syndrome, warranting minoxidil treatment. Regular monitoring of fundoscopic examination, renal function, echocardiogram, and ankle-brachial index is recommended to assess potential target organ damage for patients taking minoxidil ¹⁾.

Minoxidil is best avoided during pregnancy and breastfeeding (Pregnancy Category C, i.e., Drugs that, owing to their pharmacological effects, have caused or maybe suspected of causing harmful effects on the human fetus or neonate without causing malformations) ²⁾.

What causes hair loss in men and women?

Male pattern hair loss also called androgenetic alopecia (androgenic alopecia) is an inherited condition caused by a genetically determined excessive sensitivity to the effects of dihydrotestosterone (DHT) in some areas of the scalp that affects up to 50% of males and females ⁷⁾, ⁸⁾, ⁹⁾. Male pattern hair loss (androgenetic alopecia) is characterized by progressive loss of terminal hair of the scalp any time after puberty, in a characteristic distribution in both males and females. In males, hair loss is most prominent in the crown (the vertex, the highest point on your scalp) and frontotemporal regions, while in women the frontal hairline is typically spared with diffuse hair loss at the crown and top of head, with loss often marked by a wider center part ¹⁰⁾, ¹¹⁾, ¹²⁾.

Dihydrotestosterone (DHT) is believed to shorten the growth or anagen, phase of the hair cycle, from a usual duration of 3 to 6 years to just weeks or months ¹³⁾, ¹⁴⁾. This occurs together with miniaturization of the hair follicles and progressively produces fewer and finer hairs. The production of dihydrotestosterone (DHT) is regulated by an enzyme called 5-alpha reductase (5α-reductase). 5-alpha reductase (5α-reductase) enzyme is involved in processing androgens, which are sex hormones that direct male sexual development that help start puberty and play a role in reproductive health and body development. Specifically, the steroid 5-alpha reductase 2 enzyme is responsible for a chemical reaction that converts the hormone Testosterone to Dihydrotestosterone (DHT). DHT has a critical role in male sexual development, and a shortage of this hormone disrupts the formation of the external sex organs before birth.

Several genes are involved, accounting for differing age of onset, progression, pattern and severity of hair loss in family members. The hair loss genes are inherited from both mother and father. At this time, genetic testing for prediction of balding is unreliable.

A few women present with male pattern hair loss because they have excessive levels of androgens as well as genetic predisposition. These women also tend to suffer from acne, irregular menses and excessive facial and body hair. These symptoms are characteristic of polycystic ovarian syndrome (PCOS) although the majority of women with PCOS (polycystic ovarian syndrome) do not experience hair loss. Less often, congenital adrenal hyperplasia (CAH or 21-hydroxylase deficiency) may be responsible. Females that are losing their hair with age are more likely to present with female pattern hair loss, in which hormone tests are normal.

Figure 1. Hair loss in women (androgenic alopecia in women)

Footnote: Female pattern hair loss (androgenic alopecia in women) showing hair thinning mostly confined to the crown (top of scalp) with retention of frontal hairline.

Figure 2. Androgenetic alopecia female (female pattern baldness)

Footnote: Androgenetic alopecia in women with ‘Christmas Tree Pattern’

Figure 3. Male pattern hair loss

What is hair growth cycle?

The human scalp contains about 100,000 hair follicles. These anchor the hair to the skin and contain the cells that produce new hairs. A hair in the scalp grows for two to five years, at a rate of around 0.33 mm/day (about 1/64 inch). Variations in hair growth rate and the duration of the hair growth cycle account for individual differences in uncut hair length. Hair grows in 3 developmental stages:

1. Anagen. The anagen phase or actively hair growing phase starts the growing of new hair. The anagen phase is genetically determined and can vary from 2 to 6 years (the average is just under 3 years). Most hair follicles on the scalp are in the anagen phase.
2. Catagen. The catagen phase is a transition stage (in-between phase) between the growing and resting phases and lasts 2-3 weeks. The catagen phase is when hair growth stops and the hair follicle shrinks. About 1–3% of hairs are in the catagen phase (in-between phase).
3. Telogen. The telogen phase or resting phase is a mature hair with a root, which is held very loosely in the follicle. The telogen phase (resting phase) generally lasts about 4-5 months. Up to 10% of hairs in a normal scalp are in the telogen phase (resting phase). About 100 telogen hairs are lost from the human scalp each day.

Everyone is born with a fixed number of hair follicles on the scalp that produce hairs throughout life. Hair grows from the base of the follicle at a rate of about one centimetre a month for about three years. This growth phase is called anagen. After anagen, the hair dies (catagen hair) and no longer grows. It sits dormant in the follicle for a three-month phase called telogen. After telogen, the hair follicle undergoes another anagen phase to produce new hair that grows out of the same follicle. As it grows, the old telogen hair is dislodged or pushed out. The hair cycle continues throughout life.

At any given time, about 90% of the scalp follicles are in the Anagen stage. In this stage, stem cells from the bulge in the hair follicle multiply and travel downward, pushing the dermal papilla deeper into the skin and forming the epithelial root sheath. Root sheath cells directly above the papilla form the hair matrix. Here, sheath cells transform into hair cells, which synthesize keratin and then die as they are pushed upward away from the papilla. The new hair grows up the follicle, often alongside an old club hair left from the previous cycle.

Hair length depends on the duration of anagen stage. Short hairs (eyelashes, eyebrows, hair on arms and legs) have a short anagen phase of around one month. Anagen lasts up to 6 years or longer in scalp hair.

In the Catagen stage, mitosis in the hair matrix ceases and sheath cells below the bulge die. The follicle shrinks and the dermal papilla draws up toward the bulge. The base of the hair keratinizes into a hard club and the hair, now known as a club hair, loses its anchorage. Club hairs are easily pulled out by brushing the hair, and the hard club can be felt at the hair’s end. When the papilla reaches the bulge, the hair goes into a resting period called the Telogen stage. Eventually, anagen begins anew and the cycle repeats itself. A club hair may fall out during catagen or telogen, or as it is pushed out by the new hair in the next anagen phase.

You lose about 50 to 100 scalp hairs daily. In a young adult, scalp follicles typically spend 6 to 8 years in anagen, 2 to 3 weeks in catagen, and 1 to 3 months in telogen. Scalp hairs grow at a rate of about 1 mm per 3 days (10–18 cm/yr) in the anagen phase.

Hair grows fastest from adolescence until the 40s. After that, an increasing percentage of follicles are in the catagen and telogen phases rather than the growing anagen phase. Hair follicles also shrink and begin producing wispy vellus hairs instead of thicker terminal hairs. Thinning of the hair or baldness, is called alopecia. It occurs to some degree in both sexes and may be worsened by disease, poor nutrition, fever, emotional stress, radiation, or chemotherapy. In the great majority of cases, however, it is simply a matter of aging.

Pattern baldness is the condition in which hair is lost unevenly across the scalp rather than thinning uniformly. It results from a combination of genetic and hormonal influences. The relevant gene has two alleles: one for uniform hair growth and a baldness allele for patchy hair growth. The baldness allele is dominant in males and is expressed only in the presence of the high level of testosterone characteristic of men. In men who are either heterozygous or homozygous for the baldness allele, testosterone causes terminal hair to be replaced by vellus hair, beginning on top of the head and later the sides. In women, the baldness allele is recessive. Homozygous dominant and heterozygous women show normal hair distribution; only homozygous recessive women are at risk of pattern baldness. Even then, they exhibit the trait only if their testosterone levels are abnormally high for a woman (for example, because of a tumor of the adrenal gland, a woman’s principal source of testosterone). Such characteristics in which an allele is dominant in one sex and recessive in the other are called sex-influenced traits.

Excessive or undesirable hairiness in areas that are not usually hairy, especially in women and children, is called hirsutism. It tends to run in families and usually results from either masculinizing ovarian tumors or hypersecretion of testosterone by the adrenal cortex. It is often associated with menopause.

Contrary to popular misconceptions, hair and nails do not continue to grow after a person dies, cutting hair does not make it grow faster or thicker, and emotional stress cannot make the hair turn white overnight.

Different causes of hair loss affect the hair follicles in different phases of growth.

Figure 4. Hair growth cycle

How does minoxidil work?

Topical minoxidil functions as a stimulant for hair growth. The precise mechanism of action for minoxidil remains inadequately understood. The sulfotransferase enzyme in the human scalp converts minoxidil into minoxidil sulfate, which is the active form of minoxidil ¹⁷⁾. Differences in sulfotransferase activity among individuals can affect minoxidil’s effectiveness, leading to inconsistencies in minoxidil therapy ¹⁸⁾.

Minoxidil shortens the telogen phase to prompt the dormant hair follicles for premature transition into the anagen phase. The shortening of the telogen phase might lead to telogen effluvium following minoxidil therapy. Furthermore, minoxidil extends the anagen phase, resulting in increased hair length and thickness, thereby representing the observable outcomes of minoxidil therapy ¹⁹⁾.

The initial outcomes of minoxidil become apparent after approximately 8 weeks of initiating the treatment, with the maximum effects manifesting around 4 months. Minoxidil affects the potassium channels present in vascular smooth muscles and hair follicles ²⁰⁾. This potassium channel activity may induce the following effects:

• Stimulation of the microcirculation around the hair follicles induces arteriolar vasodilation, thereby encouraging conditions conducive to hair growth.
• Induction of the vascular endothelial growth factor expression leads to heightened vascularization around the hair follicles, thereby promoting hair growth.
• Activation of the prostaglandin-endoperoxide synthase-1 enzyme leads to the enhancement of hair growth.
• Inhibition of androgen-related effects on androgen-sensitive hair follicles.
• Direct stimulation of the hair follicles as the drug acts as an epidermal growth factor on the matrix cells, slowing their aging process and extending their anagen phase. This process is achieved through the activation of the beta-catenin pathway.
• Display of antifibrotic characteristics due to its impact on collagen synthesis.

Hypertension

Minoxidil exerts its antihypertensive effect by opening adenosine triphosphate (ATP) sensitive potassium channels. As a result, when the smooth muscle vasculature is relaxed, it reduces peripheral resistance, which ultimately helps to lower blood pressure levels. Consequently, this process increases plasma renin activity, which, in turn, triggers salt and water retention in a patient’s body. Additionally, minoxidil triggers the activation of the sympathetic nervous system, resulting in tachycardia and heightened cardiac output. Therefore, clinicians prescribe beta-blockers and diuretics alongside minoxidil to mitigate potential adverse effects ²¹⁾.

What happens if minoxidil treatment is stopped?

If Minoxidil treatment is stopped, the pretreatment appearance will normally return within 3 or 4 months. If Minoxidil is stopped after several years of use, the hair that was genetically programmed to be lost during that time will fall out.

Minoxidil special precautions

Before using minoxidil:

• tell your doctor and pharmacist if you are allergic to minoxidil or any other drugs.
• tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially guanethidine (Ismelin), other medications for high blood pressure, and vitamins.
• tell your doctor if you have or have ever had heart, kidney, liver, or scalp disease.
• you should not use minoxidil if you have pheochromocytoma (adrenal gland tumor).
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using minoxidil, call your doctor.
• plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Minoxidil may make your skin sensitive to sunlight.

It is important that your doctor check your progress at regular visits to make sure that minoxidil is working properly and to check for unwanted effects.

Your hair loss may continue for 2 weeks after you start using minoxidil. Tell your doctor if your hair loss continues after 2 weeks. Also, tell your doctor if your hair growth does not increase after using minoxidil for 4 months.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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 age to the effects of topical minoxidil in children. Safety and efficacy have not been established. The recommended initial dosage of oral minoxidil in patients younger than 12 is 0.2 mg/kg daily. Typically, the maintenance dosage of minoxidil ranges from 0.25 to 1 mg/kg per day, and the maximum recommended dosage is 50 mg per day ²²⁾. Clinicians may suggest topical minoxidil in children; however, it is considered an off-label drug indication ²³⁾.

Elderly patients

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of topical minoxidil in the elderly. However, studies have shown that minoxidil works best in younger patients who have a short history of hair loss. Minoxidil has not been studied in patients older than 65 years of age.

Oral minoxidil should be initiated at a lower dose in older patients as clinicians recommend, considering comorbidities, polypharmacy, and increased risk of falls in this population.

Pregnant women

As animal reproductive studies have indicated specific adverse effects of minoxidil in pregnant women, it is not advisable to use this drug. Minoxidil holds an U.S. Food and Drug Administration (FDA) pregnancy category C classification ²⁴⁾.

Breastfeeding women

Studies in women suggest that minoxidil poses minimal risk to the infant when used during breastfeeding. As minoxidil is excreted in breast milk, its use is not recommended in breastfeeding women ²⁵⁾.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

• Systemic cyclosporine can exacerbate adverse effects such as hypertrichosis when combined with topical minoxidil. Notably, hypertrichosis symptoms significantly improved after discontinuing topical minoxidil for 2 months ²⁶⁾.
• Coadministration of low-dose aspirin and minoxidil may diminish the effectiveness of topical minoxidil. This decrease in effectiveness is attributed to the inhibitory effect of low-dose aspirin on sulfotransferase enzymes in human hair ²⁷⁾.
• Concurrent use of guanethidine with minoxidil can cause severe hypotension ²⁸⁾

Medical Problems

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

• Any other skin problems, an irritation, or a sunburn on the scalp: These conditions may cause too much topical minoxidil to be absorbed into the body and may increase the chance of side effects.
• Heart disease or
• Hypertension (high blood pressure): Topical minoxidil has not been studied in patients who have these conditions, but more serious problems may develop for these patients if they use more medicine than is recommended over a large area and too much minoxidil is absorbed into the body.

Minoxidil uses

Minoxidil was initially developed as a potent peripheral vasodilator agent for treating severe difficult to control high blood pressure (Resistant hypertension). However, owing to the significant side effects of oral minoxidil use, Minoxidil tablet is currently used only for patients with resistant hypertension who do not adequately respond to the maximum doses of 3 different antihypertensive medications ²⁹⁾.

Androgenic alopecia and female pattern hair loss is the only indication approved by the U.S. Food and Drug Administration (FDA) for topical minoxidil ³⁰⁾.

Off-label uses of topical minoxidil are as follows ³¹⁾:

• Alopecia areata: Minoxidil has demonstrated the ability to elicit a favorable clinical response when used as a standalone treatment for alopecia areata or in conjunction with other medications, such as corticosteroids.
• Chemotherapy-induced alopecia: In this case, minoxidil has exhibited the capacity to reduce hair loss and expedite the process of hair regrowth.
• Hair transplant: Hair loss, also known as telogen effluvium, is a common observation after a hair transplant. Minoxidil can be used before and after hair transplantation to reduce hair loss in patients. However, the treatment should be temporarily suspended for 3 days before the hair transplant to prevent excessive bleeding.
• Scarring alopecia: Minoxidil has displayed evidence of having an antifibrotic effect on this condition. Consequently, topical minoxidil treatment could be a viable therapeutic option during the initial stages of dermatoses, leading to scarring alopecia, such as those stemming from scalp burns.
• Monilethrix: Minoxidil induces the synchronization of hair follicles entering the anagen phase in patients experiencing this condition.
• Loose anagen hair syndrome: Loose anagen hair syndrome is due to defective keratinization of the inner root sheath, rather than the hair shaft itself. The loose hair shaft can be easily pulled out of the follicle, leaving localized or diffuse bald areas of the scalp. Loose anagen hair syndrome results in short, brittle hair. Although both sexes may be affected, it most often presents in young girls over the age of 2 years. They usually have blond or red colored hair. It may be diagnosed by the painless extraction of at least 10 hairs on a hair pull test of which over 80% of the hairs are in the anagen phase.
• Telogen effluvium: Telogen effluvium is the name for a common cause of temporary hair loss due to the excessive shedding of resting or telogen hair after some shock to your system. New hair continues to grow. Telogen hair is also known as a club hair due to the shape of the root. Regrowth usually occurs after removal of the trigger causing telogen effluvium. However, repeated episodes of acute telogen effluvium can sometimes evolve into female pattern hair loss.
• Hereditary alopecia or hypotrichosis: Minoxidil has demonstrated its beneficial effects by promoting hair shaft thickening in hypotrichosis.

Topical Minoxidil

Minoxidil applied to the scalp is used to stimulate hair growth in adult men and women with androgenic alopecia. If hair growth is going to occur with the use of Minoxidil, it usually occurs after the medicine has been used for 4 to 6 months and lasts only as long as the medicine continues to be used. Hair loss will begin again within a few months after minoxidil treatment is stopped.

It is very important that you use minoxidil only as directed. Do not use more of it and do not use it more often than your doctor ordered. To do so may increase the chance of it being absorbed through your skin. For the same reason, do not apply minoxidil to other parts of your body. Absorption into the body may affect your heart and blood vessels and cause unwanted side effects.

Do not use any other skin products on the same skin area on which you use minoxidil. Hair coloring, hair permanents, and hair relaxers may be used during minoxidil therapy as long as the scalp is washed just before applying the hair coloring, permanent, or relaxer. Minoxidil should not be used 24 hours before and after the hair treatment procedure. Be sure to not double your doses of minoxidil to make up for any missed doses.

To apply minoxidil topical solution:

• Make sure your hair and scalp are completely dry before applying minoxidil.
• Apply the amount prescribed to the area of the scalp being treated, beginning in the center of the area. Follow your doctor’s instructions on how to apply the solution, using the applicator provided.
• Do not shampoo your hair for 4 hours after applying minoxidil.
• Immediately after using minoxidil, wash your hands to remove any medicine that may be on them.
• Do not use a hairdryer to dry the scalp after you apply minoxidil solution. Blowing with a hairdryer on the scalp may make the treatment less effective.
• Allow the minoxidil to completely dry for 2 to 4 hours after applying it, including before going to bed. Minoxidil can stain clothing, hats, or bed linen if your hair or scalp is not fully dry after using the medicine.
• Avoid transferring the medicine while wet to other parts of the body. This can occur if the medicine gets on your pillowcase or bed linens or if your hands are not washed after applying minoxidil.

To apply minoxidil topical foam:

• Open the container by matching the arrow on can ring with the arrow on cap. Pull off the cap.
• Part the hair into one or more rows to expose the hair thinning area on the scalp.
• Hold the can upside down and press the nozzle to put foam on your fingers.
• Use your fingers to spread the foam over the hair loss area and gently massage into your scalp.
• Immediately after using minoxidil, wash your hands to remove any medicine that may be on them .

If your scalp becomes abraded, irritated, or sunburned, check with your doctor before applying minoxidil.

Minoxidil topical foam or solution is for use on the scalp only. Keep minoxidil away from the eyes, nose, and mouth. If you should accidentally get some in your eyes, nose, or mouth, flush the area thoroughly with cool tap water. If you are using the pump spray, be careful not to breathe in the spray .

Do not use the foam near heat or open flame, or while smoking. Do not puncture, break, or burn the aerosol can.

Oral Minoxidil

According to the American College of Cardiology and the American Heart Association, resistant hypertension is characterized by elevated blood pressure levels exceeding the target range, despite the simultaneous utilization of 3 different classes of antihypertensive medications ³²⁾, ³³⁾, ³⁴⁾. The classes of antihypertensive medications typically include a combination of a calcium channel blocker, a renin-angiotensin-aldosterone system blocker (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. These drugs are administered at the highest daily doses a patient can tolerate. The FDA approves minoxidil for maintaining blood pressure levels in patients with resistant hypertension ³⁵⁾.

Many forms of alopecia (hair loss) are off-label indications for oral or sublingual minoxidil. Recently, multiple studies have explored the use of low-dose oral minoxidil (less than 5mg daily) for treating many forms of alopecia, including male-patterned and female-patterned hair loss, with the goal to treat hair loss without adverse reactions ³⁶⁾. The low adverse-effect profile of low-dose oral minoxidil aids in long-term adherence to treatment and positive clinical response ³⁷⁾, ³⁸⁾. More studies are needed to test the effectiveness of oral and sublingual minoxidil when treating various types of alopecia (hair loss) to improve patient outcomes and to provide an alternative for those having difficulty with topical formulations ³⁹⁾.

Minoxidil dosage

The dose of minoxidil 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 minoxidil. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of minoxidil that you take depends on the strength of the minoxidil. 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.

Hair loss

Minoxidil topical solution dosage:

• Adults: Apply 1 milliliter (mL) to the scalp two times a day.
  • Women should apply 1 mL of the 2% topical minoxidil solution to their scalp twice daily.
  • Men should apply 1 mL of 2% or 5% topical minoxidil solution to their scalp twice daily.
• Children: Use and dose must be determined by the doctor.

Minoxidil topical foam dosage form:

• Adults: Apply half a capful to the scalp two times a day.
  • Patients can apply a 5% aerosol formulation of topical minoxidil directly onto their scalp at a one-half capful dose. The medication should be used twice daily by male patients and once daily by female patients.
• Children: Use and dose must be determined by your doctor.

Scalp massage is not required following the application of minoxidil. Minoxidil uptake reaches approximately 50% within an hour and increases to 75% after 4 hours. Although certain practitioners use microneedling with topical minoxidil to potentially enhance minoxidil’s efficacy, further studies are necessary to evaluate the potential significance of this practice ⁴⁰⁾, ⁴¹⁾, ⁴²⁾.

A 2% topical minoxidil solution is effective for male patients experiencing androgenic alopecia in their frontotemporal and vertex regions. However, the 5% topical minoxidil solution provides a more significant clinical benefit than the 2% solution. The clinical response to minoxidil is notably more pronounced when the onset of alopecia occurs within 5 years, primarily among young adults, and when the hair follicles are not extensively miniaturized ⁴³⁾.

Oral minoxidil

Oral minoxidil is supplied in tablet formulations, with options of 2.5 mg and 10 mg doses. Although the U.S. Food and Drug Administration (FDA) does not approve the oral minoxidil for treating hair loss in individuals, clinical trials have demonstrated its effectiveness at dosages ranging from 0.25 to 2.5 mg daily for maintaining blood pressure levels in patients with resistant hypertension ⁴⁴⁾.

The recommended initial dosage of minoxidil for hypertensive therapy is 5 mg, administered once daily to patients younger than 12, which can be gradually escalated up to a maximum of 40 mg per day ⁴⁵⁾. Higher doses should be equally divided and administered to individuals 2 or 3 times daily to prevent excessive hypotension. The maximum recommended dosage of oral minoxidil is 100 mg per day ⁴⁶⁾. As per the American Heart Association’s guidelines for managing resistant hypertension, minoxidil should be prescribed alongside a loop diuretic and a beta-blocker to reduce potential adverse effects in patients ⁴⁷⁾.

The recommended off-label dosing of oral minoxidil for treating alopecia (hair loss) is 0.25 to 2.5 mg, administered once or twice daily in 1 or 2 equally divided doses.

What should I do if I forget a dose?

Skip the missed dose and continue your regular dosing schedule. Do not apply a double dose to make up for a missed one.

Minoxidil side effects

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

• scalp itching, dryness, scaling, flaking, irritation, or burning

Tell your doctor if you notice continued itching, redness, or burning of your scalp after you apply minoxidil. If the itching, redness, or burning is severe, wash the minoxidil off and check with your doctor before using it again.

Rare side effects:

• Minoxidil-induced telogen effluvium: The shortening of the telogen phase caused by minoxidil can result in excessive hair shedding in individuals.
• Skin irritation: This condition can lead to erythema, discomfort, and a burning sensation on the scalp.
• Scaly changes of the scalp: This condition can entail irritation or a potential worsening of seborrheic dermatitis.
• Isolated itch: appears in the area of application.
• Allergic contact dermatitis: This can lead to symptoms such as erythema, eczematous skin reactions, and pruritus. Minoxidil and propylene glycol are the primary allergens implicated in cases of allergic contact dermatitis. Patch testing can aid in identifying the underlying causative agent. If allergic contact dermatitis arises due to propylene glycol, topical minoxidil as a foam formulation can be used as an alternative option, as it does not contain propylene glycol.
• Acne at site of application
• Facial hair growth
• Inflammation or soreness at root of hair
• Reddened skin
• Swelling of face

Signs and symptoms of too much minoxidil topical being absorbed into your body:

• blurred vision or other changes in vision
• chest pain
• dizziness
• fainting
• fast or irregular heartbeat
• flushing
• headache
• lightheadedness
• numbness or tingling of hands, feet, or face
• swelling of face, hands, feet, or lower legs
• weight gain (rapid)

If you experience any of the following symptoms, see your doctor immediately:

• new or worsening chest pain
• chest pain spreading to your jaw or shoulder
• fast or pounding heartbeats
• swelling in your legs, ankles, or feet
• rapid weight gain, especially in your face and midsection
• shortness of breath
• a light-headed feeling, like you might pass out
• fluid build-up in the lungs–pain when you breathe, feeling short of breath while lying down, wheezing, gasping for breath, cough with foamy mucus
• severe skin reaction–fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Oral minoxidil is also associated with significant adverse effects:

• Rare but severe reactions include pericarditis, pericardial effusion, cardiac tamponade, exacerbating congestive heart failure, and worsening angina.
• Oral minoxidil administration can lead to significant hypotension and potential complications such as thrombocytopenia and leukopenia in individuals taking the medication ⁴⁸⁾.
• Breast tenderness and gynecomastia have also been reported as adverse effects of the medication ⁴⁹⁾.
• Hypertrichosis, edema, tachycardia, and weight gain are also caused by oral minoxidil.

Patients using topical minoxidil should undergo regular monitoring for any alterations in the scalp and the occurrence of localized or generalized hypertrichosis (excessive hair growth over and above the normal for the age, sex and race of an individual) ⁵⁰⁾. Both oral and topical minoxidil usage can lead to hypertrichosis. However, hypertrichosis is more frequently observed with the oral minoxidil formulation and when the 5% topical minoxidil solution is used compared to the 2% minoxidil solution. Research indicates that hypertrichosis is linked to minoxidil extending the anagen phase. In addition, cases of hypertrichosis have been documented in infants due to unintentional direct skin contact ⁵¹⁾.

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Minoxidil Overdose

Minoxidil overdose is a rare occurrence following standard topical minoxidil application. In cases of significant oral minoxidil ingestion, there is currently no recognized antidote for minoxidil overdose. Unintentional oral consumption of minoxidil may lead to vomiting and, in rare instances, necessitate hospitalization. Instances of hypotension, tachycardia (fast heart beat) and changes in the electrocardiogram have been reported following accidental ingestion. Intravenous fluids and pharmaceutical vasopressors can address malignant hypotension. In substantial inadvertent minoxidil ingestion, gastric lavage technique and activated charcoal administration might be essential to avert systemic toxicity in patients ⁵²⁾.

A case was reported where a young girl unintentionally ingested a topical solution of minoxidil prescribed to her father. After ingesting the medication, the girl encountered adverse effects such as hypotension and prolonged tachycardia ⁵³⁾. Intravenous fluids are essential in cases of oral minoxidil overdose, causing hypotension in individuals. Vasopressors should be administered to patients for hypotension that does not respond to standard treatment ⁵⁴⁾, ⁵⁵⁾.

Dutasteride

Dutasteride (Avodart) is an 5-alpha-reductase inhibitor (similar to finasteride) that is used to treat benign prostatic hyperplasia (BPH; enlargement of the prostate gland) and male pattern hair loss (androgenic alopecia) ¹⁾, ²⁾, ³⁾, ⁴⁾. Dutasteride works by blocking the production of a natural substance that enlarges the prostate in benign prostatic hyperplasia (BPH) and in male pattern hair loss (androgenic alopecia) dutasteride blocks the 5-alpha reductase enzyme responsible for regulating the conversion of testosterone to dihydrotestosterone (DHT). By reducing dihydrotestosterone (DHT) levels in your scalp, dutasteride decreases dihydrotestosterone (DHT) effects on your hair follicles, reversing the process of hair loss in men. The use of oral 5-alpha-reductase inhibitors (dutasteride and finasteride) in women with female pattern hair loss (FPHL) is not approved by the FDA, and they are contraindicated for pregnant women because of their teratogenicity in the male fetus ⁵⁾.

Women and children should not use dutasteride. Pregnant women or women who may become pregnant should NOT use or handle dutasteride capsules. Dutasteride can be absorbed through the skin and can cause birth defects in male fetuses. Dutasteride can cause birth defects in male fetuses (Pregnancy Category X, i.e., drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy).

Dutasteride is available only with your doctor’s prescription.

In men with benign prostatic hyperplasia (BPH) Dutasteride is used alone or in combination with tamsulosin (Flomax) to treat men who have symptoms of an enlarged prostate gland, which is also known as benign prostatic hyperplasia (BPH). Benign enlargement of the prostate is a problem that can occur in men as they get older. The prostate gland is located below your bladder. As the prostate gland enlarges, certain muscles in the prostate gland may become tight and get in the way of the tube that drains urine from the bladder. This can cause problems with urinating, such as a need to urinate often, a weak stream when urinating, or a feeling of not being able to empty the bladder completely. Dutasteride may reduce your chance of developing acute urinary retention (sudden inability to urinate) and may also decrease the chance that prostate surgery will be needed.

In the prostate gland Dutasteride blocks the action of an enzyme called 5-alpha-reductase. The 5-alpha-reductase enzyme changes testosterone to another hormone that causes the prostate to grow. As a result, the size of the prostate is decreased. The effect of dutasteride lasts only as long as the medicine is taken. If it is stopped, the prostate begins to grow again.

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.

Dutasteride was approved for use in the United States in 2001 and is available in 0.5 mg capsules generically and under the trade name Avodart to be taken by mouth. Swallow the capsules whole; do not open chew, or crush them. A fixed dose combination of dutasteride (0.5 mg) with tamsulosin (0.4 mg: an alpha blocker) is available under the trade name Jalyn. The recommended dose of dutasteride is 0.5 mg once daily with or without food. Take dutasteride 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 dutasteride exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Dutasteride is usually given long term and an effect is usually not seen until 3 to 6 months of therapy. Your symptoms may improve after you have taken dutasteride for 3 months, but it may take 6 months or longer for you to see the full benefit of dutasteride. Talk to your doctor about how you are feeling during your treatment. Dutasteride may control your symptoms but will not cure your condition. Continue to take dutasteride even if you feel well. Do not stop taking dutasteride without talking to your doctor.

Dutasteride side effects are uncommon, but include impotence and decreased libido, ejaculation disorders, overdevelopment or enlargement of the breast tissue in men (gynecomastia), dizziness and fatigue. Dutasteride also decreases serum prostate specific antigen (PSA) levels which should be monitored during therapy.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Figure 1. Dutasteride mechanism of action

Finasteride versus Dutasteride safety profile

A study comparing the safety profile of dutasteride (0.5 mg/day) and finasteride (5 mg/day) for treating benign prostatic hyperplasia (BPH) was performed by Andriole et al ⁷⁾. In the dutasteride group of 813 subjects, impotence occurred in 7%, decreased libido in 5%, and ejaculation disorder in 1% ⁸⁾. Impotence was experienced by 8%, decreased libido by 6%, and ejaculation disorder by 1% in the finasteride 5mg group (n=817) ⁹⁾. These differences were not considered significant and the safety profile of dutasteride was considered no different than finasteride by the authors based on their parallel group, comparator trial ¹⁰⁾.

Kaplan et al. ¹¹⁾ conducted a retrospective analysis of 378 consecutive men treated at a single clinic with 5 alpha-reductase inhibitor monotherapy for lower urinary tract symptoms related to benign prostatic hyperplasia (BPH). Treatment duration was five years. Of those enrolled, 197 subjects were treated with finasteride 5 mg and 211 with dutasteride 0.5 mg ¹²⁾. At 5 years, 57.4% of men in the finasteride group and 42.5% of men in the dutasteride group remained on treatment ¹³⁾. Dutasteride resulted in more sexual side effects leading to discontinuation compared to finasteride, with the incidence of erectile dysfunction, ejaculatory dysfunction, and decreased libido being significantly higher in the dutasteride group (5.1%, 2.4%, 2.7%, respectively) compared with the finasteride group (2.1%, 1.8%, 1.4%, respectively) ¹⁴⁾. Of those subjects who remained on treatment for five years, dutasteride resulted in significantly greater erectile dysfunction than finasteride. At year 5, subjects on dutasteride therapy had significantly worsened International Index of Erectile Function scores relative to baseline than did those on finasteride ¹⁵⁾. This suggests that dutasteride may have stronger negative adverse sexual effects compared to finasteride ¹⁶⁾.

How effective is dutasteride for hair loss in men?

In Gubelin Harcha et al ¹⁷⁾ multicenter, randomized, double-blind, placebo-controlled study also compared dutasteride (0.02, 0.1, or 0.5 mg), finasteride (1 mg), and placebo in the treatment of androgenetic alopecia for 917 men (20-50 years old). Dutasteride 0.5mg was found to significantly increase hair growth compared to finasteride 1 mg and placebo with a similar rate of adverse side effects. Altered libido, impotence, and ejaculation disorders were listed for all groups (dutasteride 0.5mg: 4.9%, 5.4%, and 3.3%, respectively; finasteride 1mg: 6.7%, 6.1%, 3.9%, respectively; placebo: 1.7%, 3.9%, 3.3%, respectively) ¹⁸⁾. There was no significant difference found between finasteride and dutasteride sexual side effects and additionally, a dose dependent response of sexual side effects for any of the treatment doses of dutasteride was absent ¹⁹⁾. Sexual side effects were found to decrease over time.

In Gupta et al ²⁰⁾ study comparing of oral minoxidil, finasteride, and dutasteride for treating androgenetic alopecia, dutasteride 0.5 mg/day is probably more effective than finasteride 5 mg/day, minoxidil 5 mg/day, finasteride 1 mg/day, followed by minoxidil 0.25 mg/d. Oral minoxidil predominantly causes hypertrichosis and cardiovascular system (CVS) symptoms/signs in a dose-dependent manner, whereas oral finasteride and dutasteride are associated with sexual dysfunction and neuropsychiatric side effects ²¹⁾.

In the Olsen et al ²²⁾ androgenetic alopecia study comparing multiple doses of dutasteride (0.05 mg, 0.1 mg, 0.5 mg, 2.5 mg) versus finasteride 5 mg, dutasteride 0.5 mg was shown to be significantly superior at promoting hair growth compared to finasteride 5 mg after 24 weeks ²³⁾. Dutasteride 2.5mg was also shown to be significantly more effective than dutasteride 0.5 mg at increasing hair growth ²⁴⁾. Rates of decreased libido, ejaculation disorders, and impotence were 13%, 1%, and 0% for dutasteride 2.5 mg, respectively; 1%, 1%, and 0% for dutasteride 0.5mg, respectively; 4%, 3%, and 1% for finasteride 5mg, respectively; and 3%, 0%, and 5% for placebo, respectively ²⁵⁾. Of the 13% of subjects who reported decreased libido in the dutasteride 2.5 mg treatment group, 4 resolved during treatment, 1 within 3 weeks of stopping therapy, and 1 within 8 weeks of stopping; 1 patient had decreased libido that persisted after stopping but was considered by the patient to be unrelated to the drug ²⁶⁾. Based on these findings the authors suggest that while dutasteride 0.5 mg is the recommended daily dose for BPH (dutasteride is not FDA approved for androgenetic alopecia but it is prescribed for such as an off label use), dutasteride 2.5mg is significantly more effective at reducing DHT levels and thus could have a greater therapeutic impact at these levels.

Can women with hair loss use dutasteride?

The use of oral 5-alpha-reductase inhibitors (dutasteride and finasteride) in women with female pattern hair loss (FPHL) is not approved by the FDA, and they are contraindicated for pregnant women because of their teratogenicity in the male fetus ²⁷⁾.

Women and children should not use dutasteride. Pregnant women or women who may become pregnant should NOT use or handle dutasteride capsules. Dutasteride can be absorbed through the skin and can cause birth defects in male fetuses. Dutasteride can cause birth defects in male fetuses (Pregnancy Category X, i.e., drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy).

However, doctors have prescribed dutasteride off-label as a first-line treatment in post-menopausal women with female pattern hair loss (FPHL) ²⁸⁾, ²⁹⁾, ³⁰⁾, ³¹⁾, ³²⁾. The androgen dihydrotestosterone (DHT) is thought to play a large role in inducing androgenetic alopecia and is formed from the conversion of circulating testosterone to DHT by 5-alpha reductase.

Dutasteride can reduce serum DHT levels by 90% and has been reported to treat female pattern hair loss successfully with no side effects at doses that range from 0.25 to 0.5 mg/day ³³⁾. However, Dutasteride should not be given to women of childbearing age unless they are using birth control measures due to potential feminizing effects on the male fetus or to patients with impaired liver function

A recent network meta-analysis demonstrated that the increase in total hair count at 24 weeks with 0.5 mg/day of dutasteride was more efficacious compared to that with 1 mg/day finasteride with the similar adverse events profile ³⁴⁾, ³⁵⁾. Furthermore, a Korean group analyzed the long-term effectiveness and safety profiles of finasteride and dutasteride; they reported that dutasteride-treated patients showed more significant improvement in hair growth compared to finasteride-treated patients and both medications were analogously safe (possibly with a lower incidence of sexual adverse events than previously reported; dutasteride = 1.6%, and finasteride = 1.1%) ³⁶⁾. Accordingly, oral 5-alpha reductase inhibitors represent the first-line treatment modality for androgenetic alopecia because of their effectiveness and tolerability, and dutasteride further widened therapeutic options ³⁷⁾, ³⁸⁾.

Are there any contraindications for dutasteride?

Dutasteride results in a decrease in dihydrotestosterone (DHT). Since DHT is an important androgen in sexual development, children and women who are pregnant or planning on getting pregnant should avoid use. Dutasteride should also be avoided in any persons who have had a hypersensitivity to this medication ³⁹⁾.

Does dutasteride cause any interactions with other drugs?

Using dutasteride 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.

• Ceritinib
• Clarithromycin
• Itraconazole

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

• Cimetidine
• Ciprofloxacin
• Diltiazem
• Ketoconazole
• Ritonavir
• Verapamil

Other interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Is dutasteride safe for long-term use in men?

Although dutasteride and finasteride have been established to be effective for the treatment of benign prostatic hyperplasia (BPH) and male pattern hair loss (androgenetic alopecia) by substantially reducing the levels of dihydrotestosterone (DHT) ⁴⁰⁾, ⁴¹⁾, it has also been documented that dutasteride and finasteride may increase the incidence of sexual dysfunction ⁴²⁾. Decreased libido, ejaculation disorder, and impotence are among the most commonly reported drug related side effects ⁴³⁾. Erectile dysfunction, or impotence, has been cited as the most common side effect in multiple studies for both finasteride 5 mg/day and dutasteride 0.5 mg/day, followed by decreased libido ⁴⁴⁾, ⁴⁵⁾, ⁴⁶⁾, ⁴⁷⁾, ⁴⁸⁾, ⁴⁹⁾. In the largest meta-analysis to date on5-alpha-reductase inhibitors, there was found to be a significantly increased risk of sexual dysfunction (156% increase) for men being treated with finasteride or dutasteride for benign prostatic hyperplasia (BPH), whereas there was not a significant association for those treated for androgenetic alopecia ⁵⁰⁾. Dutasteride 0.5 mg/day has also been shown to have a greater incidence of adverse sexual effects than finasteride 5 mg/day in the treatment of BPH ⁵¹⁾. Unfortunately, there is no consensus regarding the relation between 5-alpha-reductase inhibitors dosage and the likelihood of sexual dysfunction and further study is needed in this area ⁵²⁾, ⁵³⁾, ⁵⁴⁾. It is based on these findings that experts recommend doctors consider and discuss the possible sexual side effects and risk of depression with their patients prior to selecting a drug therapy ⁵⁵⁾.

How does dutasteride work?

Dutasteride is the successor to finasteride acting as a second‐generation 5‐alpha‐reductase inhibitor and functioning as a selective competitive inhibitor of type 1 and type 2 isoenzymes of 5‐alpha‐reductase designed to decrease the production of dihydrotestosterone (DHT) ⁵⁶⁾, ⁵⁷⁾, ⁵⁸⁾, ⁵⁹⁾. ⁶⁰⁾. Dutasteride is reported to be three times more potent at inhibiting the type 1 5‐alpha‐reductase enzyme and 100 times more potent at inhibiting the type 2I 5‐alpha‐reductase enzyme than finasteride ⁶¹⁾. Dutasteride comes in 2.5 and 5 mg doses, both of which have shown superior efficacy to finasteride 5 mg ⁶²⁾. Due to dutasteride’s large molecular size, it is difficult to formulate and deliver as a topical agent. However, its large size and fat soluble (lipophilic) nature contribute to it remaining on the scalp and preventing absorption into your body. If requested by clinicians, compounding pharmacies may formulate dutasteride topical solutions, although literature is sparse regarding its utility in treating androgenetic alopecia.

Dutasteride 0.5 mg/day can reduce dihydrotestosterone (DHT) serum levels by upwards of 90% in a dose dependent manner ⁶³⁾. By reducing dihydrotestosterone (DHT) levels in your scalp and your prostate gland, dutasteride decreases dihydrotestosterone (DHT) effects in your hair follicles and prostate gland, reversing the process of hair loss in men (androgenic alopecia) and reducing the size of your prostate in benign prostatic hyperplasia (BPH) ⁶⁴⁾.

Olszewska and Rudnicka ⁶⁵⁾ reported a case of a female patient with androgenetic alopecia who did not respond to minoxidil and initially benefited from finasteride. Given her persistent androgenetic alopecia, the patient was started on oral dutasteride. After 6 months of treatment, clinical and trichogram assessments revealed significant improvement in hair density ⁶⁶⁾. Several randomized, double‐blind, placebo‐controlled clinical studies have demonstrated dutasteride’s effectiveness for treating androgenetic alopecia ⁶⁷⁾, ⁶⁸⁾. Intradermal (injection into the skin) dutasteride was also reported in order to decrease the systemic side effects. Saceda‐Corralo et al. ⁶⁹⁾ administered 1 mL intradermal dutasteride 0.01% injections every 3 months for a total of three sessions to six subjects. Trichoscopy assessments revealed increased hair diameter and density, in addition to clinical improvement in androgenetic alopecia. There were no statistically significant differences in serum levels of total and free testosterone, 3 alpha androstanediol glucuronide, and dihydrotestosterone before and after treatment ⁷⁰⁾. Similar studies injecting dutasteride mesotherapy yielded promising results ⁷¹⁾, ⁷²⁾, ⁷³⁾. Overall, oral dutasteride appears to be superior to the intradermal route. However, more studies are warranted ⁷⁴⁾.

Overall, dutasteride has shown superior efficacy both in blocking DHT and promoting hair growth compared to finasteride. In a study of 399 patients, dutasteride was found to block 98.4% of DHT, while finasteride blocked about 70% ⁷⁵⁾. In another study of 416 men between 21 and 45 years of age, dutasteride was found to produce better hair count results than finasteride over a period of 12–24 weeks  ⁷⁶⁾. Despite the greater efficacy demonstrated by dutasteride, finasteride is still likely to be prescribed more often as a first‐line agent in treating male pattern baldness due to FDA approval and insurance coverage.

Dutasteride 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 this medicine, the following should be considered:

Men who have taken dutasteride should not donate blood until 6 months have passed since the last dose. Dutasteride can remain in your blood for a long time and be passed on to a pregnant woman who receives a blood transfusion.

Dutasteride may affect the results of the prostate specific antigen (PSA) test, which may be used to detect prostate cancer. Make sure you tell all of your doctors that you are using dutasteride.

Dutasteride does not usually affect normal sexual abilities for most men. You may notice that you ejaculate less fluid when you have sex.

Before taking dutasteride:

• tell your doctor and pharmacist if you are allergic to dutasteride, finasteride (Propecia, Proscar), any other medications, or any of the ingredients in dutasteride capsules. Ask your doctor or check the manufacturer’s patient information for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antifungals such as ketoconazole (Nizoral); cimetidine (Tagamet); ciprofloxacin (Cipro); diltiazem (Cardizem, Dilacor, Tiazac); ritonavir, (Norvir), troleandomycin (TAO); and verapamil (Calan, Covera, Isoptin, Verelan). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• Dutasteride may increase your risk of developing high-grade prostate cancer. Tell your doctor if you have or have ever had liver disease or prostate cancer.
• you should know that dutasteride is for use only in men. Women, especially those who are or may become pregnant, should not handle dutasteride capsules. Touching the contents of the capsules may harm the fetus. If a woman who is pregnant or who could become pregnant accidentally touches leaking capsules, she should wash the area with soap and water immediately and call her doctor.
• you should know that you should not donate blood while you are taking dutasteride and for 6 months after you stop taking this medication.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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

Dutasteride is not indicated for use in children. Safety and efficacy have not been established.

Elderly people

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of dutasteride in the elderly.

Breastfeeding women

There are no adequate studies in women for determining infant risk when using dutasteride during breastfeeding. Weigh the potential benefits against the potential risks before taking dutasteride while breastfeeding.

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 dutasteride, 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 dutasteride 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.

• Ceritinib
• Clarithromycin
• Itraconazole

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

• Cimetidine
• Ciprofloxacin
• Diltiazem
• Ketoconazole
• Ritonavir
• Verapamil

Other interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Medical Problems

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

• Liver disease: Use with caution. The effects may be increased because of slower removal of dutasteride from the body.

Dutasteride uses

Dutasteride is a 5-alpha reductase inhibitor that is used alone or with another medication (tamsulosin [Flomax]) to treat symptomatic benign prostatic hypertrophy (BPH) ⁷⁷⁾, ⁷⁸⁾, ⁷⁹⁾, ⁸⁰⁾, ⁸¹⁾, ⁸²⁾. Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT), which is important in the development and maintenance of prostatic hyperplasia. Dihydrotesterone (DHT) levels decrease during dutasteride therapy, but serum testosterone levels do not. Dutasteride usually takes several months to have an effect on prostate size and the symptoms of prostatic hypertrophy (urinary hesitancy and poor stream), unlike the alpha-1 adrenergic receptor blockers (alpha blockers) which have a more immediate effect.

Doctors also use finasteride and dutasteride off-label as a first-line treatment for male pattern hair loss (androgenetic alopecia) and in post-menopausal women with female pattern hair loss (FPHL) ⁸³⁾, ⁸⁴⁾, ⁸⁵⁾, ⁸⁶⁾, ⁸⁷⁾, ⁸⁸⁾, ⁸⁹⁾, ⁹⁰⁾. The androgen dihydrotestosterone (DHT) is thought to play a large role in inducing androgenetic alopecia and is formed from the conversion of circulating testosterone to DHT by 5-alpha reductase.

Dutasteride can reduce serum DHT levels by 90% and has been reported to treat female pattern hair loss successfully with no side effects at doses that range from 0.25 to 0.5 mg/day ⁹¹⁾. However, Dutasteride should not be given to women of childbearing age unless they are using birth control measures due to potential feminizing effects on the male fetus or to patients with impaired liver function

A recent network meta-analysis demonstrated that the increase in total hair count at 24 weeks with 0.5 mg/day of dutasteride was more efficacious compared to that with 1 mg/day finasteride with the similar adverse events profile ⁹²⁾, ⁹³⁾. Furthermore, a Korean group analyzed the long-term effectiveness and safety profiles of finasteride and dutasteride; they reported that dutasteride-treated patients showed more significant improvement in hair growth compared to finasteride-treated patients and both medications were analogously safe (possibly with a lower incidence of sexual adverse events than previously reported; dutasteride = 1.6%, and finasteride = 1.1%) ⁹⁴⁾. Accordingly, oral 5-alpha reductase inhibitors represent the first-line treatment modality for androgenetic alopecia because of their effectiveness and tolerability, and dutasteride further widened therapeutic options ⁹⁵⁾, ⁹⁶⁾.

Dutasteride dosage

The dose of dutasteride will be different for different patients. Take dutasteride exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. The following information includes only the average doses of dutasteride. If your dose is different, do not change it unless your doctor tells you to do so.

You may take dutasteride with or without food.

Swallow the capsule whole. Do not crush, chew, or open it. The contents of the capsule may irritate your lips, mouth, or throat.

Dutasteride comes with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Benign Prostatic Hyperplasia

Treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to reduce the risk of acute urinary retention and BPH-related surgery.

• Adults: 0.5 milligram (mg) once a day.

What should I do if I forget a dose?

If you miss a dose of dutasteride, 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.

Dutasteride side effects

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

• inability to have or maintain an erection
• decrease in sex drive or interest in sexual intercourse (libido)
• problems with ejaculation
• decreased sexual performance or desire
• impotence (inability in a man to achieve an erection or orgasm)
• inability to have or keep an erection (persistent erectile dysfunction)
• loss in sexual ability, desire, drive, or performance
• pain, soreness, swelling, or discharge from the breast or breasts

Rare side effects:

• chest pain or discomfort
• dilated neck veins
• extreme fatigue
• irregular breathing
• irregular heartbeat
• swelling of the face, fingers, feet, or lower legs
• trouble breathing
• weight gain

Incidence not known:

• blistering, flaking, or peeling of the skin
• cough
• difficulty with swallowing
• dizziness
• fast heartbeat
• hives or welts, itching skin, rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the skin
• tightness in the chest
• unusual tiredness or weakness

Some side effects may be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical help:

• changes in the breasts such as increased size, lumps, pain, or nipple discharge
• swelling of the face, tongue, or throat
• difficulty breathing or swallowing
• peeling skin

Taking dutasteride may increase the risk that you will develop high-grade prostate cancer (a type of prostate cancer that spreads and grows more quickly than other types of prostate cancer). Talk to your doctor about the risks of taking dutasteride.

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

Dutasteride toxicity

In general, dutasteride appears to be a fairly safe drug, and so its use is recommended ⁹⁷⁾. A literature review by Hirshburg et al. ⁹⁸⁾ analyzed studies related to adverse events of 5-alpha reductase inhibitors in relation to prostate cancer, psychological effects, their use in women and sexual health.

In large and representative populations, an increase in the incidence of prostate cancer, or an increase in high-grade prostate cancers upon detection, or a variation in the survival rate were not associated with dutasteride ⁹⁹⁾. A direct link between the use of 5-alpha reductase inhibitors and depression was not established either ¹⁰⁰⁾. The same revision indicated that there were not many studies on the use of 5-alpha reductase inhibitors in women, but the current known risks to women include birth defects in male fetuses if taken during pregnancy, a decreased libido, headache, gastrointestinal problems, isolated cases of menstrual changes, acne and dizziness. Finally, it was reported that erectile dysfunction, a decreased libido and ejaculation disorders occurred in a fairly low percentage of men ¹⁰¹⁾.

In addition, the long-term effect of dutasteride on sexual alterations is interesting as it was associated with a significant increase in impotence, a decreased libido and ejaculation disorders during the first year when compared with a healthy control, but there were no significant differences between the two groups in the second year ¹⁰²⁾.

Currently, there are no long-term studies evaluating finasteride or dutasteride use in women ¹⁰³⁾. In a recent study, Price et al ¹⁰⁴⁾ followed 137 women aged 41 to 60 years for 12 months in a double-blind, placebo-controlled, randomized study conducted at eight investigational sites in United States and found no statistical difference in side effects of finasteride 1mg daily versus placebo ¹⁰⁵⁾. The only adverse event reported in the finasteride group was one case of folliculitis, which resolved with continued treatment ¹⁰⁶⁾. Shum et al ¹⁰⁷⁾ presented a case series of four women treated with finasteride 1.25 mg daily for up to 2.5 8. years without reported side effects. The longest trial of finasteride and dutasteride in women found during the literature search was three years by Boersma et al ¹⁰⁸⁾. Unfortunately, side effects were not discussed ¹⁰⁹⁾.

Finasteride

Finasteride an antiandrogen medicine, sold under the brand names Proscar and Propecia among others, is a specific type II 5-alpha reductase inhibitor used to treat male pattern hair loss (men with androgenetic alopecia) and in men with a benign (non-cancerous) enlargement of the prostate also called benign prostatic hyperplasia (BPH) ¹⁾, ²⁾. Finasteride inhibits the enzyme, type II 5-alpha reductase, responsible for regulating the conversion of testosterone to dihydrotestosterone (DHT). By reducing DHT (dihydrotestosterone) levels in your scalp, finasteride decreases DHT’s effects on the hair follicles, reversing the process of hair loss. Finasteride has not been shown to treat thinning hair at the temples and is not used to treat hair loss in women or children ³⁾. Finasteride is used alone or in combination with another medication (doxazosin) to treat benign enlargement of the prostate gland (BPH, benign prostatic hyperplasia). Finasteride is used to treat symptoms of benign enlargement of the prostate gland (BPH) such as frequent and difficult urination and may reduce the chance of acute urinary retention (sudden inability to urinate). It also may decrease the chance that prostate surgery will be needed ⁴⁾. Finasteride treats BPH by blocking the body’s production of a male hormone that causes the prostate to enlarge. Finasteride treats male pattern hair loss by blocking the conversion of testosterone to dihydrotestosterone (DHT) in the scalp that stops hair growth. Finasteride may be prescribed for other uses; ask your doctor or pharmacist for more information.

Finasteride is not approved for use in females but has been used “off-label” in females to treat hair loss and hirsutism (extra hair growth on areas of the body such as the face, chest, and back), although these treatments are only partially effective at best ⁵⁾, ⁶⁾, ⁷⁾, ⁸⁾, ⁹⁾, ¹⁰⁾, ¹¹⁾. The effectiveness of finasteride treatment for women varies and only some studies concluded that finasteride may be considered for treatment of female pattern hair loss in patients who fail other treatment and adhere to reliable contraception during finasteride use ¹²⁾, ¹³⁾, ¹⁴⁾, ¹⁵⁾, ¹⁶⁾. With particular regard to female alopecia, finasteride is considered both effective ¹⁷⁾, ¹⁸⁾, ¹⁹⁾ and ineffective ²⁰⁾, ²¹⁾, ²²⁾, ²³⁾. Moreover, indications for finasteride dosage in women hair loss are confusing. Studies have been published reporting dose of 1 mg, 1.25 mg, 2.5 mg or 5 mg  ²⁴⁾, ²⁵⁾, ²⁶⁾, ²⁷⁾.

Topical finasteride (used on the skin only) has not been approved by the U.S. Food and Drug Administration (FDA), but has been approved in India to treat male and female pattern hair loss. Topical finasteride has been found to be as effective as oral finasteride ²⁸⁾, ²⁹⁾, ³⁰⁾.

Finasteride comes as a 1 mg tablet or a 5 mg tablet to be taken by mouth. Each dose has a different indication. Finasteride 1 mg orally once a day for male pattern hair loss (androgenetic alopecia) and finasteride 5 mg orally once a day for benign prostatic hyperplasia (BPH). For women with hirsutism (idiopathic, and related to polycystic ovary syndrome): 5 mg once daily or 2.5 mg once daily; this is an off-label use. Finasteride is usually taken once a day with or without food. Take finasteride 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 finasteride exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

If you are taking finasteride to treat male pattern hair loss (androgenetic alopecia), it may take at least 3 months before you see any improvement because hair loss and growth happen slowly over time. However, you should expect to see improvement during the first 12 months of your treatment. If you have taken finasteride for 12 months and have not noticed any improvement, further treatment probably will not help. Talk to your doctor about whether you should continue your treatment.

Finasteride will only slow hair loss while you are taking the medication. Continue to take finasteride even if you have already noticed an improvement. Do not stop taking finasteride without talking to your doctor. You will probably lose any hair that grew back while you were taking finasteride during the first 12 months after you stop taking the medication..

If you are taking finasteride to treat BPH (benign prostatic hyperplasia), you should know that finasteride may control your condition, but will not cure it. It may take at least 6 months before your symptoms improve. Continue to take finasteride even if you feel well. Do not stop taking finasteride without talking to your doctor.

Decreased libido and erectile problems are recognized side-effects of treatment with finasteride in men ³¹⁾. Some small differences have been seen in the semen of males who take finasteride, such as low sperm counts ³²⁾. Sperm levels improved when the medication was stopped. Taking finasteride may increase the risk that you will develop high-grade prostate cancer (a type of prostate cancer that spreads and grows more quickly than other types of prostate cancer) or male breast cancer ³³⁾, ³⁴⁾. Talk to your doctor about the risks of taking finasteride.

Finasteride is contraindicated in women when they are or may potentially be pregnant, because it may cause abnormalities of the external genitalia of a male fetus (Pregnancy Category X, i.e., drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.) ³⁵⁾. Touching broken or crushed finasteride tablets may harm the fetus. If a woman who is pregnant or who could become pregnant touches broken or crushed finasteride tablets, she should wash the area with soap and water immediately and call her doctor. Animal studies have suggested that exposure to large doses of finasteride when the fetal sex organs are developing (8 to 12 weeks of pregnancy) could increase the chance for some birth defects of the sex organs in a male fetus ³⁶⁾, ³⁷⁾, ³⁸⁾. The animal studies have reported hypospadias (when the opening of the penis is on the underside of the penis instead of at the tip), a shorter distance from the anus to the genitals (anogenital distance), and lower weight of the prostate and seminal vesicles (glands that help make semen) ³⁹⁾, ⁴⁰⁾.

Also in case of female finasteride users, side effects have been reported during treatment ⁴¹⁾. The top ten side effects in women were: abortion induction, abortion spontaneous, paternal drug affecting fetus, uterine cervix stenosis, menstruation irregularity, menorrhagia, endometrial hypertrophy, phalangeal agenesis, fatigue and arthritis ⁴²⁾. Regarding the adverse events on reproductive features, it is important to recall that finasteride is forbidden in pregnant women because it may cause abnormalities of the external genitalia of a male fetus, therefore, careful contraception is strongly suggested during finasteride treatment.

Other data described, in women treated for alopecia with 5 mg of finasteride, headache, menstrual irregularities, dizziness and increased body hair growth as the most common complaints ⁴³⁾. Moreover, decreased libido and gastrointestinal discomfort were also described ⁴⁴⁾. A drug-gene network analysis, in patients treated with finasteride, also revealed that “oocyte meiosis” and “progesterone-mediated oocyte maturation” pathways were affected by finasteride treatment ⁴⁵⁾. Few studies evaluated finasteride toxicity in female animal models. Of note, a paper by Alkahtane and collaborators showed altered serum biochemical parameters (e.g., alkaline phosphatase, cholesterol, glucose), increased DNA damage and histological abnormalities in the liver, spleen, kidney and heart of female Swiss albino mice treated with finasteride (0.5 or 1.5 mg/kg/day) ⁴⁶⁾.

Figure 1. Finasteride chemical structure

How effective is finasteride for hair loss in men?

The data are from three large, multicenter, placebo-controlled studies of 1,879 men with mild-to-moderate, but not complete, male pattern hair loss ⁴⁷⁾, ⁴⁸⁾, ⁴⁹⁾. The men received either oral finasteride once daily or placebo for one year. The endpoints for the studies were objective hair counts taken from a 1-inch diameter circular area, and subjective assessments of improvement by patients, investigators, and an independent panel of dermatology experts who evaluated pre- and post-treatment photographs.

The trials showed that finasteride can prevent hair loss in men with mild-to-moderate male pattern hair loss. In two of the clinical studies involving men with mild-to-moderate male pattern hair loss, 86% of men treated with finasteride maintained or showed an increase in the amount of their hair based on hair counts during the course of the studies. Only 14% of men treated with finasteride had further hair loss after 12 months of treatment, compared with 58% of placebo patients.

On-going studies have demonstrated that finasteride halts hair loss or regrows hair in 9 out of 10 men taking it longterm every day.

Is finasteride safe for long-term use in men?

Although finasteride is generally well tolerated in a study of 3,200 men, including patients on therapy for up to two years. Recently many reports described adverse effects in men during finasteride treatment, such as sexual dysfunction and mood alteration ⁵⁰⁾, ⁵¹⁾, ⁵²⁾, ⁵³⁾, ⁵⁴⁾. In addition, it has been also reported that persistent side effects may occur in some androgenetic alopecia patients. This condition, termed post-finasteride syndrome (PFS) represents a constellation of sexual, physical, and neurological symptoms that develop and persist during treatment and/or after finasteride discontinuation ⁵⁵⁾, ⁵⁶⁾, ⁵⁷⁾. Among the reported sexual and physical adverse effects associated with post-finasteride syndrome (PFS) are: loss of libido; erectile dysfunction; ejaculatory disorders; reduction in penis size; penile curvature; reduced sensation; decreased arousal and difficulty in achieving orgasm; gynecomastia; muscle atrophy; fatigue; and severely dry skin. Reported neurological (psychiatric) adverse events include: depression and anxiety; cognitive impairment; and suicidal ideation that are still present despite drug withdrawal ⁵⁸⁾. Furthermore, several case studies have linked finasteride with male infertility ⁵⁹⁾, ⁶⁰⁾, cataract and intraoperative floppy-iris syndrome ⁶¹⁾, pseudoporphyria ⁶²⁾ and T cell–mediated acute localized exanthematous pustulosis ⁶³⁾. As a result, regulatory agencies in several countries generated warnings about finasteride (e.g., Swedish Medical Products Agency, the Medicines and Healthcare Products Regulatory Agency of UK and the U.S. Food and Drug Administration) required to include multiple persistent side effects within the finasteride labels ⁶⁴⁾.

Taking finasteride may increase the risk that you will develop high-grade prostate cancer (a type of prostate cancer that spreads and grows more quickly than other types of prostate cancer) or male breast cancer ⁶⁵⁾, ⁶⁶⁾.

Can women with hair loss use finasteride?

Finasteride is not indicated for use in women with hair loss (female pattern hair loss) but is occasionally used (off-label) in postmenopausal women with hair loss. Finasteride is contraindicated in women when they are or may potentially be pregnant, because it may cause abnormalities of the external genitalia of a male fetus (Pregnancy Category X, i.e., drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.) ⁶⁷⁾

Are there any contraindications for finasteride?

Finasteride is contraindicated in those with hypersensitivity to any component of the formulation. Finasteride is not indicated for use in women or children. However, it is sometimes prescribed off-label for postmenopausal women without problems. Finasteride is contraindicated in women who are or may potentially be pregnant (Pregnancy Category X, i.e., drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.)  Women who are pregnant or may become pregnant should not use finasteride or handle the crushed or broken tablets. Finasteride can cause birth defects in male babies ⁶⁸⁾. Finasteride is contraindicated in patients who are hypersensitive to any component of the product.

Finasteride is not recommended in men that are subfertile. In men planning to have children, some doctors check sperm counts prior to starting finasteride and repeat it after 6 months of treatment. If the sperm count has reduced, finasteride should be stopped.

How does finasteride work?

Finasteride is in a class of medications called 5-alpha reductase inhibitors. Finasteride is a competitive inhibitor of types II and III 5-alpha-reductase isoenzyme, resulting in inhibition of testosterone conversion to dihydrotestosterone (DHT) ⁶⁹⁾. Finasteride has minimal selectivity for the type I 5-alpha-reductase enzyme. The type I 5-alpha-reductase isomer is present in sebaceous glands, sweat glands, dermal papillae cells, and epidermal and follicular keratinocytes. Type II 5-alpha reductase enzyme is in the outer root sheaths of hair follicles, the epididymis, vas deferens, seminal vesicles, and the prostate ⁷⁰⁾, ⁷¹⁾. Finasteride inhibits expression of the enzyme, 5-alpha reductase, which regulates the production of dihydrotestosterone (DHT). By lowering DHT levels in the scalp, it reduces DHT’s harmful effect on hair follicles. Finasteride decreases DHT concentrations in the serum and the scalp by up to 90 and 70%, respectively ⁷²⁾. However, increasing finasteride dose does not necessarily result in greater serum reduction. Dutasteride (another 5-alpha reductase inhibitor), in comparison, inhibits all three 5-alpha-reductase isoenzymes leading to a 99% reduction in serum DHT levels ⁷³⁾. Continuous use for 3 to 6 months is required before a benefit is usually seen. It may take up to 6 months before you can tell if one of these medicines is working. When you stop taking these medicines, any beneficial effects on hair growth will be lost within 6 to 12 months of discontinuing treatment. Two one-year trials encompassing 1,553 men with male-pattern hair loss found 99% of subjects to show decreased progression or the reversal of hair loss with oral finasteride ⁷⁴⁾. In addition, authors observed clinically significant increases in hair count with oral finasteride treatment compared to placebo ⁷⁵⁾. Decreased libido and erectile problems are recognized side-effects of treatment with 5-alpha-reductase inhibitors ⁷⁶⁾.

When testosterone is present in the hair follicle and it combines with the enzyme 5-alpha-reductase type 2, it produces dihydrotestosterone (DHT). Dihydrotestosterone (DHT) is the most potent hormone among the androgens [i.e, dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT)] and is considered a pure androgen as it cannot be converted into estrogen ⁷⁷⁾. DHT (dihydrotestosterone) attacks the hair follicle, causing it to shrink, finally causing the hair to fall out and not grow back and is implicated in male-pattern hair loss androgenetic alopecia pathophysiology ⁷⁸⁾. Hair follicle receptors are sensitive to DHT and thereby start the process of male or female pattern hair loss ⁷⁹⁾. Upon binding to androgen receptors in the hair follicle, dihydrotestosterone (DHT) promotes the shortening of the anagen phase and elongation of the telogen phase ⁸⁰⁾, resulting in enhanced apoptosis of hair cells and thus hair loss ⁸¹⁾. A mouse-model study found that dihydrotestosterone (DHT) promoted premature hair regression, hair miniaturization, loss of hair density, and altered hair morphology in male mice, with partial reversal with an androgen receptor antagonist, bicalutamide ⁸²⁾. In addition, those with 5-alpha-reductase enzyme deficiencies are less likely to develop male-pattern hair loss androgenetic alopecia. The role of dihydrotestosterone (DHT) in the promotion of transition to telogen and male-pattern hair loss androgenetic alopecia pathophysiology justifies the use of oral 5-alpha-reductase inhibitors, such as finasteride, in the management of hair loss ⁸³⁾.

Before taking finasteride

• tell your doctor and pharmacist if you are allergic to finasteride, any other medications, or any of the ingredients in finasteride tablets. Ask your pharmacist or check the patient information for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had liver disease or prostate cancer.
• you should know that finasteride is only for use in men. Women, especially those who are or may become pregnant should not touch broken or crushed finasteride tablets. Touching broken or crushed finasteride tablets may harm the fetus. If a woman who is pregnant or who could become pregnant touches broken or crushed finasteride tablets, she should wash the area with soap and water immediately and call her doctor. Animal studies have suggested that exposure to large doses of finasteride when the fetal sex organs are developing (8 to 12 weeks of pregnancy) could increase the chance for some birth defects of the sex organs in a male fetus ⁸⁴⁾, ⁸⁵⁾, ⁸⁶⁾. The animal studies have reported hypospadias (when the opening of the penis is on the underside of the penis instead of at the tip), a shorter distance from the anus to the genitals (anogenital distance), and lower weight of the prostate and seminal vesicles (glands that help make semen) ⁸⁷⁾, ⁸⁸⁾.
• there are no adequate studies in women for determining infant risk when using finasteride during breastfeeding. Weigh the potential benefits against the potential risks before taking finasteride while breastfeeding.
• you should know that finasteride may decrease fertility in men; decreased sexual desire, ejaculation problems, and inability to have or maintain an erection may occur during and after your treatment is stopped. Talk to your doctor about the risks of taking finasteride.
• the presence of other medical problems may affect the use of finasteride. Make sure you tell your doctor if you have any other medical problems, especially liver disease. Use with caution. The effects may be increased because of slower removal of finasteride 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 finasteride, 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 finasteride with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• St John’s Wort

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Finasteride uses

Oral finasteride (a pill taken by mouth) has been approved by the U.S. Food and Drug Administration (FDA) for use to treat male pattern hair loss in men and to treat symptoms of benign prostatic hyperplasia (BPH) in men with non-cancerous enlarged prostate ⁸⁹⁾.

Finasteride is not approved for use in females but has been used “off-label” in females to treat hair loss and hirsutism (extra hair growth on areas of the body such as the face, chest, and back), although these treatments are only partially effective at best ⁹⁰⁾, ⁹¹⁾, ⁹²⁾, ⁹³⁾, ⁹⁴⁾, ⁹⁵⁾, ⁹⁶⁾. The effectiveness of finasteride treatment for women varies and only some studies concluded that finasteride may be considered for treatment of female pattern hair loss in patients who fail other treatment and adhere to reliable contraception during finasteride use ⁹⁷⁾, ⁹⁸⁾, ⁹⁹⁾, ¹⁰⁰⁾, ¹⁰¹⁾. With particular regard to female alopecia, finasteride is considered both effective ¹⁰²⁾, ¹⁰³⁾, ¹⁰⁴⁾ and ineffective ¹⁰⁵⁾, ¹⁰⁶⁾, ¹⁰⁷⁾, ¹⁰⁸⁾. Moreover, indications for finasteride dosage in women hair loss are confusing. Studies have been published reporting dose of 1 mg, 1.25 mg, 2.5 mg or 5 mg  ¹⁰⁹⁾, ¹¹⁰⁾, ¹¹¹⁾, ¹¹²⁾.

Topical finasteride (used on the skin only) has not been approved by the U.S. Food and Drug Administration (FDA), but has been approved in India to treat male and female pattern hair loss. Topical finasteride has been found to be as effective as oral finasteride ¹¹³⁾, ¹¹⁴⁾, ¹¹⁵⁾.

Finasteride dosage

The dose of finasteride will be different for different patients. Take finasteride only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Finasteride comes with a patient information leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

You may take finasteride with or without food.

If you are taking finasteride for male pattern hair loss, it may take at least 3 months to see an effect. The medicine will not cure hair loss, but it will cause scalp hair to grow. The hair growth will only last as long as the medicine is used. The new hair will be lost within 1 year after the medicine is stopped.

If you are taking finasteride for benign prostatic hyperplasia (BPH), it may take up to 6 months to see the full effect. The medicine will not cure BPH, but it does help reduce the size of the prostate and improve symptoms. The effect on the prostate will only last as long as the medicine is used. When it is stopped, the prostate begins to grow again within a few months.

Swallow the tablet whole. Do not crush, break, or chew it. Take finasteride at the same time each day.

For oral dosage form (tablets)

• For male pattern hair loss:
  • Adults—1 milligram (mg) once a day.
  • Children—Use is not recommended.
• For benign prostatic hyperplasia (BPH):
  • Adults—5 milligrams (mg) once a day.
  • Children—Use is not recommended.

Adult dose for androgenetic alopecia (male pattern hair loss)

Use: For the treatment of male pattern hair loss (androgenetic alopecia) in men only. Safety and efficacy have been demonstrated in men between 18 to 41 years of age with mild to moderate hair loss of the vertex and anterior mid scalp area.

Dose: 1 mg orally once a day

Comments:

• Daily use for 3 months or more is necessary before benefit is observed. Continued use is recommended to sustain benefit.
• Withdrawal of treatment leads to reversal of effect within 12 months.

Adult dose for benign prostatic hyperplasia (BPH)

Use: For the treatment of benign prostatic hyperplasia (BPH).

Dose: 5 mg orally once a day

Comments:

• Dosing is the same both in monotherapy and in combination therapy.
• Not approved for the treatment of prostate cancer.
• 5-alpha reductase inhibitors reduce serum PSA levels by approximately 50%, even in the presence of prostate cancer. Health professionals should therefore be aware of how to monitor and interpret PSA levels in patients taking 5-alpha reductase inhibitors.
• Prior to the start of treatment, the risk of high-grade prostate cancer should be weighed against the benefits of 5-alpha reductase inhibitor therapy.

What should I do if I forget a dose?

Skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Finasteride side effects

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

• inability to have or maintain an erection
• decreased sexual desire
• problems with ejaculation (including decreased volume of ejaculate)
• pain in the testicles
• depression

In clinical trials, finasteride was very well tolerated in men, with most patients reporting no serious side effects. The principal side effects associated with finasteride were decreased libido (1.8% of finasteride patients versus 1.3% on placebo) and erectile dysfunction (1.3% finasteride versus 0.7% placebo). In addition, decreased volume of ejaculate was reported in 0.8% of men treated with finasteride and 0.4% of those on placebo. Gynaecomastia (breast enlargement) has also been reported. All of these side effects resolved upon discontinuation of therapy, and also resolved in many men who preferred to continue therapy. Postmarketing reports have included some patients complaining of depression, but the risk of this is likely very small.

Some side effects can be serious. If you experience any of these symptoms, see your doctor immediately:

• changes in the breasts such as increased size, lumps, pain, or nipple discharge
• rash
• itching
• hives
• swelling of the lips and face
• difficulty breathing or swallowing

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

Taking finasteride may increase the risk that you will develop high-grade prostate cancer (a type of prostate cancer that spreads and grows more quickly than other types of prostate cancer) or male breast cancer. Talk to your doctor about the risks of taking finasteride.

Finasteride toxicity

Single finasteride doses up to 400 mg and multiple doses up to 80 mg per day for three months are well-tolerated and did not result in any significant adverse reactions in the clinical studies. Until further experience is obtained, no specific treatment for an overdose with finasteride can be recommended. There are no reports of overdoses of finasteride, resulting in clinically significant toxicity ¹¹⁶⁾. However, overdoses could occur as an extension of previously reported adverse drug effects, including orthostatic hypotension.

Methotrexate

Methotrexate (MTX) is a prescription medicine called a folic acid antagonist that is used as a disease‐modifying anti‐rheumatic drug (DMARD) to treat the symptoms of psoriatic arthritis and severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body). Methotrexate is also used along with rest, physical therapy, and sometimes other medications to treat severe adult rheumatoid arthritis and juvenile rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications. Methotrexate is also used to treat certain types of cancer including cancers that begin in the tissues that form around a fertilized egg in the uterus, breast cancer, lung cancer, certain cancers of the head and neck, certain types of lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is also sometimes used to treat Crohn’s disease (condition in which the immune system attacks the lining of the digestive tract, causing pain, diarrhea, weight loss and fever), multiple sclerosis or MS (a condition in which the immune system attacks the nerves, causing weakness, numbness, loss of muscle coordination, and problems with vision, speech, and bladder control), and other autoimmune diseases (conditions that develop when the immune system attacks healthy cells in the body by mistake). Methotrexate injection is used “off-label” for treating ectopic pregnancies when surgery is not necessary, because it stops the embryo’s cells from growing and dividing, which eventually ends the pregnancy.

Methotrexate is in a class of medications called antimetabolites. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.

Methotrexate is available as an oral tablet, oral solution, and as an injection (intramuscular, intravenous, intrathecal, or subcutaneous) ¹⁾.. Your doctor will tell you how often you should take methotrexate. The schedule depends on the condition you have and on how your body responds to the medication. Your doctor may tell you to take methotrexate on a rotating schedule that alternates several days when you take methotrexate with several days or weeks when you do not take the medication. Follow these directions carefully and ask your doctor or pharmacist if you do not know when to take your medication.

• Methotrexate Orally: Usual dosing is as a weekly “pulse,” administered as a single dose or in three divided doses over 8 hourly in 24 hours every week. Folate supplementation with 1 mg per day or 5 to 7 mg once weekly should be considered for all patients to prevent bone marrow suppression. In adults, oral absorption is dependent upon the dose taken. Peak serum levels are achievable within one to two hours.
• Methotrexate Injection: Single-dose auto-injector can deliver methotrexate in certain doses such as: 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg ²⁾.
• After initiation of medical therapy with methotrexate, follow-up tests should include monitoring of complete blood count (CBC), renal function test, and liver function tests are recommended weekly for 4 weeks and then at least bi-monthly ³⁾.

If you are taking methotrexate to treat psoriasis or rheumatoid arthritis, your doctor may tell you to take the medication once a week. Pay close attention to your doctor’s directions. Some people who mistakenly took methotrexate once daily instead of once weekly experienced very severe side effects or died.

Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take methotrexate exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are taking methotrexate to treat psoriasis or rheumatoid arthritis, your doctor may start you on a low dose of the medication and gradually increase your dose. Follow these directions carefully.

If you are taking methotrexate to treat rheumatoid arthritis, it may take 3 to 6 weeks for your symptoms to begin to improve, and 12 weeks or longer for you to feel the full benefit of methotrexate. Continue to take methotrexate even if you feel well. Do not stop taking methotrexate without talking to your doctor.

Common side effects of methotrexate include headache, nausea, vomiting, abdominal pain, loss of appetite and mouth ulcers ⁴⁾, ⁵⁾. Rare but serious side effects include bone marrow suppression (myelosuppression), liver toxicity (hepatotoxicity), infection, and lung fibrosis ⁶⁾. Daily supplementation with folic acid or folinic acid can alleviate liver toxicity and gastrointestinal adverse effects ⁷⁾. A small elevation of aminotransferases level is common, but it is uncommon to have liver steatosis, liver fibrosis, and cirrhosis when taking a low dose of methotrexate. Over a long duration of treatment, ultrasound scanning and liver biopsy are required to ascertain the level of liver damage. Ask your doctor about the risks of using methotrexate for your condition.

With high methotrexate doses, patients may also experience mucosal ulceration. It may also be a sign of impending methotrexate toxicity. Alopecia, fatigue, fever, increased risk of infection, low white cell count, gastrointestinal bleeding, pancreatitis, bone marrow suppression (aplastic anemia), malignancy (lymphoproliferative disorders), infections, interstitial pneumonitis, and renal failure are other potentially life-threatening side effects ⁸⁾, ⁹⁾.

Methotrexate belongs to category X, which means it is absolutely contraindicated for use in pregnancy. Using methotrexate while you are pregnant can harm your unborn baby. Methotrexate may also cause birth defects if it is used by the father when his sexual partner becomes pregnant. If you are a woman who can bear children, your doctor may give you a pregnancy test before you start using methotrexate to make sure you are not pregnant. Female patients should use an effective form of birth control during treatment and for at least 3 months after the last dose. Male patients who have female partners should use an effective form of birth control during treatment and for at least 3 months after the last dose. Tell your doctor right away if pregnancy occurs while you are using methotrexate.

Figure 1. Methotrexate structure

How does methotrexate work?

Methotrexate is used to treat many conditions and has a distinct mechanism of action regarding its use in chemotherapy and immunosuppression in autoimmune diseases, depending on the disease and the dose ¹⁰⁾. At high doses used for cancer, methotrexate acts as an antifolate antimetabolite and blocks the folic acid metabolic pathway ¹¹⁾. In cancer, methotrexate is taken up into the cell by carriers called the human reduced folate carriers (SLC19A1), and it forms methotrexate-polyglutamate. Both the methotrexate and the methotrexate-polyglutamate inhibit the enzyme dihydrofolate reductase, which catalyzes the conversion of dihydrofolate into tetrahydrofolate, the active form of folic acid ¹²⁾. Tetrahydrofolate is necessary for the synthesis of the nucleotides of both DNA and RNA. Methotrexate-polyglutamate further inhibits the de novo purine synthesis of both purine and thymidylate synthase, thereby inhibiting DNA synthesis. This disrupts production of nucleotide bases, triggering several cellular processes that culminate in apoptosis ¹³⁾. This mechanism is utilized in the treatment of cancer because of its cytotoxic effect ¹⁴⁾.

At low doses used for autoimmune diseases or inflammatory diseases such as psoriatic arthritis, this pathway does not adequately explain its effects ¹⁵⁾. Methotrexate inhibits enzyme AICAR transformylase, leading to hindrance in Adenosine and Guanine metabolism, Adenosine accumulation; and due to anti-inflammatory action of adenosine, leads to repression of T-cell activation, down-regulation of B-cells, increasing activated CD-95 T cells sensitivity; and repression of methyltransferase activity, inhibition of the binding of beta-1 interleukin to its cell surface receptor ¹⁶⁾. The biochemical mechanisms that explain these effects remain incompletely understood.

Drug interactions- As methotrexate is highly plasma protein bound, any drug that displaces methotrexate from proteins can increase its blood levels.

Also, if any drug has effects on the renal clearance of methotrexate, its concentration may rise.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs), salicylates, trimethoprim, penicillin, warfarin, valproate, proton pump inhibitors (PPIs), cyclosporin, cisplatin increases the risk of methotrexate toxicity in the blood; aminoglycosides, neomycin, probenecid reduces the absorption of methotrexate ¹⁷⁾. The most significant and serious interactions are with NSAIDs and proton pump inhibitors (PPIs) since these are very common therapeutic choices ¹⁸⁾.

How long does it take for methotrexate to work?

Methotrexate can start working for rheumatoid arthritis within 3 to 6 weeks and symptoms continue to improve over 3 months. For other people it might take a few months before they notice any improvement in their rheumatoid arthritis symptoms. It is important to keep taking the methotrexate as usually methotrexate is working at reducing inflammation and swelling, it just takes a while before you notice pain relief and have less joint stiffness.

How do I know if methotrexate is working for rheumatoid arthritis?

Methotrexate is an immunosuppressant drug that is used to treat rheumatoid arthritis, an autoimmune disease, as well as other inflammatory conditions. It works to reduce the inflammation, pain, swelling, redness, morning stiffness, fatigue and other symptoms associated with rheumatoid arthritis.

Methotrexate also slows down how quickly rheumatoid arthritis progresses and damages joints, which is why it belongs to a group of drugs known as disease-modifying anti-rheumatic drugs (DMARDs).

To tell if methotrexate treatment is working for your rheumatoid arthritis:

• Your doctor will conduct regular blood tests and check-ups
• You can keep a track of your symptoms and looks for signs of improvement
• Imaging tests, such as x-rays and musculoskeletal ultrasound, may be used

Blood tests and check-ups are used to tell you if methotrexate is working for rheumatoid arthritis

When you first start treatment with methotrexate your doctor will conduct blood tests and check-ups every 1-2 weeks. The results from these tests will help you to know whether methotrexate is working for you and also if it’s causing side effects.

Based on the results of your tests your doctor may adjust the dose of methotrexate you take until this medication is working well for you. Once you are on a dose that is working for you, blood tests and check-ups are usually conducted every 2 to 3 months.

Blood tests that help to determine how active your rheumatoid arthritis is and show whether methotrexate is working for you include:

• Erythrocyte sedimentation rate (ESR) test – measures the amount of inflammation in your body by measuring how fast red blood cells cling together and settle on the bottom of a test turn over the course of one hour
• C-reactive protein (CRP) test – also measures inflammation by measuring CRP, which is a protein produced by the liver when there is inflammation somewhere in your body
• Multibiomarker Disease Activity (MBDA, Vectra DA) test – measures 12 biomarkers )including proteins, hormone and growth factors) to provide a single measure of disease activity. It can help to determine the aggressiveness of your disease and likelihood of a symptom flare-up should your medications change.

You’ll also know if methotrexate is working for you because your rheumatoid arthritis symptoms will start to improve. You may notice a reduction in your rheumatoid arthritis symptoms in as little as 3 to 6 weeks after starting treatment with methotrexate, but it can take up to 12 weeks after starting on a dose that works well for you for the full effects of the drug to be seen.

If methotrexate is working for you, you’re likely to experience fewer swollen and painful joints, less morning stiffness and be able to move about and perform daily activities more easily.

It’s important to remember that during the first weeks and months of treatment you may not notice any benefit in terms of improvement in your symptoms, but this does not mean this medication won’t work for you in time.

If methotrexate does not work well enough on its own, it can also be combined with painkillers, other DMARDs, and biological drugs to provide symptom relief.
Imaging tests can tell you if methotrexate is working to prevent joint damage

Imaging tests, including x-rays, musculoskeletal ultrasound and magnetic resonance imaging (MRI), are used to diagnose rheumatoid arthritis and can also be used to check for worsening joint damage while you’re on methotrexate.

These radiographic tests are used to detect inflammation, bone erosions and joint space narrowing, which indicate that rheumatoid arthritis is damaging your joints. MUSU and MRI are better at picking up bone erosion and inflammation than x-rays.

When methotrexate works it helps to slow joint damage and the progression of rheumatoid arthritis. In some people taking methotrexate, no or limited damage may be picked up on these tests (radiographic progression). However, methotrexate isn’t always able to prevent disease progression, especially in people with severe rheumatoid arthritis.

How long does methotrexate work for?

A clinical trial studied rheumatoid arthritis patients who took methotrexate for 12 weeks and then methotrexate was stopped. The methotrexate continued to be effective for 3 to 6 weeks after methotrexate was stopped and after this time the rheumatoid arthritis symptoms began to return.

• Methotrexate starts to show improvements in rheumatoid arthritis symptoms in 3 to 6 weeks.
• Methotrexate is taken long term to reduce rheumatoid arthritis symptoms and reduce disease progression.
• If you stop taking methotrexate it will take 3 to 6 weeks for the methotrexate effects to diminish and your rheumatoid arthritis symptoms to reappear.

How long can I take methotrexate for?

Methotrexate can be taken long term to help treat rheumatoid arthritis symptoms and also to help slow disease progression and joint damage. Rheumatoid arthritis is a chronic illness that does not have a cure, so medicines like methotrexate are taken to reduce the symptoms and reduce that damage caused by the disease.

There have been clinical trials that have lasted 11 years which have studied rheumatoid arthritis patients taking long term methotrexate.

These studies showed:

• sustained positive response with a 50% improvement in joint pain
• greater than 65% reduction in joint swelling index
• 11% of the patients left the study due to methotrexate toxic effects.

Why should I take folic acid with methotrexate?

Folate occurs naturally as vitamin B-9 and is an essential nutrient your body needs for cell metabolism and growth. You need folate to help with skin, hair and nail growth. Folic acid is a man-made form of this B vitamin available as a supplement. Your doctor may prescribe folic acid to be taken with your methotrexate. You should take folic acid with methotrexate to help prevent a folate deficiency. Taking methotrexate can lower levels of folate in your body. A folate deficiency can lead to symptoms like upset stomach, low blood cell counts, tiredness, muscle weakness, mouth sores, liver toxicity and nervous system symptoms. Methotrexate is a medicine that is commonly prescribed for people with rheumatoid arthritis, cancer or psoriasis.

Common symptoms of folate deficiency can include:

• tiredness or fatigue, lack of energy
• muscle weakness
• headache
• dizziness
• shortness of breath
• neurological (nervous system) problems, like the feeling of pins and needles, tingling, or burning in your hands, arms or legs
• mental health problems such as depression, confusion, memory problems, and difficulty with judgement and understanding
• upset stomach (nausea, vomiting) or stomach pain
• diarrhea
• weight loss

Before taking methotrexate

• tell your doctor and pharmacist if you are allergic to methotrexate, any other medications, or any of the ingredients in methotrexate tablets. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: certain antibiotics such as chloramphenicol (chloromycetin), penicillins, and tetracyclines; folic acid (available alone or as an ingredient in some multivitamins); other medications for rheumatoid arthritis; phenytoin (Dilantin); probenecid (Benemid); sulfonamides such as co-trimoxazole (Bactrim, Septra), sulfadiazine, sulfamethizole (Urobiotic), and sulfisoxazole (Gantrisin); and theophylline (Theochron, Theolair). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had any of the conditions mentioned in the IMPORTANT WARNING section or a low level of folate in your blood.
• tell your doctor right away if you have a change in how much or how often you urinate, rapid weight gain, swelling in the legs, ankles, or feet, or trouble breathing. These could be symptoms of a serious kidney problem.
• do not breast-feed while you are taking methotrexate and for at least 1 week after your last dose.
• methotrexate may affect fertility (ability to have children) in both men and women. However, it is important to use birth control to prevent pregnancy because methotrexate may harm the baby if a pregnancy does occur.
• limit alcohol use with methotrexate. Alcohol may increase the risk for liver problems.
• check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking methotrexate.
• check with your doctor right away if you have cough, fever, or trouble breathing. These could be symptoms of a serious lung or breathing problems (eg, acute or chronic interstitial pneumonitis).
• plan to avoid unnecessary or prolonged exposure to sunlight or ultraviolet light (tanning beds and sunlamps) and to wear protective clothing, sunglasses, and sunscreen. Methotrexate may make your skin sensitive to sunlight or ultraviolet light. If you have psoriasis, your sores may get worse if you expose your skin to sunlight while you are taking methotrexate.
• do not have any vaccinations during your treatment with methotrexate without talking to your doctor. Methotrexate may lower your body’s resistance and the vaccine may not work as well or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.
• methotrexate can lower the number of white blood cells in your blood, which increases the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:
  • If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
  • Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
  • Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
  • Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
  • Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
  • Avoid contact sports or other situations where bruising or injury could occur.
• serious skin reactions (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, or erythema multiforme) can occur with methotrexate. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, blue-green to black skin discoloration, cough, cracks in the skin, diarrhea, itching, joint or muscle pain, loss of heat from the body, 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, fever or chills, or unusual tiredness or weakness while you are using methotrexate.
• methotrexate may cause serious nerve problems. Check with your doctor right away if you have seizures, confusion, tingling or numbness in your hands, feet, or lips, trouble seeing, or headache.
• methotrexate may increase your risk for other cancers, including blood or skin cancer. The risk for skin cancer may be increased if you take cyclosporine after receiving treatment with methotrexate for psoriasis.
• methotrexate may cause a serious reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Tell your doctor right away if you have a change in urine amount, joint pain, stiffness, or swelling, lower back, side, or stomach pain, rapid weight gain, swelling of the feet or lower legs, or unusual tiredness or weakness.

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 methotrexate, 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 methotrexate 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.

• Measles Virus Vaccine, Live
• Mumps Virus Vaccine, Live
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Varicella Virus Vaccine, Live
• Zoster Vaccine, Live

Using methotrexate 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.

• Aceclofenac
• Acemetacin
• Acetazolamide
• Adenovirus Vaccine
• Amoxicillin
• Amtolmetin Guacil
• Asparaginase
• Aspirin
• Bacillus of Calmette and Guerin (BCG) Vaccine, Live
• Beet Root
• Bentiromide
• Bromfenac
• Bufexamac
• Capecitabine
• Capmatinib
• Celecoxib
• Chloral Hydrate
• Cholera Vaccine, Live
• Choline Salicylate
• Clonixin
• Dantrolene
• Darolutamide
• Dengue Tetravalent Vaccine, Live
• Dexibuprofen
• Dexketoprofen
• Dexlansoprazole
• Diclofenac
• Dicloxacillin
• Diflunisal
• Dipyrone
• Doxifluridine
• Doxycycline
• Droxicam
• Enasidenib
• Encorafenib
• Esomeprazole
• Etodolac
• Etofenamate
• Felbinac
• Fenbufen
• Fenoprofen
• Fepradinol
• Feprazone
• Floctafenine
• Floxacillin
• Flufenamic Acid
• Fluorouracil
• Flurbiprofen
• Foscarnet
• Fosphenytoin
• Furosemide
• Hydrochlorothiazide
• Ibuprofen
• Ibuprofen Lysine
• Indomethacin
• Influenza Virus Vaccine, Live
• Ketoprofen
• Ketorolac
• Leflunomide
• Levetiracetam
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Mezlocillin
• Midostaurin
• Morniflumate
• Nabumetone
• Naproxen
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Nitrous Oxide
• Omeprazole
• Oxaprozin
• Oxyphenbutazone
• Pantoprazole
• Parecoxib
• Penicillin G
• Penicillin V
• Pexidartinib
• Phenylbutazone
• Phenytoin
• Piketoprofen
• Piperacillin
• Piroxicam
• Pirprofen
• Poliovirus Vaccine, Live
• Pristinamycin
• Probenecid
• Proglumetacin
• Proguanil
• Propionic Acid
• Propyphenazone
• Proquazone
• Pyrimethamine
• Rabeprazole
• Salicylic Acid
• Salsalate
• Sapropterin
• Silver Sulfadiazine
• Simeprevir
• Smallpox Vaccine
• Sodium Salicylate
• Sulfacetamide
• Sulfacytine
• Sulfadiazine
• Sulfamethizole
• Sulfamethoxazole
• Sulfapyridine
• Sulfisoxazole
• Sulindac
• Tafamidis
• Tamoxifen
• Tegafur
• Tenoxicam
• Teriflunomide
• Tiaprofenic Acid
• Ticarcillin
• Tolfenamic Acid
• Tolmetin
• Triamterene
• Trimethoprim
• Typhoid Vaccine, Live
• Valdecoxib
• Warfarin
• Yellow Fever Vaccine
• Zonisamide

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

• Amiodarone
• Cyclosporine
• Eltrombopag
• Etoricoxib
• Mercaptopurine
• Procarbazine
• Rofecoxib
• Theophylline

Other interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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

• Cola

Other medical problems

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

• Alcohol abuse, or history of or
• Anemia or
• Leukopenia (low white blood cells) or
• Liver disease, severe or
• Thrombocytopenia (low platelet blood level) or
• Weak immune system—methotrexate tablets should not be used in patients with these conditions.
• Ascites (extra fluid in the stomach area) or
• Kidney disease or
• Pleural effusion (extra fluid in the lung)—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
• Diabetes or
• Obesity or
• Stomach or bowel problem (eg, peptic ulcers, ulcerative colitis)—Use with caution. May cause side effects to become worse.
• Infection (eg, bacteria, fungus, virus)—Use with caution. May decrease your ability to fight an infection.

Methotrexate uses

Methotrexate is an FDA-approved folic acid antagonist indicated for the treatment of rheumatoid arthritis because of its high potency and efficacy in such patients; it can also be useful in patients with juvenile idiopathic arthritis ¹⁹⁾. Gubner first suggested methotrexate use in rheumatoid arthritis after performing a double blinded-placebo controlled clinical trial of methotrexate in patients with rheumatoid arthritis ²⁰⁾. Today methotrexate is one of the major chemotherapeutic choices for various types of cancers. Methotrexate is also safe and effective for patients with psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease, vasculitis, and many other connective tissue diseases ²¹⁾. Methotrexate is also effective in patients with organ transplantation because of its anti-inflammatory and immunomodulatory activity ²²⁾. Also, methotrexate can be combined with anti-TNF agents and has shown effective in managing patients with ulcerative colitis, lymphoma (non-Hodgkin’s type), carcinoma of the breast, small-cell carcinoma of the lung, epidermal tumors of the head and neck, and carcinoma of the ovary ²³⁾. Methotrexate has the same effects as cyclosporin for patients with graft-versus-host disease (GVHD). Methotrexate is used off-label in mycosis fungoides, dermatomyositis, pityriasis rubra pilaris, eczema, sarcoidosis, non-Hodgkin’s lymphoma (advanced stage), Burkitt’s lymphoma and non-metastatic osteosarcoma.

Methotrexate monitoring

Patients taking methotrexate should undergo monitoring of complete blood count (CBC), serum creatinine, transaminases is recommended weekly for the first 4 weeks and then at least bimonthly. A complete list of the current medications should be revised to avoid any possible drug interactions before prescribing methotrexate. Liver function tests (monitoring serum AST, ALT, serum albumin levels), liver biopsy can also be done in cases of hepatotoxicity ²⁴⁾. Creatinine clearance requires monitoring (50 ml/min is necessary before prescribing methotrexate) to avoid possible kidney toxicity ²⁵⁾. Monitoring for lung toxicity is also required as the patients may have a dry cough, fever, shortness of breath (dyspnea). Baseline chest X-rays are recommended to detect interstitial, and alveolar infiltrates, hilar adenopathy, pleural effusions, and pulmonary fibrosis ²⁶⁾. Methotrexate may also cause reactivation of tuberculosis in endemic countries, so tests to eliminate the presence of tuberculosis are required. Also, monitory for bone marrow toxicity as myelosuppression can occur due to folate deficiency. A sudden dip in blood counts must alert to that possibility.

Methotrexate contraindications

You should not use methotrexate if you are allergic to it. You may not be able to take methotrexate if you have:

• alcoholism, cirrhosis, or chronic liver disease;
• low blood cell counts;
• a weak immune system or bone marrow disorder; or
• if you are pregnant or breastfeeding.

Methotrexate can harm an unborn baby if the mother or the father is using methotrexate.

• If you are a woman, you may need to have a negative pregnancy test before starting methotrexate. Use effective birth control to prevent pregnancy while you are using methotrexate and for at least 6 months after your last dose.
• If you are a man, use effective birth control if your sex partner is able to get pregnant. Keep using birth control for at least 3 months after your last dose.
• Tell your doctor right away if a pregnancy occurs while either the mother or the father is using methotrexate.

Pregnant or breastfeeding women should avoid using methotrexate due to the elevated risk of teratogenicity and excretion into breast milk.

Methotrexate may cause injury or death to an unborn baby and should not be used during pregnancy to treat arthritis or psoriasis. However, methotrexate is sometimes used to treat cancer during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant.

Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you have low blood cell counts, a weak immune system, alcoholism or chronic liver disease, or if you are breastfeeding.

Caution is necessary for using methotrexate for patients who have pre-existing blood disorders, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia ²⁷⁾. In cases of rheumatoid arthritis or psoriasis, it is contraindicated to use methotrexate in patients with chronic liver disease, liver cirrhosis, alcoholic hepatitis, or chronic alcoholism. It is also not recommended to use methotrexate in HIV/AIDS, blood dyscrasias, renal dysfunction and during radiotherapy ²⁸⁾.

Methotrexate can cause serious or fatal side effects. Tell your doctor if you have diarrhea, mouth sores, cough, shortness of breath, upper stomach pain, dark urine, numbness or tingling, muscle weakness, confusion, seizure, or skin rash that spreads and causes blistering and peeling.

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

• liver problems, especially fluid in your stomach (ascites);
• kidney disease;
• lung problems, especially fluid in the lungs (pleural effusion);
• radiation treatments; or
• a stomach ulcer or ulcerative colitis.

Methotrexate dosage

Take methotrexate only as directed by your doctor. The dose of methotrexate will be different for different patients. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take methotrexate depend on the medical problem for which you are using methotrexate. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of methotrexate. If your dose is different, do not change it unless your doctor tells you to do so.

Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. Do not take methotrexate everyday to treat conditions other than cancer. Read and follow the patient instructions that come with methotrexate. Talk to your doctor or pharmacist if you have any questions.

Measure the oral liquid medicine with a marked measuring spoon, oral syringe, or medicine cup.

Swallow the tablet whole. Do not crush, break, or chew it. Do not take the tablet if you cannot swallow it.

For patients with rheumatoid arthritis, psoriasis, or polyarticular juvenile idiopathic arthritis: Your doctor may give you folic acid or folinic acid supplement to help reduce the unwanted effects of methotrexate.

For patients with cancer: Do not take folic acid or folinic acid supplement unless directed by your doctor.

Do not take methotrexate with foods that are rich in milk.

For oral methotrexate dosage form (tablets)

• For acute lymphoblastic leukemia (ALL)
  • Adults and children—Dose is based on body size and must be determined by your doctor. At first, 20 milligrams (mg) per meter squared (m²) of body size once a week. Your doctor may adjust your dose as needed and tolerated.
• For mycosis fungoides
  • Adults—
    • Used alone: 25 to 75 milligrams (mg) once a week.
    • Used with other medicines: Dose is based on body size and must be determined by your doctor. The dose is usually 10 mg per meter squared (m²) of body size 2 times a week.
  • Children—Use and dose must be determined by your doctor.
• For non-Hodgkin lymphoma
  • Adults—2.5 milligrams (mg) 2 to 4 times a week. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 10 mg per week.
  • Children—Use and dose must be determined by your doctor.
• For polyarticular juvenile arthritis (pJIA)
  • Children—Dose is based on body size and must be determined by your doctor. At first, 10 milligrams (mg) per meter squared (m²) once a week. Your doctor may adjust your dose as needed and tolerated.
• For psoriasis
  • Adults—At first, 10 to 25 milligrams (mg) once a week. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 30 mg per week.
  • Children—Use and dose must be determined by your doctor.
• For rheumatoid arthritis
  • Adults—At first, 7.5 milligrams (mg) once a week Your doctor may adjust your dose as needed and tolerated.
  • Children—Use and dose must be determined by your doctor.

For oral methotrexate dosage form (solution)

• For acute lymphoblastic leukemia (ALL)
  • Children—Dose is based on body size and must be determined by your doctor. At first, 20 milligrams (mg) per meter squared (m(2)) of body size once a week. Your doctor may adjust your dose as needed.
• For polyarticular juvenile idiopathic arthritis (pJIA)
  • Children—Dose is based on body size and must be determined by your doctor. At first, 10 milligrams (mg) per meter squared (m(2)) of body size once per week. Your doctor may adjust your dose as needed.

Adult dose for Acute Lymphoblastic Leukemia (ALL)

Use: Acute lymphoblastic leukemia (ALL)

Note: A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in anti-leukemic therapy.

• Induction: 3.3 mg/m²/day orally or parenterally (in combination with prednisone 60 mg/m²) daily for 4 to 6 weeks
• Maintenance dose during remission: 30 mg/m² orally or IM 2 times a week
• Alternate maintenance dose during remission: 2.5 mg/kg IV every 14 days

Comments:

• When relapse occurs, reinduction of remission can usually be obtained by repeating the initial induction regimen.
• Acute lymphoblastic leukemia in children and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Adult dose for Choriocarcinoma

Use: Gestational trophoblastic disease (GTD) including gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole

• 15 to 30 mg orally or IM daily for a 5-day course; courses are usually repeated for 3 to 5 times, with rest periods of one or more weeks between courses, until any manifesting toxic symptoms subside

Comments:

• The effectiveness of therapy is evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.
• One to two courses of therapy after normalization of hCG is usually recommended.
• Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with this drug has been recommended.
• Chorioadenoma destruens is an invasive form of hydatidiform mole. This drug is administered in these disease states in doses like those recommended for choriocarcinoma.

Adult dose for Trophoblastic Disease

Use: Gestational trophoblastic disease (GTD) including gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole

• 15 to 30 mg orally or IM daily for a 5-day course; courses are usually repeated for 3 to 5 times, with rest periods of one or more weeks between courses, until any manifesting toxic symptoms subside

Comments:

• The effectiveness of therapy is evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.
• One to two courses of therapy after normalization of hCG is usually recommended.
• Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with this drug has been recommended.
• Chorioadenoma destruens is an invasive form of hydatidiform mole. This drug is administered in these disease states in doses like those recommended for choriocarcinoma.

Adult dose for Burkitt’s Tumor and Lymphoma

Uses: Burkitt’s tumor and lymphoma

• Burkitt’s tumor Stages 1 to 2: 10 to 25 mg orally once a day for 4 to 8 days
• Burkitt’s tumor Stage 3: Methotrexate is commonly given concomitantly with other antitumor agents
• Duration of therapy: All stages usually require several courses of therapy interposed with 7 to 10 day rest periods
• Lymphosarcoma Stage 3: 0.625 to 2.5 mg/kg orally daily as a part of combination chemotherapy

Adult dose for Meningeal Leukemia

Use: Treatment and prophylaxis of meningeal leukemia

• 12 mg (maximum 15 mg) intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable

Comments:

• Administration at intervals of less than 1 week may result in increased subacute toxicity.
• The preserved formulations of this drug contain benzyl alcohol and must not be used for intrathecal or high dose therapy.

Adult dose for Mycosis Fungoides

Use: Mycosis fungoides (cutaneous T cell lymphoma)

Early stage dosing: 5 to 50 mg orally or parenterally once a week; alternatively, 15 to 37.5 mg 2 times a week may be used in patients who have responded poorly to weekly therapy

Comments:

• Therapy with this drug as a single agent appears to produce clinical responses in up to 50% of patients treated.
• Dose reduction or cessation is guided by patient response and hematologic monitoring.

Adult dose for Osteosarcoma

Use: Osteosarcoma

Initial dose: 12 g/m² IV as a 4-hour infusion (in combination with other chemotherapeutic agents); if this dose is not adequate to achieve a peak serum concentration of 1000 micromolar at the end of the infusion, the dose may be increased to 15 g/m²

Treatments may occur at 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 weeks after surgery.

Comments:

• If the patient is vomiting or unable to tolerate oral medication, leucovorin given IV or IM should be added to this regimen at the same dose and schedule as the methotrexate.
• Consult product labeling or local protocol for dosage of concomitant medications in the chemotherapy regimen.

Adult dose for Psoriasis

Use: For the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.

• Single dose: 10 to 25 mg/week orally, IM, IV, or subcutaneously until adequate response is achieved
• Divided dose: 2.5 mg orally every 12 hours for 3 doses once a week
• Maximum dose: 30 mg/week

Comments:

• Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period.
• The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

Adult dose for Rheumatoid Arthritis

Use: For severe active rheumatoid arthritis in patients who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs)

• Single dose: 7.5 mg orally or subcutaneously once a week
• Divided dose: 2.5 mg orally every 12 hours for 3 doses once a week
• Maximum weekly dose: 20 mg
• Duration of therapy: Unknown

Comments:

• Dosages may be adjusted gradually to achieve optimal response.
• Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg per week.
• Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

Children dose for Acute Lymphoblastic Leukemia

Use: Childhood acute lymphoblastic leukemia (ALL)

Note: A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in anti-leukemic therapy.

• Induction: 3.3 mg/m²/day orally or parenterally (in combination with prednisone 60 mg/m²) daily for 4 to 6 weeks
• Alternate induction: 20 mg/m² orally once a week as a component of a multi-agent combination
• Maintenance dose during remission: 30 mg/m² orally or IM 2 times a week
• Alternate maintenance dose during remission: 2.5 mg/kg IV every 14 days

Comments:

• When relapse occurs, reinduction of remission can usually be obtained by repeating the initial induction regimen.
• Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Children dose for Meningeal Leukemia

Use: Treatment and prophylaxis of meningeal leukemia

• Less than 1 year old: 6 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
• One year old: 8 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
• Two years old: 10 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
• Three years and older: 12 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable

Comments:

• Administration at intervals of less than 1 week may result in increased subacute toxicity.
• The preserved formulations of this drug contain benzyl alcohol and must not be used for intrathecal or high dose therapy.

Children dose for Juvenile Rheumatoid Arthritis

Use: For children with active polyarticular-course juvenile rheumatoid arthritis who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs)

• Initial dose: 10 mg/m² orally or subcutaneously once a week
• Maximum dose: 20 mg/m²/week (although there is experience with doses up to 30 mg/m²/week in children, there are too few published data to assess how doses over 20 mg/m²/week might affect the risk of serious toxicity in children; experience suggests that children receiving 20 to 30 mg/m²/week [0.65 to 1 mg/kg/week] may have better absorption and fewer GI side effects if this drug is administered either IM or subcutaneously)

Comments:

• Dosages may be adjusted gradually to achieve optimal response.
• Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg per week.
• Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

What should I do if I forget a dose?

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

Dose adjustments

Administration of methotrexate should be delayed until recovery if:

• The white blood cell (WBC) count is less than 1500/microliter
• The neutrophil count is less than 200/microliter
• The platelet count is less than 75,000/microliter
• The serum bilirubin level is greater than 1.2 mg/dL
• The SGPT level is greater than 450 Units
• Mucositis is present, until there is evidence of healing
• Persistent pleural effusion is present; this should be drained dry prior to infusion

Methotrexate side effects

Get emergency medical help if you have signs of an allergic reaction to methotrexate: hives, difficult breathing, swelling in your face or throat or a severe skin reaction (fever, sore throat, burning in your eyes, skin pain, red or purple skin rash that spreads and causes blistering and peeling).

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

• dizziness
• drowsiness
• headache
• swollen, tender gums
• decreased appetite
• reddened eyes
• hair loss

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

• blurred vision or sudden loss of vision
• seizures
• confusion
• weakness or difficulty moving one or both sides of the body
• sudden chest pain, wheezing, dry cough, cough with mucus, chest pain, feeling short of breath
• fever, chills, swollen lymph glands, night sweats, weight loss
• blisters or ulcers in your mouth, red or swollen gums, trouble swallowing
• vomiting, diarrhea, blood in your urine or stools
• skin changes such as redness, warmth, swelling, or oozing
• loss of consciousness
• low blood cell counts – fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath
• kidney problems – little or no urination, swelling in your feet or ankles
• liver problems – swelling around your midsection, right-sided upper stomach pain, nausea, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes)
• nerve problems – confusion, weakness, drowsiness, coordination problems, feeling irritable, headache, neck stiffness, vision problems, loss of movement in any part of your body, seizure
• signs of tumor cell breakdown – tiredness, weakness, muscle cramps, nausea, vomiting, diarrhea, fast or slow heart rate, tingling in your hands and feet or around your mouth.

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

Methotrexate toxicity

High-dose methotrexate is the term for methotrexate doses higher than 500 mg/ml. Patients may experience nausea, mucosal ulceration, alopecia, fatigue, fever, increased risk of infection, leukopenia, gastrointestinal bleeding, pancreatitis, cirrhosis, aplastic anemia, cancer (lymphoproliferative disorders), infections, interstitial pneumonitis, renal impairment, and teratogenesis ²⁹⁾. To manage methotrexate toxicity: immediate leucovorin administration. In the case of renal failure, adequate hydration and urinary alkalinization with sodium bicarbonate are necessary.

The three antidotes used for methotrexate toxicity are leucovorin, thymidine, and glucarpidase ³⁰⁾. Leucovorin is the reduced active form of folic acid. It rescues normal cells from the toxic effects caused by methotrexate’s inhibition of reduced folates ³¹⁾. Leucovorin is particularly effective in preventing myelosuppression, gastrointestinal toxicity, and neurotoxicity during methotrexate treatment. Thymidine rescues cells from the cytotoxic effects of methotrexate; however, its use is still under investigation and is always given together with the other drugs. Glucarpidase converts methotrexate into DAMPA and glutamate, two nontoxic metabolites, thus rapidly removing methotrexate in patients with renal dysfunction. Glucarpidase, in combination with leucovorin, is a common therapy for methotrexate toxicity. A single dose of glucarpidase reduces plasma methotrexate concentrations by 97% or more within 15 minutes. Hydration and urine alkalinization is also continued in patients requiring glucarpidase. Leucovorin therapy should continue for 48 hours after glucarpidase administration ³²⁾.

Hemodialysis and hemoperfusion can also lower methotrexate levels. Intrathecal overdoses require CSF drainage and exchange, steroids, antidotes, and suspension of the medications that interfere with methotrexate clearance (e.g., NSAIDs, salicylates, trimethoprim, penicillin, warfarin, valproate, proton pump inhibitors, cyclosporin, cisplatin).

What can I do to help prevent the potential side-effects from methotrexate?

The following steps are essential:

• Get a blood test every 4-6 weeks.
• Take 1-mg of folic acid (a vitamin) every morning. This will help reduce the chance of developing mouth ulcers.
• Keep in close touch with your doctor. It is very important that your doctor check your progress at regular visits to make sure methotrexate is working properly and to check for unwanted effects. Blood and urine tests may be needed to check for unwanted effects.

Pregabalin

Pregabalin also called Lyrica is an anti-epileptic drug or an anticonvulsant. Pregabalin is available only with your doctor’s prescription. Pregabalin works by slowing down impulses in the brain that cause seizures or epilepsy. Pregabalin also affects chemicals in the brain that send pain signals across the nervous system or damaged nerves in the body. Pregabalin is used to treat pain caused by fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) or nerve pain (neuropathic pain from damaged nerves) in people with diabetes called diabetic neuropathy that can occur in your arms, hands, fingers, legs, feet, or toes and herpes zoster post-herpetic neuralgia (the burning, stabbing pain or aches that may last for months or years after an attack of shingles), or spinal cord injury. Pregabalin is also used with other medications (adjunctive therapy) to treat partial-onset seizures in adults and children aged at least 1 month of age and older. Pregabalin will not cure epilepsy and will only work to control seizures for as long as you continue to take it.

Pregabalin is available in capsules in varying concentrations from 25 to 300 mg under the brand name of Lyrica, an oral solution (liquid) and as an extended-release (long-acting) tablet to take by mouth. Pregabalin capsules and oral solution are usually taken with or without food two or three times a day. Pregabalin extended-release tablets are usually taken once daily after an evening meal. Take pregabalin 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.

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

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

Take pregabalin exactly as directed. Pregabalin may be habit forming. Do not take a larger dose, take it more often, or take it for a longer period of time than prescribed by your doctor.

Pregabalin may help control your symptoms but will not cure your condition. It may take several weeks or longer before you feel the full benefit of pregabalin. Continue to take pregabalin even if you feel well. Do not stop taking pregabalin without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. If you suddenly stop taking pregabalin, you may experience withdrawal symptoms, including trouble falling asleep or staying asleep, nausea, diarrhea, headaches, or seizures. Your doctor will probably decrease your dose gradually over at least 1 week.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with pregabalin and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the manufacturer’s website to obtain the Medication Guide.

Most reported adverse effects caused by pregabalin were mild to moderate intensity, dose-dependent, and occurred within the first two weeks of initiating treatment. The most common side effects of pregabalin are dose related and include peripheral swelling (edema), weight gain, dizziness, somnolence, confusion, headache, blurred vision, tremor and ataxia ¹⁾. The most common adverse reactions reported across all patient populations in premarketing controlled trials, which occurred in greater than or equal to 5% of patients taking pregabalin and twice the rate reported by patients receiving placebo, were: somnolence, dizziness, blurred vision, difficulty with concentration/attention, dry mouth, edema, and weight gain ²⁾, ³⁾. Rare but potentially severe adverse events include depression, suicidal ideation and behaviors, angioedema, and hypersensitivity reactions ⁴⁾, ⁵⁾.

Weight gain associated with pregabalin is dose-dependent and occurred in up to 14% of patients receiving 600 mg per day.

Following rapid or abrupt discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, nervousness, irritability, hyperhidrosis, and diarrhea ⁶⁾.

Chronic use of pregabalin can result in physical dependence, and there is a risk of abuse associated with its use, especially in patients on opioid medicines or who have a history of substance abuse ⁷⁾.

Pregabalin special precautions

Before taking pregabalin:

• tell your doctor and pharmacist if you are allergic to pregabalin, any other medications, or any of the ingredients in pregabalin preparations. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: angiotensin converting enzyme (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), captopril (Capoten, in Capozide), enalapril (Vasotec, in Vaseretic, Lexxel), fosinopril (Monopril), lisinopril (Prinivil, Zestril, in Prinzide, Zestoretic), moexipril (Univasc, in Uniretic), perindopril (Aceon), quinapril (Accupril, in Accuretic, Quinaretic), ramipril (Altace), and trandolapril (Mavik, in Tarka); antidepressants; antihistamines; medications for anxiety including lorazepam (Ativan); medications for mental illness or seizures; certain medications for diabetes such as pioglitazone (Actos, in Duetact) and rosiglitazone (Avandia, in Avandaryl, Avandamet); opioid (narcotic) pain medications including hydrocodone (in Hydrocet, in Vicodin, others), morphine (Avinza, Kadian, MSIR, others), or oxycodone (OxyContin, in Percocet, others); sedatives; sleeping pills; and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you drink or have ever drunk large amounts of alcohol, use or have ever used street drugs, or have overused prescription medications. Also tell your doctor if you have or have ever had swelling of the eyes, face, lips, tongue, or throat; vision problems; heart failure; bleeding problems or a low number of platelets (type of blood cell needed for blood clotting) in your blood, or lung, heart, or kidney disease.
• tell your doctor if you are pregnant or if you or your partner plans to become pregnant. Also tell your doctor if you are breastfeeding. If you or your partner becomes pregnant while you are taking pregabalin, call your doctor. Pregabalin has caused decreased fertility in male animals and birth defects in the offspring of male and female animals who were treated with the medication. There is not enough information to tell if pregabalin causes these problems in humans.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking pregabalin.
• you should know that pregabalin may make you dizzy or drowsy. Do not drive a car operate machinery, or do other dangerous activities until you know how this medication affects you. Ask your doctor when you may do these activities.
• do not drink alcohol while taking pregabalin. Alcohol can add to the drowsiness caused by this medication.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking pregabalin for the treatment of epilepsy, mental illness, or other conditions. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as pregabalin to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as 1 week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as pregabalin, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to pregabalin 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.

Kidney impaired patients

Pregabalin is eliminated primarily by kidney excretion. Adjust the dose in patients with impaired kidney function. According to drug manufacturers the following are recommendations on dose reductions for patients with reduced creatinine clearance (CrCl) and those undergoing hemodialysis.

• Creatinine clearance (CrCl) greater than or equal to 60 mL/min- no dose modification recommended
• Creatinine clearance (CrCl) 30 – 60 mL/min – 50% dose of recommended daily dose
• Creatinine clearance (CrCl) 15- 30 mL/min – 25% dose of recommended daily dose
• Creatinine clearance (CrCl) less than or equal to 15 mL/min – 16% to 8% dose of recommended daily dose
• Supplementary dosage of approximately an additional 25 mg of recommended daily dose following hemodialysis is recommended

Children

Appropriate studies have not been performed on the relationship of age to the effects of pregabalin in children younger than 1 month of age for partial onset seizures. Safety and efficacy have not been established for other conditions.

Breastfeeding women

Pregabalin has been detected in the milk of lactating women; thus, breastfeeding is not advisable, and an alternative agent is preferred ⁸⁾. There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking Pregabalin while breastfeeding.

Pregnancy

Pregabalin may cause fetal harm. Advise patients there is a potential risk to the fetus ⁹⁾. To monitor pregnancy outcomes in women exposed to pregabalin during pregnancy and provide information on the effects of in utero exposure to pregabalin, clinicians should help enroll pregnant patients in the North American Antiepileptic Drug Pregnancy Registry (https://www.aedpregnancyregistry.org).

Liver Impairment

Although not explicitly studied, because pregabalin is not protein-bound, it is unlikely that patients with hepatic impairment require dosing modifications.

Elderly patients

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of pregabalin in the elderly. However, elderly patients are more likely to have unwanted effects (eg, dizziness, blurred vision, confusion, or clumsiness) and age-related kidney problems, which may require an adjustment in the dose for patients receiving pregabalin.

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

• Acepromazine
• Alfentanil
• Alprazolam
• Amobarbital
• Anileridine
• Aripiprazole
• Asenapine
• Baclofen
• Benperidol
• Benzhydrocodone
• Bromazepam
• Buprenorphine
• Buspirone
• Butabarbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Carphenazine
• Chloral Hydrate
• Chlordiazepoxide
• Chlorpromazine
• Chlorzoxazone
• Clobazam
• Clonazepam
• Clorazepate
• Clozapine
• Codeine
• Cyclobenzaprine
• Dexmedetomidine
• Diacetylmorphine
• Diazepam
• Dichloralphenazone
• Difenoxin
• Dihydrocodeine
• Diphenhydramine
• Diphenoxylate
• Doxylamine
• Droperidol
• Enflurane
• Esketamine
• Estazolam
• Eszopiclone
• Ethchlorvynol
• Ethopropazine
• Ethylmorphine
• Fentanyl
• Flibanserin
• Fluphenazine
• Flurazepam
• Fluspirilene
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Halazepam
• Haloperidol
• Halothane
• Hexobarbital
• Hydrocodone
• Hydromorphone
• Hydroxyzine
• Isoflurane
• Ketamine
• Ketazolam
• Ketobemidone
• Levorphanol
• Lorazepam
• Loxapine
• Magnesium Oxybate
• Meclizine
• Melperone
• Meperidine
• Mephobarbital
• Meprobamate
• Meptazinol
• Mesoridazine
• Metaxalone
• Methadone
• Methdilazine
• Methocarbamol
• Methohexital
• Methotrimeprazine
• Methylene Blue
• Midazolam
• Molindone
• Moricizine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nicomorphine
• Nitrazepam
• Nitrous Oxide
• Olanzapine
• Opium
• Opium Alkaloids
• Orlistat
• Orphenadrine
• Oxazepam
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Perampanel
• Perazine
• Periciazine
• Perphenazine
• Phenobarbital
• Pimozide
• Piperacetazine
• Pipotiazine
• Piritramide
• Potassium Oxybate
• Prazepam
• Primidone
• Prochlorperazine
• Promazine
• Promethazine
• Propofol
• Quazepam
• Quetiapine
• Ramelteon
• Remifentanil
• Remimazolam
• Remoxipride
• Secobarbital
• Sertindole
• Sodium Oxybate
• Sufentanil
• Sulpiride
• Suvorexant
• Tapentadol
• Temazepam
• Thiethylperazine
• Thiopental
• Thiopropazate
• Thioridazine
• Tilidine
• Tizanidine
• Tolonium Chloride
• Topiramate
• Tramadol
• Triazolam
• Trifluoperazine
• Trifluperidol
• Triflupromazine
• Trimeprazine
• Zaleplon
• Zolpidem
• Zopiclone
• Zotepine

Other Interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Alcohol or drug abuse, history of or
• Angioedema (severe swelling), history of or
• Congestive heart failure or
• Diabetes: May cause side effects to become worse.
• Behavior changes, history of or
• Bleeding disorder or
• Depression, history of or
• Edema (body swelling or fluid retention) or
• Heart rhythm problem (eg, prolonged PR interval) or
• Lung or breathing problems (eg, respiratory depression) or
• Thrombocytopenia (low platelets in the blood): 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.

How does pregabalin work?

Pregabalin is an alkylated analogue of gamma-aminobutyric acid (GABA) and is structurally related to gabapentin. However, pregabalin does not directly bind to GABA-A or GABA-B receptors ¹⁰⁾. Additionally, Pregabalin is not metabolized to a GABA receptor agonist. In animal models, pregabalin binds to presynaptic voltage-gated calcium channels at the alpha-2-delta subunit in central nervous system tissues. The binding of the alpha-2-delta subunit decreases the depolarization-induced influx of calcium into neurons and reduces the release of excitatory neurotransmitters by hyperexcited neurons ¹¹⁾, ¹²⁾, ¹³⁾. This action may account for the anticonvulsant and analgesic effects of pregabalin. Pregabalin has no known activity at sodium channels, dopamine receptors, serotonin receptors, opiate receptors and does not modify cyclooxygenase activity ¹⁴⁾.

Pregabalin has antiepileptic, analgesic, and anxiolytic effects. Pregabalin has been shown to be effective in reducing neuropathic pain from diabetic and postherpetic neuropathy and is an effective anticonvulsant ¹⁵⁾.

Pregabalin works in different ways:

• In epilepsy Pregabalin stops seizures by reducing the abnormal electrical activity in your brain
• With nerve pain Pregabalin blocks pain by affecting the pain messages traveling through your brain and down your spinal cord
• In anxiety Pregabalin stops your brain from releasing the chemicals that make you feel anxious.

Pregabalin uses

Pregabalin was approved for use in the United States in 2004 to treat epilepsy and anxiety. Pregabalin is an anticonvulsant and neuropathic pain agent. Pregabalin works in the central nervous system (CNS) to control seizures and pain. Pregabalin is used with other medicines to help control partial-onset seizures (convulsions) in the treatment of epilepsy in patients 1 month of age and older. Pregabalin will not cure epilepsy and will only work to control seizures for as long as you continue to take it.

Pregabalin United States Food and Drug Administration (FDA)-approved indications ¹⁶⁾, ¹⁷⁾, ¹⁸⁾, ¹⁹⁾:

• Treatment of nerve pain or neuropathic pain associated with diabetic peripheral neuropathy (diabetic neuropathy or pain caused by nerve damage from diabetes)
• Treatment of nerve pain or neuropathic pain associated with spinal cord injury
• Neuropathic pain originating from postherpetic neuralgia (nerve pain that occurs after shingles)
• Treatment of fibromyalgia (muscle pain and stiffness).
• Adjunctive therapy for partial-onset seizures in adults with epilepsy

Pregabalin Off-label Uses ²⁰⁾, ²¹⁾, ²²⁾:

• Generalized anxiety disorder
• Social anxiety disorder
• Bipolar disorder
• Insomnia
• Chronic pain conditions
• Chronic Pruritus (chronic itch)
• Chronic cough
• Migraine
• Restless leg syndrome

There is significant disagreement regarding the effectiveness of pregabalin for the psychiatric disorders listed above. Therefore, prescribers should be careful and monitor patients for therapeutic success when treating patients with pregabalin ²³⁾.

Pregabalin dosage

Pregabalin is only available on prescription. It comes as capsules, tablets (extended release) or a liquid that you swallow. Take Ppregabalin exactly as prescribed by your doctor and read all medication guides or instruction sheets about pregabalin. Your doctor may occasionally change your dose. Pregabalin recommended initial dose for neuropathic pain is 50 to 75 mg two to three times daily, the maximum dose being 300 mg daily. Higher doses are used in treating seizures. The dose should be increased and tapered gradually.

Take pregabalin exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

Pregabalin capsule or oral liquid may be taken with or without food.

Take the extended-release tablet after an evening meal. Swallow it whole. Do not crush, break, or chew it.

Measure the oral liquid using a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.

Call your doctor if your symptoms do not improve, or if they get worse.

Do not stop using pregabalin suddenly, even if you feel fine. Stopping suddenly may cause increased seizures or unpleasant withdrawal symptoms. Follow your doctor’s instructions about tapering your dose for at least 1 week before stopping completely.

In case of emergency, wear or carry medical identification to let others know you take seizure medication.

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

The dose of pregabalin 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 pregabalin. 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.

Diabetic nerve pain

For oral dosage forms (capsules and solution):

• Adults: At first, 50 milligrams (mg) 3 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 300 mg per day (maximum therapeutic dose is 300 mg/day). The dose can increase up to 300 mg/day within one week of starting treatment ²⁴⁾.
• Children: Use and dose must be determined by your doctor.

For oral dosage forms (extended-release tablets):

• Adults: At first, 165 milligrams (mg) once a day for 1 week. Your doctor may increase your dose as needed and tolerated. However, the dose is usually not more than 330 mg per day.
• Children: Use and dose must be determined by your doctor.

Partial-onset seizures

For oral dosage forms (capsules and solution):

• Adults and children 17 years of age and older: At first, 150 milligrams (mg) per day given in 2 or 3 divided doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 600 mg per day. The effective dose is 150 mg to 600 mg per day, divided 2 or 3 times per dosing. The suggested starting dose is no greater than 150 mg per day. The total dose can increase to a maximum of 600 mg per day.
• Children 1 month of age and older weighing 30 kilograms (kg) or more: Use is based on body weight and must be determined by your doctor. The usual dose is 2.5 milligram per kilogram (mg/kg) per day given in 2 or 3 divided doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 10 mg/kg (600 mg) per day.
• Children 1 month of age and older weighing less than 30 kilograms (kg): Use is based on body weight and must be determined by your doctor. The usual dose is 3.5 milligram per kilogram (mg/kg) per day given in 3 divided doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 14 mg/kg per day.
• Children younger than 1 month of age: Use and dose must be determined by your doctor.

Fibromyalgia

For oral dosage forms (capsules and solution):

• Adults: At first, 75 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 450 mg per day. The recommended therapeutic dose is 300 mg to 450 mg per day. The recommended starting dose is 150 mg/day divided into twice per day dosing. The dose can increase to 300 mg per day within one week of starting treatment. Patients with suboptimal pain relief on 300 mg per day may further increase to 450 mg per day, divided into twice per day dosing.
• Children: Use and dose must be determined by your doctor.

Post-herpetic neuralgia

For oral dosage forms (capsules and solution):

• Adults: At first, 75 to 150 milligrams (mg) 2 times a day, or 50 to 100 mg 3 times a day. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 600 mg per day. The recommended therapeutic dose is 150 mg to 300 mg per day, divided into dosing 2 or 3 times per day. The recommended starting dose is 75 mg two times per day or 50 mg three times per day. The dose can increase up to 300 mg per day within one week of starting treatment. After 2 to 4 weeks of treatment with 300 mg per day, patients with suboptimal pain relief can be increased to 600 mg per day, divided into twice per day or three times per dosing.
• Children: Use and dose must be determined by your doctor.

For oral dosage forms (extended-release tablets):

• Adults: At first, 165 milligrams (mg) once a day for 1 week. Your doctor may increase your dose to 330 mg as needed and tolerated. However, the dose is usually not more than 660 mg per day.
• Children: Use and dose must be determined by your doctor.

Spinal cord injury nerve pain

For oral dosage forms (capsules and solution):

• Adults: At first, 75 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 600 mg per day. The dose may be increased to 150 mg twice per day within one week of initiating treatment. Patients with suboptimal pain relief following 2 to 3 weeks of treatment with 150 mg twice a day may be increased up to 300 mg twice per day. In spinal cord injury, pain improvement can be seen as early as one week after initiating treatment. However, to evaluate the efficacy of pregabalin, it is recommended to try the medication for 4 to 6 weeks if tolerated by the patient ²⁵⁾.
• Children: Use and dose must be determined by your doctor.

Refractory Chronic Cough

Pregabalin is off-label used in refractory chronic cough conditions. The initial starting dose is 75 mg per day, which may increase by 75 mg per day during the first week of treatment. The maximum dose can be up to 300 mg per day, divided into three times per dosing ²⁶⁾.

Generalized Anxiety Disorder (GAD)

Pregabalin is also off-label used in generalized anxiety disorder. The initial starting dose is 75 mg per day, which may increase by 75 mg per day during the first week of treatment. The maximum dose can be up to 300 mg per day, divided into three times per dosing ²⁷⁾.

Social Anxiety Disorder (SAD)

Pregabalin is off-label used as mono or adjuvant therapy in social anxiety disorder, cough, and chronic refractory conditions. The initial starting dose is 100 mg three times a day, which may increase by 150 mg per day over one week. This dose may go up to 600 mg daily based on response and tolerability ²⁸⁾.

Chronic Pruritus (Chronic Itch)

Pregabalin is also off-label used as a preferred treatment in patients with brachioradial pruritus, a rare type of chronic pruritus that usually localized at the dorsolateral part of the forearms. Itching, burning, or pain are common symptoms at the involved areas. The causal factors are still unknown but sun exposure and/or cervical spine lesions seem to be trigerring or precipiting factors ²⁹⁾. Neuropathogenic mechanism plays role in etiopathogenesis of brachioradial pruritus, therefore, antiepileptic drugs such as gabapentin, oxcarbazepine. and pregabalin are suggested medications for BRP. Herein, we report three cases with brachioradial pruritus successfully treated with pregabaline. The initial starting dose is 75 mg twice daily, which may increase by 150 mg to 300 mg in two to three divided doses daily. This dose may go up to 600 mg daily in oncology patient populations ³⁰⁾.

Restless Legs Syndrome

Another off-label use of pregabalin is in restless legs syndrome. The initial starting dose is 50 mg to 75 mg daily before bedtime, which may increase by 75 mg to 150 mg every week. The usual therapeutic dose is up to 150 mg to 450 mg daily based on the effectiveness and tolerability of therapy ³¹⁾.

What should I do if I forget a dose?

If you are taking pregabalin capsules or the oral solution and forget to take a dose and remember a few hours later, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If you are taking pregabalin extended-release tablets and forget to take a dose after your evening meal, take the missed dose before bedtime after a snack. If you miss taking the dose prior to bedtime, take your dose the following day after breakfast. If you miss taking the dose after breakfast, take your dose at the usual time after an evening meal and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Pregabalin side effects

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

• tiredness
• dizziness
• headache
• dry mouth
• nausea
• vomiting
• constipation
• gas
• bloating
• ”high” or elevated mood
• speech problems
• difficulty concentrating or paying attention
• difficulty remembering or forgetfulness
• anxiety
• lack of coordination
• loss of balance or unsteadiness
• uncontrollable shaking or jerking of a part of the body
• muscle twitching
• weakness
• increased appetite
• weight gain
• back pain

Some side effects can be serious. If you experience any of these symptoms, see your doctor immediately:

• blurred vision, double vision, or other changes in eyesight
• hives
• rash
• itching
• blisters
• swelling of the eyes, face, throat, mouth, lips, gums, tongue, head or neck
• swelling of the arms, hands, feet, ankles, or lower legs
• shortness of breath
• wheezing
• muscle pain, tenderness, soreness, or weakness, especially if it comes along with fever
• chest pain
• difficulty breathing; bluish-tinged skin, lips, or fingernails; confusion; or extreme sleepiness

If you have diabetes, you should know that pregabalin has caused skin sores in animals. Pay extra attention to your skin while taking pregabalin, and tell your doctor if you have any sores, redness, or skin problems.

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

Pregabalin overdose

There is limited information regarding overdose with pregabalin. The highest known accidental overdose of pregabalin during clinical development was 8000 mg; this event was without significant clinical consequences. There is no specific antidote for overdose with pregabalin.

The most commonly reported adverse events with overdose were reduced consciousness, confusional state, agitation, depression/anxiety, and restlessness in the postmarketing studies. In addition, heart block, seizures, and death have also been reported in some patients taking combination with other central nervous system depressants ³²⁾.

Pregabalin overdose treatment

• If required, elimination of unabsorbed drugs can be performed by gastric lavage or emesis. General supportive care should be provided to the patient. Maintain airway and monitor vital signs and clinical status of the patient. Contact a Certified Poison Control Center (https://poisonhelp.hrsa.gov/poison-centers/find-poison-center) for up-to-date information on the management of overdose with pregabalin. The national, toll-free Poison Help line, 1-800-222-1222, connects you to your local poison center and is your resource for help in a poisoning emergency. You can call from anywhere in the United States and many territories.
• Pregabalin can be removed by standard hemodialysis procedures, resulting in approximately 50% clearance of pregabalin in 4 hours.

Pregabalin Contraindications

Pregabalin is contraindicated in patients who have a known hypersensitivity to pregabalin. Hypersensitivity reactions have occurred in patients receiving pregabalin, including angioedema ³³⁾. There are no adequate studies with pregabalin in pregnant women. Pregabalin may cause fetal harm. Advise patients there is a potential risk to the fetus ³⁴⁾. Pregabalin has been detected in the milk of lactating women; thus, breastfeeding is not advisable, and an alternative agent is preferred ³⁵⁾. There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking Pregabalin while breastfeeding.

Diazepam

Diazepam also known under the brand name Valium, belongs to a class of medications called benzodiazepines, that acts as an anxiolytic used to relieve anxiety. Diazepam or valium is used to treat anxiety, and seizures or fits. Diazepam is also used along with other medications to control muscle spasms and spasticity caused by certain neurological disorders such as cerebral palsy (condition that causes difficulty with movement and balance), paraplegia (inability to move parts of the body), athetosis (abnormal muscle contractions), and stiff-person syndrome (a rare disorder with muscle rigidity and stiffness). Diazepam is also used in hospital to reduce alcohol withdrawal symptoms, such as agitation, trembling, confusion and anxiety or difficulty sleeping. Diazepam or valium can also be taken to help you relax before an operation or other medical or dental treatments. This is known as a pre-med. To get diazepam, you need a prescription written for you by a doctor. Your doctor may have prescribed diazepam for another reason. If you are unsure about why you are taking diazepam, ask your doctor.

Diazepam is a benzodiazepine. Benzodiazepines belong to the group of medicines called central nervous system (CNS) depressants, which are medicines that slow down the nervous system. Diazepam works by increasing the levels of a calming chemical in your brain, a neurotransmitter called gamma-aminobutyric acid (GABA), which work by calming abnormal overactivity in the brain. The sedative activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutyric acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA-A receptor.

Diazepam comes as tablets, a solution, and as a concentrate (liquid) to take by mouth, or in a rectal tube – medicine that’s squeezed into your bottom (anus). It can also be given as an injection in hospital. Diazepam is usually taken 1 to 4 times a day and may be taken with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take diazepam exactly as directed.

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

After oral administration of diazepam >90% is absorbed, the average time to achieve peak plasma concentrations is 1 to 1.5 hours. Absorption is delayed and decreased when administered with a meal. There is an increase in the mean time to achieve peak concentrations to approximately 2.5 hours in the presence of food.

Diazepam is mostly broken down by the microsomal enzymes CYP2C19 and CYP3A4 enzymes to several active metabolites, mainly desmethyldiazepam. Other minor active metabolites include oxazepam and temazepam. The average half-lives of oral diazepam and desmethyldiazepam are about 46 and 100 hours, respectively ¹⁾.

You’ll usually take diazepam for no longer than 2 to 4 weeks. If you’re prescribed diazepam for more than 4 weeks, your dose may be reduced gradually when you stop taking it to prevent withdrawal symptoms.

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

Diazepam helps most people with anxiety but some people have side effects.

The most common side effects of diazepam include:

• tiredness
• sleepiness
• muscle weakness
• unsteadiness

It can also make you forgetful and dizzy.

There are other rare side effects. Tell your doctor at once or go to the emergency room of your nearest hospital if you experience any of these symptoms:

• sudden excitation or anxiety
• feelings of restlessness, agitation or anger
• abnormal behavior
• hallucinations (hearing, seeing or smelling things that aren’t there)
• difficulties in breathing
• serious sleep disturbances

In general, diazepam should be used only for short periods, around 2 to 4 weeks, unless advised by your doctor. Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long-term use can be potentially dangerous. After stopping, cognitive problems may persist for six months or longer.

Diazepam is not recommended during pregnancy or breastfeeding. An increase in congenital malformations has been suggested with minor tranquilizer use, especially during the first trimester.

• If diazepam (valium) is used during pregnancy, or if the patient becomes pregnant while taking diazepam (valium), the patient should be apprised of the potential harm to the fetus.
• Neonates exposed to single high doses of diazepam (valium) during labor and delivery should be monitored for irregularities in fetal heart rate, hypotonia, poor sucking, hypothermia, and moderate respiratory depression.
• If used during pregnancy, monitor the newborn for acute withdrawal syndrome symptoms during the postnatal period.
• A pregnancy exposure registry is available here (https://www.aedpregnancyregistry.org).

Figure 1. Diazepam chemical structure

Before taking diazepam

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

Diazepam pregnancy warnings

Diazepam is classified as a former FDA pregnancy category D, indicating positive evidence of human fetal risk. Still, the benefits from use in pregnant women may be acceptable despite the risk ²⁾. Animal models have revealed evidence of teratogenicity, decreased number of pregnancies, lower surviving offspring numbers, and long-term changes in cellular immune responses, brain neurochemistry, and behavior. Cleft palate, central nervous system malformations/encephalopathy, and permanent functional disturbances occurred in animal models at maternally toxic doses. Neonatal flaccidity, respiratory/feeding difficulties, and hypothermia have been reported in humans. Use during the first and third trimesters may be associated with an increased risk of teratogenicity and withdrawal symptoms in the newborn, respectively. However, additional studies are needed to confirm.

Diazepam readily crosses the placental barrier, and use during pregnancy may result in neonatal withdrawal soon after birth ³⁾. Symptoms of neonatal withdrawal include high-pitched cry, hypertonia, tremor, irritability, feeding difficulties, sleep/wake disturbances, gastrointestinal and autonomic disturbances, respiratory problems, and failure to thrive ⁴⁾. The onset of withdrawal in a neonate whose mother has taken diazepam during the pregnancy could be anywhere from the first days of life to the first few weeks. During the last trimester of pregnancy, diazepam use can result in “floppy infant syndrome,” characterized by hypotonia, hypothermia, lethargy, respiratory distress, and suckling difficulties ⁵⁾, ⁶⁾.

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, using diazepam is not expected to increase the chance of birth defects above the background risk. Older studies suggested a less than 1 in 100 (less than 1%) increased chance of cleft lip and/or cleft palate if a person uses diazepam in the first trimester of pregnancy ⁷⁾, ⁸⁾, ⁹⁾, ¹⁰⁾, ¹¹⁾, ¹²⁾. A cleft lip or cleft palate is when the lip and/or roof of mouth formed with a split and can need surgery to correct. More recent studies that are larger and better-designed have not found an increased chance of oral clefts or other birth defects with diazepam use in pregnancy ¹³⁾, ¹⁴⁾.

Some, but not all, studies have reported an increased chance for preterm delivery (delivery before 37 weeks of pregnancy), low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth), and/or smaller head size in babies born to a person who was using diazepam and other benzodiazepines in pregnancy ¹⁵⁾, ¹⁶⁾. Two of these studies followed the exposed children as they grew and reported they had reached normal weight ranges by 8-10 months of age ¹⁷⁾, ¹⁸⁾. In one study head circumferences remained smaller than expected at 18 months of age ¹⁹⁾.

Based on the studies reviewed, it is not known if taking diazepam increases the chance for behavior or learning issues. Two studies have followed children who were exposed to diazepam during pregnancy until the children were up to 18 months or 3 years of age. These studies reported that the children were more likely to show certain behaviors, such as anxiety, sadness, and fearfulness ²⁰⁾, ²¹⁾, ²²⁾.

Diazepam breastfeeding warnings

Diazepam gets into breast milk in small amounts. Diazepam stays in the body longer than some other benzodiazepines do. If you use diazepam regularly while breastfeeding there is a chance it could build up in the baby’s system and cause sleepiness or affect your child’s weight gain. If you suspect the baby has any symptoms like trouble feeding, breathing, gaining weight or being overly sleepy, contact your baby’s healthcare provider.

The product label for diazepam recommends people who are breastfeeding not use this medication. But, the benefit of using diazepam may outweigh possible risks. Your healthcare providers can talk with you about using diazepam and what treatment is best for you. If you need to use a benzodiazepine regularly while breastfeeding, it might be preferred to use one that clears from the body more quickly than diazepam does. Be sure to talk to your healthcare provider about all of your breastfeeding questions.

Some studies have shown diazepam’s relative infant dose (RID) to be approximately 9% ²³⁾. The relative infant dose (RID) is the dose received via breast milk relative to the mothers. A relative dose below 10% is within an acceptable range regarded as reasonably safe in the short term ²⁴⁾. However, due to diazepam’s long half-life, its metabolites may accumulate in a breastfed infant. Therefore, you should monitor an infant breastfed by a mother receiving diazepam for drowsiness, decreased feeding, lethargy, and failure to thrive. Discontinue breastfeeding in cases with high doses of diazepam or when repeated administration will be necessary. However, when a single dose of diazepam is required for a procedure or seizure, the clinician should advise the mother to wait six to eight hours before resuming nursing, particularly with a preterm infant ²⁵⁾, ²⁶⁾.

Excreted into human milk: Yes

Comments:

• Sedation, weight loss, and feeding difficulties have occurred in nursing infants.
• The American Academy of Pediatrics considers diazepam for which the effect on nursing infants is unknown but may be of concern if exposure is prolonged.
• The WHO considers diazepam compatible with breastfeeding if given in a single dose; repeated doses should be avoided, if possible. Breastfed infants should be monitored for drowsiness. Short-acting benzodiazepines (e.g., oxazepam, lorazepam) may be preferred.

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 diazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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

• Flumazenil

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

• Abametapir
• Alfentanil
• Alprazolam
• Amobarbital
• Anileridine
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Clonazepam
• Cobicistat
• Codeine
• Conivaptan
• Dantrolene
• Daridorexant
• Dexmedetomidine
• Diacetylmorphine
• Difenoxin
• Dihydrocodeine
• Diphenoxylate
• Doxylamine
• Esketamine
• Eslicarbazepine Acetate
• Ethchlorvynol
• Ethylmorphine
• Etravirine
• Fedratinib
• Fentanyl
• Fexinidazole
• Flibanserin
• Fosnetupitant
• Fosphenytoin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Ketobemidone
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Netupitant
• Nicomorphine
• Opium
• Opium Alkaloids
• Orlistat
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Phenytoin
• Piritramide
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remifentanil
• Remimazolam
• Ropeginterferon Alfa-2b-njft
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tilidine
• Tramadol
• Trazodone
• Zolpidem

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

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

Other interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using diazepam with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use diazepam, or give you special instructions about the use of grapefruit juice. Grapefruit juice may increase the amount of diazepam in your blood. It’s a good idea to avoid grapefruit or grapefruit juice while taking diazepam.

Caffeine is a stimulant and may reduce the calming effects of diazepam. It’s best not to have drinks like coffee, tea, cola and energy drinks because they contain caffeine.

Do not drink alcohol while you’re taking diazepam.

Other medical problems

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

• Alcohol or drug abuse or dependence, or history of, or
• Depression, or history of or
• Lung or breathing problems (eg, respiratory depression) or
• Mental health problems, or history of or
• Seizures, history of—Use with caution. May make these conditions worse.
• Breathing problems, severe or
• Glaucoma, narrow-angle or
• Liver disease, severe or
• Myasthenia gravis or
• Sleep apnea (temporary stopping of breathing during sleep)—Should not be used in patients with these conditions.
• Kidney disease or
• Liver disease, mild or moderate—Use with caution. The effects may be increased because of slower removal of diazepam from the body.

Is diazepam addictive?

It is possible to become addicted to diazepam. To reduce the risk of becoming addicted, it’s best to take the lowest diazepam dose that treats your symptoms, and to take it for only a short time (2 to 4 weeks). You’re more likely to get addicted if you need to take a higher diazepam dose for a longer time, or if you’ve ever had problems with alcohol or drugs.

What will happen if I stop taking diazepam?

If you have been taking a high dose of diazepam or have been taking it for a long time, your doctor will probably recommend reducing your dose gradually.

If you suddenly stop taking diazepam, you may get some side effects, such as:

• confusion
• seizures or fits
• depression
• feeling nervous or irritable
• sweating
• diarrhea

You’re less likely to get these side effects if you reduce your diazepam dose gradually.

Can I drink alcohol while taking diazepam?

Do not drink alcohol while you’re taking diazepam. Alcohol can increase the effects of diazepam. It can make you go into a very deep sleep. There’s a risk you will not be able to breathe properly, and you may have difficulty waking up.

Who can take diazepam?

Most adults aged 18 years and over can take diazepam tablets and liquid. People aged over 65 might need to take a lower dose.

Children aged 1 month and older can take it for muscle spasms.

Diazepam rectal tubes can be used by adults and children.

Who may not be able to take diazepam?

Diazepam is not suitable for some people. To make sure it’s safe for you, tell your doctor before starting to take diazepam if you:

• have ever had an allergic reaction to diazepam or any other medicine
• have liver or kidney problems
• have myasthenia gravis, a condition that causes muscle weakness
• have sleep apnoea, a condition that causes breathing problems when you’re asleep
• have depression or thoughts of harming yourself or suicide
• have been diagnosed with a personality disorder
• have ever had problems with alcohol or drugs
• have recently had a loss or bereavement
• have arteriosclerosis, a condition that affects the blood flow to your brain
• have low levels of a protein called albumin in your blood
• are trying to get pregnant, are already pregnant or breastfeeding
• are over 65
• are going to be put to sleep (have a general anaesthetic) for an operation or other medical treatment.

When will I feel better after taking diazepam?

Diazepam will work quite quickly or more slowly depending on what you’re taking it for:

• seizures or fits – diazepam rectal tubes should start to work within 10 minutes
• anxiety – you should start to feel a bit better within a few hours, but it may take a week or 2 for you to feel the full effects
• muscle spasms – you should begin to feel less pain after 15 minutes. Your muscles will start to relax when you have been taking diazepam regularly for a few days.

Oral diazepam tablets have a more reliable absorption and controlled release when compared to intramuscular (IM). When administered intravenously (IV), diazepam has an onset of action within 1 to 3 minutes, while oral dosing onset ranges between 15 to 60 minutes. In addition, diazepam is long-lasting, with a duration of action of more than 12 hours.

Will diazepam affect my contraception?

Diazepam will not affect any type of contraception, including the combined pill and emergency contraception. But some contraceptive pills can keep diazepam in your body for longer and increase its effect.

You can also get bleeding in between your periods if you take diazepam and contraceptive pills together. But your contraception will still work.

I need to take diazepam throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?

Babies that were exposed to diazepam throughout pregnancy or late in pregnancy might have withdrawal symptoms starting soon after delivery or within several days of birth. Symptoms might include breathing problems, jitteriness, excessive crying, and trouble maintaining their body temperature. Some newborns may have loose muscle tone, sluggishness, and trouble latching on to feed (called “floppy infant syndrome”). Some babies might need to spend more time in the hospital to help manage these symptoms. The symptoms are expected to go away within a few weeks.

If a male takes diazepam, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?

Based on the studies reviewed, it is not known if the use of diazepam can affect fertility or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy.

Can I drive or ride a bike when I’m taking diazepam?

Do not drive a car or ride a bike if diazepam makes you sleepy, gives you blurred vision, or makes you feel dizzy, clumsy or unable to concentrate or make decisions. This may be more likely when you first start taking diazepam, but it could happen at any time, for example when starting another medicine.

It’s an offence to drive a car if your ability to drive safely is affected. It’s your responsibility to decide if it’s safe to drive. If you’re in any doubt, do not drive.

Even if your ability to drive is not affected, the police have the right to request a saliva sample to check how much diazepam is in your body.

Can I operate machinery or tools while I’m taking diazepam?

Do not operate machinery or tools if you get any side effects, such as feeling sleepy, being forgetful, or poor co-ordination.

What are benzodiazepines?

Benzodiazepines are drugs that belong to the group of medicines called central nervous system (CNS) depressants or sedatives, which are medicines that slows down messages traveling between your brain and your body. Other central nervous system (CNS) depressants include alcohol, cannabis and heroin. The central nervous system (brain and spinal cord) effects of benzodiazepines are believed to be mediated by activation of gamma aminobutyric acid (GABA) A receptors and modulation of their inhibition of neurotransmission ²⁷⁾. Because benzodiazepines are controlled substances with abuse potential, they are available only with your doctor’s prescription with special attention directed toward the patient’s addiction history before these agents are prescribed.

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

Benzodiazepines may be prescribed to:

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

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

Benzodiazepines can cause a person to overdose, particularly when used with alcohol or other drugs. Benzodiazepines are associated with dependence and withdrawal symptoms, even after a short period of use which is why benzodiazepines are not the first option for pharmacological treatment of insomnia (difficulty falling asleep or staying asleep), anxiety or other health concerns ²⁸⁾.

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

Table 1. Benzodiazepines pharmaceutical names

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

Benzodiazepines all share similar activity and clinical effects, but variability in dosing, pharmacokinetics, rapidity of uptake and half-life make them more suited for one or another of these indications. Thus, estazolam, flurazepam, quazepam, temazepam and triazolam are generally used as sleeping pills, whereas alprazolam, chlordiazepoxide, diazepam, and lorazepam are used largely for the treatment of anxiety. Clobazam, clonazepam, and clorazepate are used as anticonvulsants, and high dose, parenteral diazepam and lorazepam are used for status epilepticus. Parenteral midazolam, diazepam and lorazepam are also used as anesthetics or anesthetic premedications. Alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium) and lorazepam (Ativan) are listed among the top 100 most commonly prescribed medications in United States ³⁰⁾. According to the American Psychiatric Association report on benzodiazepines, 11 to 15 percent of the adult population has taken a benzodiazepine one or more times during the preceding year, but only 1 to 2 percent have taken benzodiazepines daily for 12 months or longer ³¹⁾. In psychiatric treatment settings and in substance-abuse populations, however, the prevalence of benzodiazepine use, abuse and dependence is substantially higher than that in the general population ³²⁾.

How does diazepam work?

Diazepam is a benzodiazepine. Benzodiazepines are central nervous system depressants and they all increase activity at receptors for the neurotransmitter gamma-aminobutyric acid (GABA). The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) inhibits the activity of neurons, slowing down the workings of your brain and nervous system. Specifically, benzodiazepines bind at an allosteric site at the interface between the alpha and gamma subunits on GABA-A receptor chloride ion channels ³³⁾. The allosteric binding of diazepam at the GABA-A receptor increases the frequency at which the chloride channel opens, leading to an increased conductance of chloride ions. This shift in charge leads to a hyperpolarization of the neuronal membrane and reduced neuronal excitability ³⁴⁾.

Specifically, the allosteric binding within the limbic system, thalamus, and hypothalamus leads to the anxiolytic effects seen with diazepam ³⁵⁾. Allosteric binding within the spinal cord and motor neurons is the primary mediator of the myorelaxant effects seen with diazepam ³⁶⁾. Mediation of the sedative, amnestic, and anticonvulsant effects of diazepam is through receptor binding within the cortex, thalamus, and cerebellum ³⁷⁾.

Similarly, other sites for drug and neurotransmitter binding are associated with the GABA receptor complex, which serves as a primary site of action of benzodiazepines, barbiturates and other sedative-hypnotics, such as alcohol ³⁸⁾. Benzodiazepines and barbiturates act at separate binding sites on the receptor to potentiate the inhibitory action of GABA. They do so by allosterically altering the receptor (changing its conformation) so that it has a greater binding affinity for GABA. Ethanol modifies the receptor by altering the membrane environment so that it has increased affinity for GABA and the other sedative-hypnotic drugs. That benzodiazepines, barbiturates and ethanol all have related actions on a common receptor type, which explains their pharmacologic synergy and cross tolerance. Thus, benzodiazepines are used during alcohol detoxification.

With long-term high-dose use of benzodiazepines (or ethanol), there is an apparent decrease in the efficacy of GABA-A receptors, presumably a mechanism of tolerance ³⁹⁾. When high-dose benzodiazepines or ethanol are abruptly discontinued, this “down-regulated” state of inhibitory transmission is unmasked, leading to characteristic withdrawal symptoms such as anxiety, insomnia, autonomic hyperactivity and, possibly, seizures.

Common effects of benzodiazepines include:

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

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

Diazepam uses

Diazepam is FDA approved for the management of anxiety disorders, short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, management of certain refractory epilepsy patients, and adjunct in severe recurrent convulsive seizures, and an adjunct in status epilepticus. Off-label (non-FDA approved) use for diazepam includes sedation in the ICU and short-term treatment of spasticity in children with cerebral palsy ⁴⁰⁾. In 2020, diazepam (Valtoco) was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy ⁴¹⁾. Diazepam is also the most commonly used benzodiazepine for “tapering” benzodiazepine dependence due to the drug’s comparatively long half-life, allowing for more efficient dose reduction. Benzodiazepines have a relatively low toxicity in overdose ⁴²⁾. To get diazepam, you need a prescription written for you by a doctor. Your doctor may have prescribed diazepam for another reason. If you are unsure about why you are taking diazepam, ask your doctor.

Diazepam has a number of uses, including:

• Treatment of anxiety, panic attacks, and states of agitation ⁴³⁾
• Treatment of neurovegetative symptoms associated with vertigo ⁴⁴⁾
• Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal ⁴⁵⁾
• Short-term treatment of insomnia ⁴⁶⁾
• Treatment of muscle spasms
• Treatment of tetanus, together with other measures of intensive treatment ⁴⁷⁾
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, stroke, multiple sclerosis and spinal cord injury (long-term treatment is coupled with other rehabilitative measures) ⁴⁸⁾
• Palliative treatment of stiff-person syndrome
• Pre- or postoperative sedation, anxiolysis or amnesia (e.g., before endoscopic or surgical procedures) ⁴⁹⁾
• Treatment of complications with stimulant overdoses and psychosis, such as cocaine or methamphetamine ⁵⁰⁾
• Used in treatment of organophosphate poisoning and reduces the risk of seizure induced brain and cardiac damage.
• Preventive treatment of oxygen toxicity during hyperbaric oxygen therapy ⁵¹⁾
• Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed ⁵²⁾, ⁵³⁾

Diazepam dosage

Diazepam dosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have. Take diazepam exactly as prescribed by your doctor. Follow the directions on your prescription label and read all medication guides or instruction sheets. Never use diazepam in larger amounts, or for longer than prescribed. Tell your doctor if you feel an increased urge to use more of diazepam. MISUSE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH. Keep diazepam where others cannot get to it. Selling or giving away diazepam is against the law.

• Treatment of acute alcohol withdrawal symptoms: Initial dosing should be 10 mg IM or IV. If needed, a follow-up dose of 5 to 10 mg is permissible 3 to 4 hours later. If using the oral tablet, dosing is 10 mg every 6 to 8 hours within the first 24 hours, then 5mg every 6 to 8 hours after that as needed ⁵⁴⁾
• Treatment of anxiety: 2 to 10 mg can be given orally 2 to 4 times daily. If given parentally, dosing can be 2 to 10 mg and repeated in 3 to 4 hours, if needed ⁵⁵⁾
• Treatment of muscle spasms: 2 to 10 mg can be given orally 3 to 4 times daily. If given parentally, an initial dose of 5 to 10 mg can be followed by another 5-10mg dose in 3 to 4 hours, if necessary ⁵⁶⁾
• Treatment of preoperative anxiety: Dosing is 10 mg IM before surgery ⁵⁷⁾
• For sedation in the ICU: Loading dose of 5 to 10 mg for initial administration, followed by a maintenance dose of 0.03 to 0.10 mg/kg every 0.5 to 6 hours ⁵⁸⁾
• Treatment of seizures: 2 to 10 mg orally dosed 2 to 4 times daily as adjunctive maintenance therapy. Rectal gel 0.2mg/kg is an option for intermittent management of seizures. It may be repeated in 4 to 12 hours if needed. Do not exceed five uses per month or more than one dose every five days.
• Skeletal muscle relaxant: 2 to 10 mg, dosed 3 to 4 times daily as an adjunct therapy.
• Treatment of status epilepticus: 0.15 to 0.20 mg/kg IV per dose and may be repeated once needed. Do not exceed 10 mg per single dose. Rectal administration of 0.2 to 0.5 mg/kg administered one time. Do not exceed 20 mg per dose ⁵⁹⁾.

Adult dose for anxiety

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

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

Comments:

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

Adult dose for alcohol withdrawal symptoms

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

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

Adult dose for muscle spasm

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

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

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

Adult dose for seizures

Uses:

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

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

Rectal:

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

Adult dose for status epilepticus

Use: Adjunct to status epilepticus and severe recurrent convulsive seizures

Parenteral:

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

Comments:

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

Adult dose for light anesthesia

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

Preoperative Medication: 10 mg IM once before surgery

Comments:

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

Adult dose as premedication for endoscopy or radiology

Uses:

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

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

Endoscopic Procedures:

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

Comments:

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

Geriatric dose for seizures

Uses:

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

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

Rectal:

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

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

Geriatric dose for alcohol withdrawal symptoms

Uses:

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

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

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

Comments:

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

Geriatric dose for anxiety

Uses:

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

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

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

Comments:

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

Geriatric dose for muscle spasm

Uses:

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

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

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

Comments:

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

Diazepam dose adjustments for debilitated patients

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

Parenteral: Initial dose: 2 to 5 mg once a day

Rectal:

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

What should I do if I forget a dose?

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

Children dose for seizures

Uses:

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

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

Rectal:

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

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

Children dose for status epilepticus

Use: Adjunct in status epilepticus and severe recurrent convulsive seizures

Parenteral:

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

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

Children dose for anxiety

Uses:

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

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

Comments:

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

Children dose for muscle spasm

Uses:

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

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

Comments:

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

Children dose for seizure prophylaxis

Uses:

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

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

Comments:

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

Children dose for tetanus

Use: Tetanus

Parenteral:

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

Comment: Respiratory assistance should be available for patients.

Diazepam side effects

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

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

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

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

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

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

After you stop using diazepam, get medical help right away if you have symptoms such as:

• unusual muscle movements,
• being more active or talkative,
• sudden and severe changes in mood or behavior,
• confusion,
• hallucinations,
• seizures,
• suicidal thoughts or actions.

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

Diazepam tolerance and withdrawal

Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome ⁶⁰⁾. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms ⁶¹⁾.

Benzodiazepine withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life ⁶²⁾.

Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen ⁶³⁾. Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation ⁶⁴⁾.

Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100% ⁶⁵⁾

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines ⁶⁶⁾. Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction ⁶⁷⁾. The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer ⁶⁸⁾. In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently ⁶⁹⁾.

Diazepam dependence

Improper or excessive use of diazepam can lead to dependence. At a particularly high risk for diazepam misuse, substance use disorder or dependence are:

• People with a history of a substance use disorder or substance dependence. Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers ⁷⁰⁾.
• People with severe personality disorders, such as borderline personality disorder ⁷¹⁾

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in such instances is not recommended.

People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts ⁷²⁾.

Diazepam is a good choice for tapering for those using high doses of other benzodiazepines since it has a long half-life thus withdrawal symptoms are tolerable ⁷³⁾. The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately ⁷⁴⁾.

Diazepam contraindications

Use of diazepam should be avoided, when possible, in individuals with:

• Ataxia
• Severe hypoventilation
• Acute narrow-angle glaucoma
• Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two)
• Severe renal deficiencies (for example, patients on dialysis)
• Liver disorders
• Severe sleep apnea
• Severe depression, particularly when accompanied by suicidal tendencies
• Psychosis
• Pregnancy or breast feeding
• Caution required in elderly or debilitated patients
• Coma or shock
• Abrupt discontinuation of therapy
• Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of hallucinogens or some stimulants, where it is occasionally used as a treatment for overdose)
• History of alcohol or drug dependence
• Myasthenia gravis, an autoimmune disorder causing marked fatiguability
• Hypersensitivity or allergy to any drug in the benzodiazepine class

Caution

• Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders ⁷⁵⁾.
• Pediatric patients
  • Less than 18 years of age, this treatment is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment. The smallest possible effective dose should be used for this group of patients ⁷⁶⁾
  • Under 6 months of age, safety and effectiveness have not been established; diazepam should not be given to those in this age group ⁷⁷⁾
• Elderly and very ill patients can possibly experience apnea or cardiac arrest. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of people. The elderly metabolise benzodiazepines much more slowly than younger adults, and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels ⁷⁸⁾. Doses of diazepam are recommended to be about half of those given to younger people, and treatment limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly. Diazepam can also be dangerous in geriatric patients owing to a significant increased risk of falls ⁷⁹⁾.
• Intravenous or intramuscular injections in hypotensive people or those in shock should be administered carefully and vital signs should be monitored.
• Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, can result in floppy infant syndrome ⁸⁰⁾. Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth ⁸¹⁾.

Diazepam overdose

The most common symptom of a diazepam overdose is falling into a deep sleep or “coma” while still being able to breathe well enough. Other symptoms may include:

• Bluish-colored lips and fingernails
• Blurred vision, double vision
• Breathing is slow, labored, or stopped
• Confusion
• Depression
• Dizziness
• Drowsiness, lack of alertness
• Loss of consciousness
• Excitability
• Hiccups
• Rapid side-to-side movement of the eyes
• Rash
• Stomach upset
• Tiredness
• Tremor
• Weakness, uncoordinated movement

In case of overdose, call the poison control helpline or your local emergency services number. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number.

Before calling emergency, have this information ready:

• Person’s age, weight, and condition
• Name of product (ingredients and strength, if known)
• Time it was swallowed
• Amount swallowed
• If the medicine was prescribed for the person

Take the container to the hospital with you, if possible.

At the hospital emergency room, the doctors will measure and monitor vital signs, including temperature, pulse, breathing rate, and blood pressure.

Tests that may be done include:

• Blood and urine tests
• Chest x-ray
• CT scan
• ECG (electrocardiogram, or heart tracing)

Treatment may include:

• Fluids through a vein (by IV)
• Medicine like flumazenil (Anexate) to reverse the effect of the diazepam overdose and treat other symptoms
• Activated charcoal
• Laxatives
• Breathing support, including a tube through the mouth into the lungs and connected to a breathing machine (ventilator)

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D. J. Greenblatt and colleagues ⁸²⁾ reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately-deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.

Recovery from a diazepam overdose is very likely. Complications such as pneumonia, muscle damage from lying on a hard surface for a long period of time, or brain damage from lack of oxygen may result in permanent disability ⁸³⁾, ⁸⁴⁾.. People who inject large amounts of this drug through a vein (intravenously or IV) have a worse outcome than those who swallow too many pills. Furthermore, overdoses of diazepam with alcohol, opiates, or other depressants may be fatal ⁸⁵⁾.

Tizanidine

Tizanidine is a short-acting muscle relaxant that is used to treat muscle spasms caused by multiple sclerosis (MS), stroke and brain or spinal injury ¹⁾, ²⁾. Tizanidine has also been shown to be clinically effective in managing patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes. It is also prescribed off-label for migraine headaches, insomnia, and as an anticonvulsant. Tizanidine can also be applied as part of a detoxification therapy regimen in patients exhibiting analgesic rebound headaches to assist with analgesic withdrawal. Tizanidine works by slowing action in your brain and nervous system to allow your muscles to relax. Tizanidine was approved for use in the United States in 1996 and currently several million prescriptions are filled yearly.

Tizanidine comes as a tablet and a capsule of 2, 4 or 6 mg to be takeb by mouth. Tizanidine is usually taken consistently either always with or always without food two or three times a day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tizanidine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Tizanidine capsules may be opened and sprinkled on soft foods such as applesauce. Talk to your doctor before opening the capsules because the effects of tizanidine when used in this manner may be different than when swallowing the capsule whole.

Tizanidine in the capsule is absorbed differently by the body than tizanidine in the tablet, so one product cannot be substituted for the other. Each time you have your prescription filled, look at the tablets or capsules in the bottle and make sure that you have received the right product. If you think you received the wrong medication, talk to your doctor or pharmacist right away.

Your doctor will probably start you on a low dose of tizanidine and gradually increase your dose, depending on your response to this medication. The recommended starting dose of tizanidine is 2 mg every 6 to 8 hours, up to a maximum of 3 doses in 24 hours. Do not take more than 36 mg of tizanidine in a 24-hour period ³⁾. Too much of tizanidine can damage your liver and a few of which have been fatal ⁴⁾. Cold or allergy medicine, narcotic pain medicine, sleeping pills, other muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by tizanidine.

Do not stop taking tizanidine without talking to your doctor. If you suddenly stop taking tizanidine, your heart may beat faster and you may have increased blood pressure or tightness in your muscles. Your doctor will probably decrease your dose gradually.

Tizanidine common side effects include tiredness, drowsiness, dizziness, muscular weakness, dry mouth and occasionally low blood pressure (hypotension).

How long does it take for tizanidine to work?

Tizanidine normally starts working 1 to 2 hours after taking it ⁵⁾, ⁶⁾. It wears off about 3 hours to 6 hours after taking it. Tizanidine can be taken up to 3 times a day to help relieve muscle spasms.

How long does tizanidine stay in my body?

Tizanidine is metabolized extensively in the liver by cytochrome P450-1A2 to inactive metabolites ⁷⁾. Tizanidine has an elimination half-life of 2.5 hours, follows linear pharmacokinetics, and is excreted 60% through urine and 20% through feces ⁸⁾. The maximum effect of tizanidine occurs about 1 hour to 2 hours after taking a dose. It wears off in about 3 to 6 hours after taking it. Tizanidine is typically given no more than 3 times a day. Tizanidine is usually taken up to 3 times in one day, starting at 2mg per dose. Allow 6 to 8 hours to pass between doses. Do not take more than 36 mg in a 24-hour period ⁹⁾. Too much of tizanidine can damage your liver ¹⁰⁾.

Does tizanidine lower my blood pressure?

Tizanidine is known to cause low blood pressure (hypotension). In some cases, it may cause low blood pressure that is so low that you could faint or pass out. The chances of fainting can be lowered if your doctor raises the dose of tizanidine very slowly. You may also have to be careful when you move from a sitting position to a standing position. In clinical trials, the most common side effects of tizanidine were dry mouth, sleepiness, dizziness and asthenia (defined as weakness, fatigue and/or tiredness).

Can I take tizanidine to help me sleep?

Tizanidine can cause sleepiness, but it has not been approved by the U.S. Food and Drug Administration (FDA) to treat sleep disorders. Tizanidine is a skeletal muscle relaxant. It is approved by the FDA to help relieve muscle spasms.

Sleep medicines called hypnotics can be prescribed by your doctor to help reduce the time it takes you to fall asleep. The most commonly used hypnotics are:

• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)
• Ramelteon (Rozerem)

How does tizanidine work?

Tizanidine is an imidazoline derivative and a centrally acting alpha-2 receptor agonist ¹¹⁾. Tizanidine inhibits the release of excitatory amino acids like glutamate and aspartate from spinal interneurons ¹²⁾. Consequently, tizanidine enhances the presynaptic inhibition of motor neurons. Tizanidine has significant action on spinal polysynaptic pathways ¹³⁾.

The overall effect of these actions is to reduce the facilitation of spinal motor neurons. Similarly, alpha-2 receptor-mediated inhibition of inter-neuronal activity appears to underlie tizanidine’s additional anti-nociceptive (pain reliever) and anti-convulsant activities. Spasm frequency and clonus are also reduced by tizanidine ¹⁴⁾.

Tizanidine also has an affinity for the alpha-1 receptors but to a lesser degree, which may explain its mild and transitory effect on the cardiovascular system compared to clonidine despite their structural and biochemical similarity ¹⁵⁾.

Tizanidine monitoring

• Creatinine and liver function tests require measurement at baseline, then one month after the maintenance dose is achieved. Periodically monitor liver function tests in patients managed with tizanidine chronically and in higher doses ¹⁶⁾
• Monitor blood pressure and heart rate before increasing the dosage because of the risk of severe hypotension associated with the higher dose ¹⁷⁾
• Monitor the level of spasticity by Ashworth and modified Ashworth Scales ¹⁸⁾
• In patients with multiple sclerosis, monitor spasticity using Multiple Sclerosis Spasticity Scale (MSSS-88) ¹⁹⁾

Tizanidine precautions

Tizanidine is a short-acting muscle relaxant that should be taken only for daily activities that require relief from muscle spasms. You should not take tizanidine if you are also taking fluvoxamine (Luvox) or ciprofloxacin (Cipro).

Do not use tizanidine at a time when you need muscle tone for safe balance and movement during certain activities. In some situations, tizanidine may endanger your physical safety to be in a state of reduced muscle tone.

Switching between tablets and capsules, or changing the way you take tizanidine with regard to eating can cause an increase in side effects or a decrease in therapeutic effect. Follow your doctor’s instructions carefully. After making any changes in how you take tizanidine, contact your doctor if you notice any change in how well the medicine works or if it causes increased side effects.

Avoid drinking alcohol. It can increase some of the side effects of tizanidine.

Before taking tizanidine:

• tell your doctor and pharmacist if you are allergic to tizanidine or any other medications.
• tell your doctor if you are taking ciprofloxacin (Cipro) or fluvoxamine. Your doctor will probably tell you not to take tizanidine if you are taking either of these medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: acyclovir (Zovirax); amiodarone (Cordarone, Pacerone); baclofen; cimetidine (Tagamet); clonidine (Catapres, Catapres-TTS); dantrolene (Dantrium); diazepam (Valium); famotidine (Pepcid, Pepcid AC); medications for anxiety, seizures, or high blood pressure; mexiletine (Mexitil); oral contraceptives (birth control pills); propafenone (Rythmol); fluoroquinolones such as gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin); ticlopidine (Ticlid); sedatives; sleeping pills; tranquilizers; verapamil (Calan, Covera, Isoptin, Verelan); and zileuton (Zyflo). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Other medications may also interact with tizanidine, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have or have ever had kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking tizanidine, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tizanidine.
• 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 tizanidine 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 tizanidine. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.tizanidine can decrease muscle tone, so be careful when walking or doing other activities where you rely on your muscle tone to help with your posture or balance.

Patients with Liver Impairment

The consequence of Hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. However, tizanidine is extensively metabolized by the liver; therefore, hepatic impairment would significantly influence the pharmacokinetics of tizanidine. Therefore, tizanidine should be avoided or used with extreme caution in patients with hepatic impairment.

Patients with Kidney Impairment

Tizanidine should be used cautiously in patients with renal impairment (creatinine clearance < 25 mL/min), as clearance is decreased by more than 50%. Start with a low dose, evaluate the response to therapy, and if a higher dose is needed, the dose can be increased rather than increasing the frequency of administration. The clinician should monitor the patient closely for adverse drug reactions such as dry mouth, drowsiness, asthenia, and dizziness as indicators of toxicity.

Pregnancy

The use of tizanidine in managing spinal cord injury during pregnancy has been described in case reports.[22] However, it is important to note that tizanidine is a former FDA pregnancy category-C and should be used only if indicated after careful risk-benefit evaluation.

Breastfeeding

Tizanidine is a lipid-soluble drug; hypothetically, it may be present in breast milk; its use during lactation is not advised.

Tizanidine drug interactions

Taking tizanidine with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before using opioid medication, a sleeping pill, a muscle relaxer, or medicine for anxiety or seizures.

Tell your doctor about all your other medicines, especially:

• acyclovir
• ticlopidine
• zileuton
• birth control pills
• antibiotic – ciprofloxacin, levofloxacin, moxifloxacin, or ofloxacin
• blood pressure medicine – clonidine, guanfacine, methyldopa
• heart rhythm medicine – amiodarone, mexiletine, propafenone, verapamil
• stomach acid medicine – cimetidine, famotidine

This list is not complete. Other drugs may interact with tizanidine, including prescription and over-the-counter medicines, vitamins, and herbal products.

Tizanidine contraindications

• Hypersensitivity to tizanidine or its ingredients is a contraindication to the use of tizanidine.
• Tizanidine use requires caution in patients with hepatic impairment. Review articles on tizanidine report cases of severe hepatotoxicity, acute liver failure, and death ²⁰⁾
• According to product labeling, tizanidine use requires caution in patients with renal impairment (creatinine clearance < 25 mL/min). In such patients, decrease the dose. If high doses are necessary, increase the individual dosage rather than the dosage frequency.

Tizanidine uses

Tizanidine is an U.S. Food and Drug Administration (FDA) approved muscle relaxant caused by multiple sclerosis (MS), spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), and traumatic brain injury ²¹⁾. Tizanidine has also been shown to be clinically effective in managing patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes. It is also prescribed off-label for migraine headaches, insomnia, and as an anticonvulsant. Tizanidine can also be applied as part of a detoxification therapy regimen in patients exhibiting analgesic rebound headaches to assist with analgesic withdrawal.

Tizanidine FDA-approved uses:

• Tizanidine is indicated for spasticity management due to multiple sclerosis, spinal cord injury, stroke, amyotrophic lateral sclerosis, and traumatic brain injury ²²⁾, ²³⁾, ²⁴⁾.

Tizanidine Off-label Use:

• Chronic neck and lower back pain ²⁵⁾
• Rebound headaches due to analgesic withdrawal ²⁶⁾
• Chronic migraine headaches ²⁷⁾
• Refractory insomnia in spastic quadriplegic patients ²⁸⁾
• Regional musculoskeletal pain syndromes ²⁹⁾

Placebo-controlled studies confirm the significant efficacy of tizanidine in reducing muscle spasm in patients with spinal cord-induced spasticity. Medical literature suggests that patients with severe spasticity are more likely to benefit from tizanidine. Drug comparison studies have shown no differences in the efficacy of tizanidine compared with baclofen or diazepam. The tizanidine treatment group did not report increased weakness compared to the controls. Furthermore, patients given tizanidine experienced fewer side effects than those using controlled substances ³⁰⁾.

Studies exhibit that tizanidine, baclofen, and diazepam effectively decreased excessive muscle tone in patients with multiple sclerosis (MS) or cerebrovascular lesions. Muscle strength improved in all three treatment groups, but the improvement was most significant with tizanidine. Shakespeare et al. ³¹⁾ also reported similar findings showing no differences in efficacy between tizanidine, baclofen, and dantrolene compared to diazepam. However, diazepam was associated with more sedation. Another study by Lataste et al. ³²⁾ showed no significant differences between tizanidine and baclofen or diazepam for muscle tone, muscle spasms, clonus, muscle strength, or overall anti-spastic effect. However, tizanidine tolerance is slightly better than diazepam and baclofen.

Groves et al. ³³⁾ report no significant differences between tizanidine, baclofen, or diazepam for spasticity by Ashworth score. However, applying global tolerability to treatment favored tizanidine compared to baclofen and diazepam.

A recent study indicates that tizanidine and other alpha-2 agonists can be used for medically supervised opioid withdrawal ³⁴⁾.

Animal studies have shown that tizanidine provides benefits in the perioperative period and the management of neuropathic pain, such as trigeminal neuralgia, similar to the effects of clonidine under similar circumstances.

The American Academy of Neurology guidelines reports that tizanidine should be used for generalized spasticity in cerebral palsy, for segmental/localized spasticity treatment with botulinum toxin-A is more effective ³⁵⁾.

Tizanidine dosage

Tizanidine is taken orally as 2 mg, 4 mg, and 6 mg capsules or as 2 mg and 4 mg tablets. Dosage starts with 2 mg orally and may repeat every 6 to 8 hours as needed. The dosage may gradually increase by 2 to 4 mg per dose for 1 to 4 days in between until there is a noticeably significant reduction of spasticity. Maximum dosing is three doses every 24 hours, up to 36 mg daily ³⁶⁾.

If tizanidine is used for more than nine weeks or given in high doses ranging from 20 mg to 36 mg daily, taper the dose gradually. The recommendation is to taper the dose to 2 to 4 mg daily to reduce the risk of tachycardia, rebound hypertension, and increased spasticity ³⁷⁾.

The patient may open the capsule and sprinkle the contents into food. Patients can take tizanidine with food or on an empty stomach. It is important to note that the extent of absorption is greater when taken with food. The tablet and capsule dosage forms are not bioequivalent when administered with food. Therefore, the clinician should counsel the patient to take tizanidine with or without food but be consistent to avoid fluctuations in concentration ³⁸⁾. It is also important to recognize that smoking decreases tizanidine’s plasma concentration and exposure ³⁹⁾.

What should I do if I forget a dose?

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

Tizanidine side effects

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

• dizziness ⁴⁰⁾
• drowsiness
• blurred vision
• weakness
• nervousness
• depression
• hallucination
• vomiting
• tingling sensation in the arms, legs, hands, and feet
• dry mouth (xerostomia) ⁴¹⁾
• rhinitis (runny nose)
• constipation
• diarrhea
• stomach pain
• heartburn
• increased muscle spasms
• back pain
• rash
• sweating

Some tizanidine side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• nausea
• extreme tiredness
• unusual bleeding or bruising
• lack of energy
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• unexplained flu-like symptoms
• seeing things or hearing voices that do not exist
• slow heartbeat
• changes in vision

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

Tizanidine withdrawal symptoms:

• rapid heart rate (tachycardia)
• rebound hypertension
• increased spasticity
• withdrawal symptoms are more likely to occur when discontinuing tizanidine abruptly ⁴²⁾

Symptoms of tizanidine overdose may include:

• drowsiness
• extreme tiredness
• confusion
• slow heartbeat (bradycardia)
• fainting
• dizziness
• slow or shallow breathing
• loss of consciousness
• coma

Management of tizanidine overdose

• There is no antidote for tizanidine toxicity.
• Tizanidine overdose management is by close monitoring of airways, administration of intravenous fluid, and vasopressors as necessary ⁴³⁾
• The pediatric case report described an overdose of tizanidine in spastic quadriplegia and toxicity presented with multiple organ dysfunction in the absence of sepsis ⁴⁴⁾
• A recent case report described the altered mental status and hemodynamic instability due to tizanidine overdose, and naloxone 10 mg IV administration improved Richmond Agitation-Sedation Scale (RASS) ⁴⁵⁾. The study concluded that naloxone could be used in tizanidine overdose in emergency settings; however, naloxone does not reverse the hemodynamic parameters ⁴⁶⁾.

Baclofen

Baclofen also known as beta‐4‐chlorophenyl‐gamma‐aminobutyric acid, sold by brand names Kemstro, Lioresal, Fleqsuvy, Lyvispah, Ozobax and Gablofen, is a prescription muscle relaxant drug that is used to treat pain and certain types of spasticity (muscle stiffness and tightness) most often used by people with multiple sclerosis, spinal cord injuries, or other spinal cord diseases ¹⁾, ²⁾, ³⁾, ⁴⁾, ⁵⁾, ⁶⁾ . Baclofen reduces the number and severity of muscle spasms and relieves pain, clonus and muscle rigidity due to spasticity. Baclofen was approved for use in the United States in 1977 and is widely used with several million prescriptions filled yearly ⁷⁾, ⁸⁾.

Baclofen is a gamma-amino butyric acid type B (GABA_B) agonist that acts as an agonist of the GABA B receptor, thereby activating potassium channels and reducing calcium conductance leading to hypotonia and muscle relaxation ⁹⁾. Baclofen acts on the nerves in the central nervous system (brain and spinal cord) primarily at the level of the spinal cord by stopping synaptic reflexes to reduce the messages that are sent out by the central nervous system (brain and spinal cord) to cause muscle contraction, therefore decreasing the number and severity of muscle spasms caused by multiple sclerosis or spinal cord conditions. Baclofen also relieves pain and improves muscle movement. Baclofen may also be used to relieve other conditions as determined by your doctor. Baclofen does not cure these problems, but it may allow other treatment, such as physical therapy, to be more helpful in improving your condition.

Baclofen is indicated primarily for treatment of spasticity from spinal cord injuries and multiple sclerosis. Baclofen has been used off label as add-on therapy to help people with alcohol use disorder with alcohol abstinence and withdrawal ¹⁰⁾, ¹¹⁾, ¹²⁾.

Baclofen comes as a tablet and a solution (liquid) to take by mouth. Baclofen is also available in various generic forms as well as under the brand names of Lioresal and Remular in tablets of 10 or 20 mg and in formulations for intrathecal injections of 0.5 mg/mL. The recommended adult dose for spasticity is 10 to 20 mg orally three to four times daily at evenly spaced intervals. The dose should be increased and tapered gradually.

Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take baclofen exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Use an oral syringe (measuring device) to accurately measure and take your dose of baclofen solution. Ask your pharmacist for an oral syringe if one is not included with your medication.

If baclofen tablets or liquid do not work well for you or your child, you may be prescribed a baclofen injection. This will be given by a specialist doctor in hospital. Baclofen can also be given through a pump that is fitted under the skin.

The most common side effects of baclofen are transient sedation, confusion, muscle weakness, vertigo, nausea, drowsiness, dizziness and fatigue ¹³⁾.

Continue to take baclofen even if you feel well. Do not stop taking baclofen without talking to your doctor, especially if you have taken large doses for a long time. Abruptly stopping baclofen can cause seizures, fever, confusion, muscle stiffness, or hallucinations. Your doctor probably will want to decrease your baclofen dose gradually.

Baclofen key points to remember:

• Baclofen reduces pain and discomfort caused by muscle spasms.
• Baclofen is not recommended for use in patients with Parkinson disease and stroke due to a lack of reassuring data. In addition, baclofen is not indicated for skeletal muscle spasms associated with rheumatologic disorders.
• Baclofen tablets and liquid start to work after 1 hour after taking it. However, it might take a few days before you find the right dose to control your symptoms.
• Baclofen common side effects include feeling sleepy and feeling sick (nausea).
• Close supervision of patients being treated with baclofen who have depression or a history of previous suicide attempts is recommended.
• Recent coronial inquiries into 2 deaths have highlighted the need for health professionals to be alert to the well documented risk of overdose with baclofen ¹⁴⁾.
• Do not stop taking baclofen without talking to your doctor. Abrupt discontinuation of oral baclofen therapy might cause seizures and hallucinations. Gradual dose reduction is recommended to prevent withdrawal symptoms ¹⁵⁾, ¹⁶⁾.
• If your doctor decides to stop your treatment, your dose will be reduced gradually over 1 to 2 weeks.
• It’s best not to drink alcohol while you are taking baclofen until you know how it affects you. There’s a risk alcohol may increase drowsy side effects and make you very sleepy.

How long does baclofen take to work?

Baclofen tablets and liquid start to work after 1 hour of taking it. However, it might take a few days before you find the right dose to control your symptoms. Baclofen is usually started at a low dose and slowly increased over a few days.

What will happen if I stop taking baclofen?

If your doctor decides to stop your treatment, your Baclofen dose will be reduced gradually over 1 to 2 weeks.

This will stop you getting withdrawal symptoms such as:

• feeling anxious or confused
• seeing things that are not there (hallucinations)
• seizures or fits
• changes in mood or behavior
• a fast heartbeat
• muscle spasms getting worse

Can I drive or ride a bike while taking baclofen?

Baclofen may make you feel tired, sleepy or dizzy and can affect your vision. It might be best to stop driving and cycling for the first few days of treatment until you know howBaclofen makes you feel.

It’s an offence to drive a car if your ability to drive safely is affected. It’s your responsibility to decide if it’s safe to drive.

Can I drink alcohol while taking baclofen?

Alcohol may increase the drowsy (sedative) effects of baclofen tablets and make you very sleepy. It’s best not to drink alcohol while you are taking baclofen until you know how the medicine makes you feel.

Will recreational drugs affect baclofen?

Using cannabis, heroin or methadone with baclofen will increase the drowsy effects of baclofen. It can make you go into a very deep sleep. There’s a risk you will not be able to breathe properly, and you may have difficulty waking up.

Using cocaine or other stimulants like MDMA (ecstasy) and amphetamines with baclofen can also make you drowsy.

Talk to your doctor if you think you might use recreational drugs while taking baclofen.

Is baclofen addictive?

Yes, Baclofen is addictive. Those who engage in baclofen abuse – including taking higher doses than prescribed or mixing it with alcohol or drugs – are at an increased risk of developing an addiction to the drug.

Usually, baclofen addiction begins with increased tolerance, which is when the person has to use more of the drug to experience the same effect. A patient who’s becoming tolerant to the drug may take more than their doctor prescribed to them to experience relief.

Eventually, physical dependence may occur, which is when the person experiences withdrawal symptoms when they aren’t taking the drug. Oftentimes, people who are physically dependent on a drug may keep taking it simply to avoid withdrawals.

After a while, however, their tolerance will continue to grow, and their drug use will become more severe. There are also some people who take baclofen to get high.

Like alcohol and other GABA agonists, baclofen can produce a high when taken in high enough doses, which can encourage further drug-taking behavior. As previously mentioned, there’s a high risk of baclofen overdose when the drug is consistently abused.

If you notice that your tolerance to baclofen has increased, speak to your doctor right away. Do not take higher doses than you’ve been prescribed.

Signs of Baclofen Abuse

People who abuse their prescription drugs may exhibit certain physical and behavioral signs. Some signs of baclofen abuse to look out for include:

• Doctor shopping (switching from one doctor to the next for prescriptions)
• Lying or stealing to get more of the drug
• Mood swings
• Decreased performance at school, work, or home
• Withdrawal from loved ones
• Lack of interest in activities they once liked
• Stupor
• Hallucinations
• Seizures
• Shock
• Difficulty breathing
• Cardiac arrest
• Coma
• Death

If you’re taking baclofen or any prescription muscle relaxers, be sure to take them exactly as prescribed. If you experience any adverse side effects while taking a prescription medication, speak to your doctor about adjusting your dose or other alternatives.

Will baclofen affect my contraception?

Baclofen does not affect any type of contraception, including the combined pill or emergency contraception.

However, if baclofen makes you sick (vomit) or have severe diarrhea for more than 24 hours, your contraceptive pills may not protect you from pregnancy. Check the pill packet to find out what to do.

Baclofen Mechanism of Action

Baclofen also known as beta‐4‐chlorophenyl‐gamma‐aminobutyric acid (GABA-B) is an agonist at the beta subunit of gamma-aminobutyric acid on mono and polysynaptic neurons at the spinal cord level and brain ¹⁷⁾. The thinking is that baclofen reduces the release of excitatory neurotransmitters in the pre-synaptic neurons and stimulates inhibitory neuronal signals in the post-synaptic neurons with resultant relief of spasticity ¹⁸⁾. Baclofen is also found to have an affinity for voltage-gated calcium channels. However, its clinical efficacy in this regard is still unclear ¹⁹⁾.

Baclofen has a 70% to 85% bioavailability and is rapidly absorbed through the gastrointestinal tract following oral administration. Peak plasma concentrations are generally observed 2 to 3 hours after ingestion. The absorption is dose-dependent and increases with higher doses. Due to the short half-life of 2 to 6 hours, baclofen should be administrated frequently to achieve optimal effect. Seventy percent of baclofen is eliminated in an unchanged form by renal excretion and the remaining via feces. Thereby, baclofen is a useful agent in patients with impaired hepatic function or a high potential for cytochrome P450-mediated drug-drug interactions. Research has observed significant inter-individual variability in baclofen’s absorption and elimination processes.

Baclofen special precautions

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if baclofen is working properly and to decide if you should continue to take it.

Do not suddenly stop using baclofen without checking first with your doctor. You may need to slowly decrease your dose before stopping it completely. Unwanted side effects (eg, hallucinations, seizures, high fever, rhabdomyolysis) may occur if baclofen is stopped suddenly.

Baclofen will add to the effects of alcohol and other central nervous system depressants (medicines that slow down the nervous system, possibly causing drowsiness). Some examples of central nervous system depressants are antihistamines or medicine for hay fever, other allergies, or colds, sedatives, tranquilizers, or sleeping medicine, prescription pain medicine or narcotics, medicine for seizures or barbiturates, other muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using baclofen.

Baclofen may cause dizziness, drowsiness, vision problems, or clumsiness or unsteadiness in some people. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, and able to see well.

Baclofen may affect blood sugar levels. If you notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

Using Baclofen while you are pregnant may cause neonatal withdrawal syndrome in your newborn babies. Tell your doctor right away if your baby has shakiness or tremors, seizures, or increased muscle tone.

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 or vitamin supplements.

Before taking Baclofen:

• Use with caution when used in patients with urinary retention or respiratory disease.
• History of autonomic dysreflexia: Abrupt baclofen withdrawal or the presence of nociceptive stimuli can cause an autonomic dysreflexic episode.
• Gastrointestinal disorders: Use caution in patients with peptic ulcer disease, decreased GI motility, and/or GI obstructive disorders.
• Use caution in patients with confusional states, psychotic issues, or schizophrenia; it may cause exacerbation of the condition. In addition, patients treated with baclofen injection should be kept under surveillance because exacerbations of these conditions have been observed with oral administration.
• Use caution in patients with kidney impairment, as baclofen is primarily eliminated via the kidneys.
• Seizure disorder: Loss of seizure control is reported in patients treated with baclofen; monitor patients with a history of seizure disorder by checking electroencephalogram periodically.
• Co-administration of epidural morphine and baclofen injection is reported to cause dyspnea and hypotension.
  Because of the risk of sedation, patients should refrain from operating automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. In addition, the central nervous system effects of baclofen may be additive to those of alcohol and other central nervous system (CNS) depressants.
• Tell your doctor and pharmacist if you are allergic to baclofen, any other medications, or any of the ingredients in baclofen tablets and oral solution. Ask your pharmacist for a list of the ingredients.
• Tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antidepressants, medications for anxiety, medications for mental illness, medications for seizures, sedatives, sleeping pills, or tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• Tell your doctor if you have or have ever had epilepsy, a stroke, a rheumatic disease, cerebral palsy, Parkinson’s disease, a psychiatric condition such as schizophrenia or a confusional state, or kidney disease.
• Tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking baclofen, call your doctor immediately.
• You should know that baclofen may make you drowsy. 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 baclofen. Alcohol can make the side effects from baclofen worse.

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

Who can take baclofen?

Most adults and children aged 1 month and older can take baclofen tablets and liquid.

Baclofen injection can be given to adults and children aged 4 years and over.

How long to take baclofen for?

You may need to take baclofen for a long time to control muscle spasms.

If you’ve been having baclofen through an injection or pump for a long time, you may find that it stops working as well as it used to. You may need to stop having treatment for a short time to give your body a rest. Your doctor will be able to give you advice on this.

Stopping baclofen

If you stop taking baclofen suddenly, you may get withdrawal side effects such as:

• feeling anxious or confused
• seeing things that are not there (hallucinations)
• seizures or fits
• changes in mood or behavior
• a fast heartbeat
• muscle spasms getting worse

You doctor will reduce your dose gradually before stopping it completely. This will help prevent these side effects.

Who may not be able to take baclofen?

Baclofen is not suitable for some people. To make sure it’s safe for you, tell your doctor before taking Baclofen if you:

• have ever had an allergic reaction to baclofen or any other medicine
• have a stomach ulcer
• have lung, kidney or liver disease
• have a mental health condition
• have epilepsy
• have Parkinson’s disease
• have diabetes
• have ever had a stroke
• are being treated for high blood pressure
• have difficulty peeing
• have a rare blood disorder called porphyria
• are pregnant, trying to get pregnant or breastfeeding

Baclofen contraindications

Baclofen is contraindicated in patients with hypersensitivity to baclofen or any component of its formulation. The baclofen injection solution is not recommended for intravenous, subcutaneous, intramuscular, or epidural administration.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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 age to the effects of Baclofen oral liquid and granules in children younger than 12 years of age. Safety and efficacy have not been established.

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

Elderly people

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Baclofen oral liquid and granules in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution for patients receiving Baclofen.

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of baclofen tablet in the elderly. Side effects such as hallucinations, confusion or mental depression, other mood or mental changes, and severe drowsiness may be especially likely to occur in elderly patients, who are usually more sensitive than younger adults to the effects of Baclofen.

Balofen and pregnancy warnings

Baclofen should be used during pregnancy only if the benefit outweighs the risk.

• US FDA pregnancy category: Not Assigned. The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.
• Australian TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

Baclofen given orally in animal studies has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses at approximately 13 times on a mg/kg basis, or 3 times on a mg/m² basis, the maximum oral dose recommended for humans; this dose also caused reductions in food intake and weight gain in the dams. There are no controlled data in human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans.

Baclofen and breastfeeding

There are no adequate studies in women for determining infant risk when using Baclofen during breastfeeding, but information shows that it passes into breast milk in small amounts. Weigh the potential benefits against the potential risks before taking Baclofen while breastfeeding.

Contact your pharmacist or doctor as soon as possible if your baby:

• is not feeding as well as usual or seems to have a dry mouth
• seems unusually sleepy
• is sweaty or develops a rash
• is being sick or has diarrhea
• is causing you any other concerns

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 Baclofen, it is especially important that your healthcare provider know if you are taking any of medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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

• Alfentanil
• Alprazolam
• Amifampridine
• Benzhydrocodone
• Bromazepam
• Buprenorphine
• Bupropion
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Cannabis
• Cetirizine
• Clobazam
• Clonazepam
• Codeine
• Daridorexant
• Dexmedetomidine
• Dihydrocodeine
• Donepezil
• Doxylamine
• Esketamine
• Fentanyl
• Flibanserin
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lacosamide
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meperidine
• Methadone
• Metoclopramide
• Midazolam
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Remifentanil
• Remimazolam
• Ropeginterferon Alfa-2b-njft
• Scopolamine
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Topiramate
• Tramadol
• Trazodone
• Zolpidem
• Zuranolone

Other Interactions

Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of Baclofen with alcohol or tobacco.

Mixing baclofen with herbal remedies and supplements

There’s not enough information to say that herbal remedies and supplements are safe to take with baclofen. They’re not tested in the same way as pharmacy and prescription medicines. They’re generally not tested for the effect they have on other medicines.

Other Medical Problems

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

• Autonomic dysreflexia, history of or
• Diabetes or
• Epilepsy or
• Mental illness or problems (eg, psychosis, schizophrenia) or
• Ovarian cysts or
• Posture or balance problems or
• Stroke, recent—Use with caution. May make these conditions worse.
• Kidney disease—The effects may be increased because of slower removal of Baclofen from the body.

Baclofen uses

Baclofen is a muscle relaxant that is used to relieve muscle spasms, cramping or tightness caused by conditions such as ²⁰⁾, ²¹⁾, ²²⁾, ²³⁾, ²⁴⁾, ²⁵⁾, ²⁶⁾:

• Cerebral palsy. Baclofen is also considered for short-term treatment for spasticity associated with cerebral palsy in children and adolescents.
• Meningitis
• Motor neurone disease
• Multiple sclerosis (MS)
• Conditions affecting your brain, spinal cord and nervous system causing stiff limbs and/or some bladder dysfunctions.

Long-term (chronic) muscle stiffness can happen in conditions where the nerves that supply your muscles have been damaged. In these conditions, the muscles shorten (contract) tightly, and can then become stiff and harder to use. This is called muscle spasticity. Baclofen works by relaxing your muscles, which reduces pain and discomfort.

FDA-approved indications ²⁷⁾:

• Baclofen is FDA-approved for managing reversible spasticity, particularly to relieve flexor spasms, clonus, concomitant pain, common sequelae of spinal cord lesions, and multiple sclerosis.
• Intrathecal baclofen administration is FDA-approved for managing spasticity of cerebral origins, such as traumatic brain injury or severe spasticity of spinal cord origin that is unresponsive to treatment with maximum doses of oral baclofen, tizanidine, and/or dantrolene. However, intrathecal baclofen might be considered for patients who experience intolerable adverse effects or fail to respond to oral therapy.

Baclofen Off-labeled Uses ²⁸⁾, ²⁹⁾, ³⁰⁾:

• Baclofen is currently prescribed off-label to treat alcohol use disorder³¹⁾, ³²⁾, ³³⁾:
  • Baclofen is used off-label to manage alcoholic liver disease.
  • Maintain alcohol abstinence by decreasing alcohol cravings and alcohol-related anxiety.
• Trigeminal neuralgia, gastroesophageal reflux disease, and hiccups.

Intrathecal baclofen

Baclofen is a muscle relaxant that works on the nerves in the brain and spinal cord, reducing the messages that are sent out by the nervous system to cause muscle contraction. It is used in children to treat severe muscle spasm (spasticity), due to cerebral palsy or other conditions that affect the brain or spinal cord. It acts on the whole body and does not target specific muscles.

The benefits of baclofen relaxing muscles include:

• Improved ability to move joints
• Less pain due to muscle spasm or cramps

Before you or your child’s doctors decide if intrathecal baclofen is right for you or your child, many specialists will thoroughly assess your child. You or your child may be seen by an orthopaedic surgeon, a neurosurgeon, different specialists, an occupational therapist and a physiotherapist.

There are many factors to consider when deciding who should have intrathecal baclofen treatment. Intrathecal baclofen does not suit every person or every family. You will need to live close to a medical center that can manage the baclofen therapy and you or your child will need to attend many appointments. All the people who help care for you or your child need to learn about baclofen and its side effects.

Once you or your child’s doctors and you have decided that intrathecal baclofen therapy might be right for you or your child, you will be booked in for a trial of the therapy, which will take place in hospital and involve a general anaesthetic. There are two types of trial:

• A bolus trial also called a single-dose test trial involves an injection of baclofen into the space surrounding your child’s spinal cord.
• A five-day catheter trial also called a tube trial involves an operation to have a tube placed in the spine. The tube is joined to an access port through which baclofen is delivered to your child’s spine.

The doctor will choose the most appropriate trial for you or your child. If you or your child responds well to the trial, you will have an appointment with a neurosurgeon to discuss the operation to insert the pump and how the pump works.

While your child is asleep (under a general anaesthetic), a neurosurgeon will implant the pump (about the size of a computer mouse) into you or your child’s abdomen on one side near the hip bone. Joined to the pump is a long catheter, which is inserted into the space surrounding your spinal cord. You or your child will be in the operating theatre for about two hours.
A very small computer, called a programmer, tells the pump how much medicine to release. The baclofen will last from one to six months, depending on you or your child’s dose. When the medicine is running low, you or your child will have an appointment to have you or your child’s pump refilled.

Intrathecal baclofen works differently for every person. Even though they have done a trial, your doctors cannot predict exactly how you or your child will respond to intrathecal baclofen therapy.

Complications of intrathecal baclofen therapy

Complications are rare, but it is important to know the possible side effects and what to do if something goes wrong. Side effects of baclofen may include constipation, nausea and blurred vision. These usually settle over time, but if they continue, they can be managed in various ways, which you can discuss with your child’s doctor.

Possible complications of intrathecal baclofen include:

• overdose of baclofen
• underdose (not enough) of baclofen
• infection of the site around the pump or tube
• infection of the wound from the surgery
• catheter kink (bent tubing), which prevents the flow of baclofen
• catheter break, causing a leak of baclofen
• catheter disconnection from pump, preventing baclofen from reaching spinal cord
• pump stops working properly.

Baclofen overdose primarily arises from drug screening before pump implantation or human error during pump refilling and programming. Baclofen overdose may cause altered mental status, somnolence, seizure, hypothermia, respiratory depression, and coma. In the presence of Baclofen overdose symptoms, the medical staff should empty the pump reservoir, and the patient should receive symptomatic management ³⁴⁾. In patients when the lumbar puncture is not contraindicated, consider withdrawing 30-40 mL of CSF to reduce baclofen CSF concentration.

See your child’s baclofen doctor or take your child to the hospital emergency room if:

• your child has a temperature higher than 100.4 °F (38 ºC)
• there is redness or inflammation around the surgery site
• there is swelling around the pump area
• your child is drowsy or you can’t wake them
• your child has slow breathing
• you think your child is too ‘floppy’
• your child is unusually sweaty, itchy or grumpy
• your child’s muscles are tighter than usual
• you are concerned about the pump
• you hear beeping from the pump.

Monitoring

Administration of baclofen with any other central nervous system depressants requires close monitoring. Patients with epilepsy should be monitored with a regular electroencephalogram due to deterioration in seizure control when receiving baclofen ³⁵⁾.

Monitor for signs and symptoms of baclofen withdrawal if the dose is reduced or discontinued ³⁶⁾.

Intrathecal baclofen use requires careful attention to program the infusion pump and monitor its function, pump alarms, and refill schedules ³⁷⁾.

Closely monitor when the initial phase of pump use and when adjusting the dosing rate and/or the concentration in the reservoir as small errors can result in subtherapeutic level or toxic levels.

Monitor for signs or symptoms of overdose which may occur suddenly, especially in the initial screening phase, dose-titration phase, and reintroduction of therapy after temporary cessation of treatment.

Baclofen dosage

Take Baclofen exactly as directed by your doctor. Do not take more of it, do not take it more often, or do not take it longer than your doctor ordered.

Baclofen comes with a patient information and instructions leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

To use Baclofen granules:

• Open the packet and empty all the granules directly into your mouth. The granules will dissolve in your mouth or can be swallowed. You may drink water after taking the medicine.
• You may mix the granules with 1 tablespoon (15 mL) of liquid (eg, apple juice or milk) or soft foods (eg, applesauce, pudding, or yogurt). Take this mixture within 2 hours of mixing.
• Baclofen can also be given using a nasogastric or gastric feeding tube. Mix the granules with 1 tablespoon (15 mL) of liquid (eg, apple juice or milk). Give this mixture within 2 hours of mixing. After Baclofen is given, flush the tube with an additional 1 tablespoon (15 mL) of water.
• Take all the contents of the packet to get a full dose. Do not take only part of this medicine. Do not save a portion for later use.

Measure the oral liquid with a marked measuring spoon, oral syringe, or medicine cup.

The dose of Baclofen 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 Baclofen. 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 Baclofen. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take Baclofen depend on the medical problem for which you are using Baclofen.

Muscle relaxation

• For oral dosage form (granules):
  • Adults and children 12 years of age and older: At first, 5 milligrams (mg) 3 times a day for 3 days. Your doctor may increase your dose by 5 mg every 3 days as needed and tolerated. However, the dose is usually not more than 80 milligrams (mg) per day (20 mg four times a day).
  • Children younger than 12 years of age: Use and dose must be determined by your doctor.
• For oral dosage form (solution):
  • Adults and children 12 years of age and older: At first, 5 milliliters (mL) 3 times a day for 3 days. Your doctor may increase your dose by 5 mL every 3 days as needed and tolerated. However, the dose is usually not more than 80 milligrams (mg) per day (20 mg four times a day).
  • Children younger than 12 years of age: Use and dose must be determined by your doctor.
• For oral dosage form (tablets):
  • Adults and teenagers: At first, 5 milligrams (mg) 3 times a day. Your doctor may increase your dose by 5 mg every 3 days until the desired response is reached. However, the dose is not more than 80 mg per day.
  • Children: Use and dose must be determined by your doctor.

What should I do if I forget a dose?

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

Baclofen side effects

Baclofen may cause side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common side effects:

• confusion
• constipation
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• headache
• increased need to urinate
• nausea
• passing urine more often
• sweating
• trouble sleeping
• unusual tiredness or weakness

Less common or rare side effects:

• diarrhea
• loss of appetite
• muscle or joint pain
• numbness or tingling in the hands or feet
• stomach pain or discomfort
• stuffy nose
• weight gain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

• dizziness
• weakness
• confusion
• headache
• nausea
• constipation
• difficulty falling asleep or staying asleep
• tiredness
• frequent urination

Some side effects can be serious. If you experience either of the following symptoms, see your doctor immediately:

• seeing things or hearing voices that do not exist (hallucinations)
• seizures

Baclofen overdose

The risks of Baclofen overdose are particularly pronounced when using high doses for off-label treatment of alcohol-use disorder. In case of Baclofen overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number for help.

Symptoms of Baclofen overdose may include:

• blurred vision or vision problems
• dizziness
• vomiting
• drowsiness
• irregular, fast or slow, or shallow breathing
• difficulty breathing
• lightheadedness
• loss of strength or energy
• muscle pain or weakness
• weak muscle tone
• pale or blue lips, fingernails, or skin
• seizures
• sleepiness or unusual drowsiness
• trouble breathing
• unusual weak feeling
• coma.

Overdosed on baclofen tablets has reported vomiting, drowsiness, muscular hypotonia, accommodation disorders, coma, respiratory depression, and seizures. When the patient is alert, consider vacating the stomach immediately by inducing emesis and then performing lavage. In the unconscious patients, do not induce vomiting. Before beginning lavage, secure the airway with an endotracheal tube. Avoid the use of respiratory stimulants and adequately maintain respiratory exchange.

What is Theophylline

Theophylline is a xanthine derivative bronchodilator that works by relaxing smooth muscles in your lungs making it easier for you to breathe by making your lungs less sensitive to allergens and other causes of bronchospasm. Theophylline is used to prevent and treat symptoms such as wheezing, shortness of breath, and chest tightness caused by asthma, chronic bronchitis, emphysema or chronic obstructive pulmonary disease (COPD) and other lung diseases.

Theophylline is a drug derived from methylxanthine (a purine derivative) and has smooth muscle relaxant, bronchial dilation, diuretic, cardiac and central nervous system (CNS) stimulant activities ¹⁾. Naturally present in tea and cocoa beans in small amounts, it was initially extracted and synthesized in 1895, and used as a diuretic. Theophylline was approved for use in the United States in 1982 and is available in multiple generic forms for oral and intravenous use.

Theophylline comes as a tablet, capsule, solution, and syrup to take by mouth. Typical capsule or tablet sizes are 100, 200 and 300 mg. Typical dose regimens are 100 to 300 mg three to four times daily. Theophylline usually is taken every 6, 8, 12, or 24 hours. Syrups are available for use in children. Extended release formulations are also available in sizes of 100 to 600 mg which are typically given twice daily. Dosage is highly individualized. Intravenous formations are available for management of acute asthmatic attacks. Theophylline is marketed under multiple brand names including Asmalix, Elixophyllin, Quibron-T, Respbid, Theobid, Duracaps, and Uniphyl. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take theophylline exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Take this medication with a full glass of water on an empty stomach, at least 1 hour before or 2 hours after a meal. Do not chew or crush the extended-release (long-acting) tablets; swallow them whole. Extended-release capsules (e.g., Theo-Dur Sprinkles) may be swallowed whole or opened and the contents mixed with soft food and swallowed without chewing.

Theophylline controls symptoms of asthma and other lung diseases but does not cure them. Continue to take theophylline even if you feel well. Do not stop taking theophylline without talking to your doctor.

Common side effects of theophylline include dizziness, headache, insomnia, restlessness, tachycardia, palpitations, flushing, nausea, abdominal discomfort and diaphoresis, largely due to the effects of theophylline on the CNS, heart and muscle tissue.

Theophylline mechanism of action

Theophylline is a xanthine derivative that induces relaxation of smooth muscles in the bronchial tree causing bronchodilation. Theophylline also reduces the airway responsiveness to histamine, adenosine, methacholine, and allergens. Theophylline exerts these effects mainly through two distinct mechanisms ²⁾:

• Theophylline acts as a competitive nonselective phosphodiesterase inhibitor (inhibiting type III and type IV phosphodiesterase), which increases the level of intracellular cAMP, activates protein kinase A, inhibits TNF-alpha and leukotriene synthesis, and also decreases inflammation and innate immunity.
• Theophylline is also a nonselective adenosine receptor antagonist. It acts on A1, A2, and A3 receptors with almost the same affinity and this possibly explains the cardiac effects of theophylline. Adenosine-mediated channels also increase the contraction force of diaphragmatic muscles through enhancing their calcium uptake ³⁾.

Other proposed mechanisms of action of theophylline include ⁴⁾:

• It inhibits nuclear factor-kappaB. This prevents the translocation of the pro-inflammatory transcription factor (nuclear factor-kappaB) to the nucleus, reducing the expression of known inflammatory genes in COPD and asthma).
• Increases interleukin-10 secretion; interleukin-10 has broad anti-inflammatory effects.
• Increases histone deacetylase 2 through inhibiting phosphoinositide 3-kinase-delta.
• Decreases Poly(ADP-ribose)polymerase-1 (PARP-1).
• Increases apoptosis of inflammatory cells (T cells, neutrophils)

Theophylline special precautions

Before taking theophylline:

• tell your doctor and pharmacist if you are allergic to theophylline or any other drugs.
• tell your doctor and pharmacist what prescription medications you are taking, especially allopurinol (Zyloprim), azithromycin (Zithromax), carbamazepine (Tegretol), cimetidine (Tagamet), ciprofloxacin (Cipro), clarithromycin (Biaxin), diuretics (‘water pills’), erythromycin, lithium (Eskalith, Lithobid), oral contraceptives, phenytoin (Dilantin), prednisone (Deltasone), propranolol (Inderal), rifampin (Rifadin), tetracycline (Sumycin), and other medications for infections or heart disease.
  tell your doctor and pharmacist what nonprescription medications and vitamins you are taking, including ephedrine, epinephrine, phenylephrine,
• phenylpropanolamine, or pseudoephedrine. Many nonprescription products contain these drugs (e.g., diet pills and medications for colds and asthma), so check labels carefully. Do not take these medications without talking to your doctor; they can increase the side effects of theophylline.
• tell your doctor if you have or have ever had seizures, ulcers, heart disease, an overactive or underactive thyroid gland, high blood pressure, or liver disease or if you have a history of alcohol abuse.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking theophylline, call your doctor.
• tell your doctor if you use tobacco products. Cigarette smoking may decrease the effectiveness of theophylline.

Precautions

• Patients with cardiovascular disease: Use cautiously in patients who have cardiac arrhythmias (excluding bradyarrhythmias); at it may exacerbate arrhythmias.
• Patients with cystic fibrosis: Use cautiously in patients with cystic fibrosis, as increased theophylline clearance may occur in these patients.
• Patients with hepatic impairment: Use cautiously in patients with hepatic impairment such as cirrhosis, cholestasis, acute hepatitis because there is an increased risk of severe and potentially fatal complications. This is because clearance decreases by 50% or more in these patients. Frequent monitoring and dose reduction of theophylline are required in these patients.
• Patients with hyperthyroidism: Use cautiously in patients with hyperthyroidism, as increased theophylline clearance may occur.
• Patients with peptic ulcer disease: Use cautiously in patients who have active peptic ulcer disease, as the use of theophylline may exacerbate peptic ulcer.
• Patients with seizure disorders: Use cautiously in patients who have seizure disorders, as use may exacerbate the seizure disorder.

Special Populations

• Elderly patients: Use with extreme caution in elderly patients as these patients are at an increased risk of serious theophylline toxicity.
• Pediatric patients: The dose must be selected with caution, and regular monitoring of concentrations should be performed (especially if the child is younger than 1 year of age) as the rate of clearance varies greatly in these patients.

Special dietary instructions

Drinking or eating foods high in caffeine, like coffee, tea, cocoa, and chocolate, may increase the side effects caused by theophylline. Avoid large amounts of these substances while you are taking theophylline.

Theophylline in Pregnancy

Theophylline is classified as a pregnancy category C drug. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Theophylline should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus ⁵⁾.

Theophylline in Breastfeeding

The manufacturer makes no recommendation regarding use during lactation.

Excreted into human milk: Yes

Comments:

• Theophylline may cause irritability or other mild toxicities in nursing infants.
• The breastmilk theophylline concentration is about equal to the mother’s serum concentration.
• Serious adverse effects are unlikely unless maternal serum concentrations are toxic.

Theophylline contraindications

• Theophylline is contraindicated if the patient previously developed a hypersensitivity reaction to the drug or any component of its formulation (such as allergy to corn-related products (in injection use only).
• Other contraindications include hypersensitivity to xanthine derivatives and patients with coronary artery disease (where the cardiac stimulation effect of theophylline might prove harmful).

Theophylline uses

Theophylline is used to prevent and treat symptoms such as wheezing, shortness of breath, and chest tightness caused by asthma, chronic bronchitis, emphysema or chronic obstructive pulmonary disease (COPD) and other lung diseases. Theophylline is sometimes used to treat breathing problems in premature infants.

Theophylline has a very narrow therapeutic window, and its interaction with various other drugs has led to the limitation of its use. The serum theophylline levels must be monitored directly to avoid toxicity as the adverse effects of theophylline are related to its plasma concentration and have been observed when plasma levels exceed 20 mg/L. Some patients have also experienced adverse effects at low plasma concentrations. The dose is gradually increased until therapeutic plasma concentrations are achieved to reduce side effects.

Medical Uses

• Chronic obstructive pulmonary disease
• Asthma
• Infant Apnea
• Anosmia which is currently under investigation. A clinical study in 2008 reported that theophylline could potentially improve the sense of smell in those with anosmia.

Asthma Exacerbations

Treatment of asthma exacerbation with theophylline is not recommended by the current clinical practice guidelines (2018 GINA Report, Global Strategy for Asthma Management and Prevention; National asthma education and prevention program-NAEPP 2007) ⁶⁾.

COPD Management

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2018, the management of acute chronic obstructive pulmonary disease (COPD) with IV theophylline is not recommended by the current clinical practice guidelines due to its significant side effects ⁷⁾.

Theophylline administration

Theophylline can be used as an oral agent (rapid or slow-release tablets, solution, syrup, or capsule) or in a more soluble form such as aminophylline (an ethylenediamine salt) that can be used orally or intravenously. Cautiously administer theophylline in a patient who has consumed large amounts of foods or drinks with high caffeine content as this could potentially increase the risk of side effects of theophylline.

Theophylline monitoring

Because of the small therapeutic window of theophylline and its many side effects, physicians should monitor the following in the patient:

• The heart rate of the patient
• CNS effects (headache, insomnia, irritability)
• The respiratory rate
• Patient’s arterial or capillary blood gases
• Patient’s electrolyte concentrations, fluid balance, and acid-base balance should be monitored during prolonged IV therapy.

Serum theophylline levels should be checked after the initiation of therapy, prior to increasing dose and if any signs or symptoms of toxicity are observed. Worsening of the current illness, an occurrence of a new illness, or any change in the patient’s treatment protocol that may alter theophylline clearance should also prompt the physician to check serum levels of theophylline. Attention should also be paid to the infusion site.

Oral Theophylline

For patients taking oral treatment, serum concentrations are monitored at 6-month intervals for rapidly developing children and at annual intervals for all others patients (if their symptoms are well controlled).

IV Theophylline

Loading dose: The serum concentration of theophylline should be checked 30 minutes after the completion of an intravenous loading dose in patients with no theophylline use in the last 24 hours to determine if additional loading may be required (if the serum concentration is less than 10 mcg/mL) or to delay initiating the constant IV infusion (if the serum concentration is greater than 20 mcg/mL).

Infusion: Serum concentration of theophylline should be measured to one expected half-life (approximately 4 hours in young children [ages 1 to 9 years], or around 8 hours in otherwise healthy adults, who do not smoke) after administering a continuous infusion, then checked every 12 to 24 hours to establish if any further adjustments are required, and then at 24 hour intervals for the remainder of the infusion.

Theophylline intravenous

Patients can be administered intravenous (IV) theophylline for acute bronchospasm. Those who are not currently taking theophylline should be given a loading dose of 5 to 7 mg/kg intravenously followed by a maintenance dose of 0.4 to 0.6 mg/kg per hour intravenously to maintain serum levels at 10 to 15 mg/L.

IV aminophylline had frequently been used in the management of acute exacerbations of COPD and asthma but is used much less frequently now as it is far less effective than nebulized beta2-agonists. The currently recommended loading dose is 6 to 7 mg/kg administered intravenously over 20 to 30 minutes. After this, a maintenance dose of 0.5 mg/kg per hour is administered. In patients already taking theophylline, or those who have any factors that decrease its clearance from the body, doses should be halved, and its plasma level checked more frequently. In patients with cardiac decompensation, cor pulmonale, older patients or those on medications that are known to decrease theophylline clearance, the infusion rate of theophylline should not be increased above 17 mg per hour unless the patient remains symptomatic, their steady-state serum concentrations are consistently below 10 mcg/mL, and their serum concentrations can be observed at 24-hour intervals. Administering solutions comprising dextrose concurrently through the same administration route as blood may result in hemolysis or pseudoagglutination, and should be avoided.

Theophylline oral

Theophylline tablets are rapidly absorbed, but plasma concentrations show wide fluctuations and are therefore not currently recommended. Several sustained-release preparations that are absorbed in a relatively constant rate provide steady plasma concentrations of the drug over a 12 to 24-hour period. It should be taken consistently with or without food (as this helps to maintain a more consistent serum drug level).

• The 12-hour formulation: This could be taken once every 24-hours in patients who are non-smokers (who have appropriate total body clearance of theophylline) and in patients who have low dosage requirements. Only after theophylline has titrated to therapeutic levels in the patient, can the 12-hour formulation be considered. The once-daily dosing should be based on the twice-daily dosing and initiated at the end of the every 12-hour dosing interval. Do not give the once-daily dosing to the patient at night (after the evening meal).
• The 24-hour formulation: Take each morning around the same time and avoid taking it at night (after the evening meal). In patients whom a higher dose is required (13 mg/kg or greater than or equal to 900 mg, whichever one is less), should take the medication less than 60 minutes before a high-fat meal (as a significant increase in the peak serum level and absorption could occur). Patients should consistently take theophylline either in a fasting state or with food (as this helps to maintain a more consistent serum drug level). The twice-daily dosing could be considered for those who metabolize theophylline quickly (for example, smokers, younger patients, and some nonsmoking adults) and those who still have symptoms at the end of the dosing interval. The first dose should be administered in the morning and the second one around 10 to 12 hours after the first dose (but before eating the evening meal). Administration at night should be avoided.

Other Routes

Administering by inhalation is both irritating and ineffective. Administration of theophylline through intramuscular injections is very painful and should never be given.

Dosing Considerations

• If aminophylline is being administered, the dose should be increased by 25% (as aminophylline is 79% to 86% theophylline).
• The ideal body weight should be used to calculate the dose.
• Aminophylline or immediate-release theophylline should be used for per-oral loading ⁸⁾.

Theophylline therapeutic level

Therapeutic Levels for theophylline ⁹⁾:

• For children: 5 to 15 mcg/mL
• For adults: 10 to 20 mcg/mL
• Toxic serum concentration: greater than 20 mcg/mL ¹⁰⁾.

Toxic doses of theophylline can be as low as 7.5 mg/kg ¹¹⁾. When taken orally, 80% to 100% of theophylline is absorbed in the gastrointestinal tract. Peak serum levels can occur from 30 to 120 minutes for immediate release formulations. Sustained release formulations have peak levels between 6 and 10 hours. Intravenously, theophylline takes 30 minutes to reach peak levels. Therapeutic serum levels range from 10 to 20 mcg/mL. Toxic levels are considered to be 20 mcg/mL or higher. However, toxic effects can be seen within therapeutic levels as well. Cardiac dysrhythmias, seizures, and death can be seen with levels of 80 to 100 mcg/mL. Chronic toxicity can be seen at levels of 40 to 60 mcg/mL. Fifty percent to 65% of theophylline is protein-bound in the circulation. Volume distribution is small, at 0.45 L/kg. The half-life varies with age. A half-life of 4 to 8 hours is seen in young adults. A shorter half-life is seen in newborns. Theophylline is metabolized in the liver by the cytochrome P450 system and excreted by the kidneys. Therefore, any agents or pathology that alters the cytochrome P450 system or renal function can have a substantial effect on theophylline levels ¹²⁾.

Theophylline dosage

The dose of theophylline 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 theophylline. If your dose is different, do not change it unless your doctor tells you to do so.

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

To treat symptoms of asthma, bronchitis, and emphysema (COPD):

For oral dosage form (elixir or tablets):

• Adults, teenagers, and children above 1 year of age weighing more than 45 kilograms (kg)—At first, 300 milligrams (mg) per day, divided and given every 6 to 8 hours. Your doctor may adjust your dose as needed. However, the total dose is usually not more than 600 mg per day.
• Older adults—The dose must be determined by your doctor. However, the total dose is usually not more than 400 milligrams per day, divided and given every 6 to 8 hours.
• Children and teenagers 1 to 15 years of age weighing less than 45 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. At first, the dose is 12 to 14 milligrams (mg) per kg of body weight per day, divided and given every 4 to 6 hours. Your doctor may adjust your dose as needed. However, the total dose is usually not more than 20 mg per kg of body weight per day or 600 mg per day.
• Infants younger than 1 year of age—Dose is based on body weight and age and must be determined by your doctor.

For oral dosage form (extended-release capsules):

• Adults, teenagers, and children 12 years of age and older weighing more than 45 kilograms (kg)—At first, 300 to 400 milligrams (mg) as a single dose, usually in the morning, or divided and given two times per day. Your doctor may adjust your dose as needed. However, the total dose is usually not more than 600 mg per day.
• Older adults—The dose must be determined by your doctor. However, the total dose is usually not more than 400 milligrams per day as a single dose, usually in the morning, or divided and given two times per day.
• Children and teenagers 12 to 15 years of age weighing less than 45 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. At first, the dose is 12 to 14 milligrams (mg) per kg of body weight per day as a single dose, usually in the morning, or divided and given two times per day. Your doctor may adjust your dose as needed. However, the total dose is usually not more than 20 mg per kg of body weight per day or 600 mg per day.
• Children younger than 12 years of age—Use and dose must be determined by your doctor.

For oral dosage form (extended-release tablets):

• Adults, teenagers, and children 6 years of age and older weighing more than 45 kilograms (kg)—At first, 300 milligrams (mg) per day, divided and given every 12 hours. Your doctor may adjust your dose as needed. However, the total dose is usually not more than 600 mg per day.
• Older adults—The dose must be determined by your doctor. However, the total dose is usually not more than 400 milligrams per day, divided and given every 12 hours.
• Children and teenagers 6 to 15 years of age weighing less than 45 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. At first, the dose is 12 to 14 milligrams (mg) per kg of body weight per day, divided and given every 12 hours. Your doctor may adjust your dose as needed. However, the total dose is usually not more than 20 mg per kg of body weight per day or 600 mg per day.
• Children younger than 6 years of age—Use and dose must be determined by your doctor.

What should I do if I forget a dose?

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

Theophylline side effects

The most common theophylline side effects are nausea and vomiting, headache, increased stomach acid secretion, and gastroesophageal reflux, which could be due to phosphodiesterase inhibition. CNS (central nervous system) symptoms (irritability, lightheadedness, and dizziness) have also been observed in patients. In severe cases, seizures have also occurred. At high serum concentrations, adenosine A1A-receptor antagonism could lead to convulsions and cardiac arrhythmias ¹³⁾.

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

• upset stomach
• stomach pain
• diarrhea
• headache
• restlessness
• insomnia
• irritability

If you experience any of the following symptoms, call your doctor immediately:

• vomiting
• increased or rapid heart rate
• irregular heartbeat
• seizures
• skin rash

Theophylline toxicity

Theophylline toxicity can lead to gastrointestinal distress, insomnia, and tremor. Severe nausea and vomiting, cardiac arrhythmias, hypotension, and convulsions have also been reported, more commonly in cases of overdosage. Very large overdoses, such as those during suicide attempts could potentially be lethal because of the development of arrhythmias and convulsions.

• Activated charcoal may prevent absorption by adsorbing the drug in the intestine.
• Beta-blockers could potentially be used for reversing the severe cardiovascular toxicity caused by theophylline.
• Intravenous benzodiazepines may abort seizures ¹⁴⁾.

Theophylline has 2 primary mechanisms. One mechanism is that theophylline blocks adenosine receptors, which has both therapeutic and toxic effects such as bronchodilation, tachycardia, cardiac arrhythmias, seizures, and cerebral vasoconstriction. At larger doses, theophylline inhibits phosphodiesterase causing increased cyclic adenosine monophosphate resulting in increased levels of adrenergic activation and catecholamine release. In theophylline toxicity, epinephrine levels can be 4- to 8-times higher than normal, and norepinephrine concentrations can be 4- to 10-times higher than normal. Increased catecholamine concentrations have a variety of adverse effects such as cardiac arrhythmias, metabolic acidosis, hyperglycemia, and hypokalemia. Chronic theophylline toxicity can occur when there is an accumulation of the drug due to metabolism being overwhelmed or inhibited. It can also occur when clearance is decreased ¹⁵⁾.

Theophylline toxicity symptoms

Depending on the dose, route of administration, and coingestants, there is a wide spectrum of clinical effects of theophylline toxicity, ranging from abdominal pain to cardiac arrhythmias to seizures.

• General: Agitation, irritability, restlessness
• Cardiovascular: Sinus tachycardia, ventricular tachycardia atrial fibrillation, supraventricular tachycardia, hypotension, cardiac arrest
• Respiratory: Tachypnea, acute lung injury, respiratory alkalosis
• Gastrointestinal (GI): Nausea, vomiting, abdominal pain
• Neurological: Tremors, hallucinations, seizures ¹⁶⁾

Theophylline toxicity treatment

Most patients with theophylline toxicity are successfully managed with supportive care. Airway, breathing, circulation, and hemodynamic monitoring are essential to the care of patients with theophylline toxicity. Intubation with ventilator support may be required for airway protection.

Gastrointestinal (GI) decontamination: Activated charcoal (1 g/kg) by mouth or nasogastric tube is recommended in patients that present to the emergency department within if there are no contraindications to activated charcoal. Gastric lavage or induced emesis is not recommended in theophylline toxicity. Whole bowel irrigation is controversial as animal models do not demonstrate that it is a beneficial therapy. Multiple-dose activated charcoal is recommended for acute theophylline toxicity if there are no contraindications.

Hypotension-isotonic saline (20 mL/kg): Hypotension refractory to IV fluid administration, an alpha agonist such as phenylephrine is recommended. Primarily alpha agonists such as norepinephrine can be used as well. Treatment of hypotension with a beta antagonist should only be used in consultation with a toxicologist.

Nausea and vomiting: Ondansetron is recommended. Metoclopramide can be used in cases that are refractory to ondansetron.

Cardiac arrhythmias: Treatment of cardiac arrhythmias should be managed according to advanced cardiac life support and pediatric advanced life support protocols.

Seizures: In adults benzodiazepines (lorazepam, midazolam, diazepam) are the first-line treatment for theophylline-induced seizures. Phenobarbital and continuous infusion of propofol or midazolam can be used for seizures refractory to benzodiazepines. In pediatrics, benzodiazepines are the first-line treatment for seizures. Phenobarbital or continuous infusion of midazolam or pentobarbital or propofol can be used refractory seizures.

Hemodialysis: In acute overdose, hemodialysis is indicated for life-threatening arrhythmias and seizures, theophylline levels greater than 100 mcg/mL, clinical instability, or increased theophylline levels despite appropriate care. In chronic theophylline toxicity, hemodialysis is indicated with severe symptoms, such as life-threatening arrhythmias, seizures, and theophylline levels greater than 60 mcg/mL in patients between the ages of 6 months to 60 years, or levels greater than 50 mcg/mL in patients of age less than 6 months or greater than 60 years. Hemodialysis is preferred as opposed to hemoperfusion. However, if hemodialysis is not available, hemoperfusion may be used instead. Decisions to initiate hemodialysis or hemoperfusion should always be made in consultation with a medical toxicologist.

Hypokalemia: Potassium supplementation Is recommended for patients with ventricular arrhythmias or potassium levels less than 3 mEq/L ¹⁷⁾.

Phenytoin

Phenytoin formerly known as diphenylhydantoin, is the most commonly used major anti-epileptic agent. Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin works by decreasing abnormal electrical activity in the brain. Phenytoin was first approved for use in the United States in 1946, and currently more than 3 million prescriptions are filled yearly. Current indications for phenytoin are treatment and prevention of generalized tonic-clonic (grand mal) seizures and complex partial seizures and management of status epilepticus. Phenytoin is available generically in oral and parenteral formulations.

Since its discovery in 1908, phenytoin has become one of the most well-studied anticonvulsants ¹⁾. With an average monthly cost of $30, it has also become one of the most widely used anticonvulsants, listed on the World Health Organization’s List of Essential Medicines.

Phenytoin is available only with your doctor’s prescription.

Phenytoin comes as an extended-release (long-acting) capsule, a chewable tablet, and a suspension (liquid) to take by mouth. Oral forms include tablets and capsules of 100 to 300 mg, including extended release formations for once daily dosing. Commercial names include Dilantin. Chewable tablets and oral suspensions are available for pediatric use. The chewable tablet and suspension are usually taken two or three times a day. The recommended dose of phenytoin for chronic use is 100 mg three times daily. The extended-release capsules are usually taken 1 to 4 times a day. Take phenytoin 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 phenytoin 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 phenytoin and gradually increase your dose, not more often than once every 7 to 10 days.

Different phenytoin products are absorbed by the body in different ways and cannot be substituted for one another. If you need to switch from one phenytoin product to another, your doctor may need to adjust your dose. Each time you receive your medication, check to be sure that you have received the phenytoin product that was prescribed for you. Ask your pharmacist if you are not sure that you received the right medication.

Shake the liquid well before each use to mix the medication evenly. Use an accurate measuring device to be sure you receive the correct amount of medication. Ask your doctor or pharmacist if you have any questions about how to measure your dose.

Swallow the extended-release capsules whole; do not split, chew, or crush them. Do not take capsules that are discolored.

You may chew the chewable tablets thoroughly before swallowing them, or you may swallow them whole without chewing.

If you are receiving formula or supplements through a feeding tube, talk to your doctor about when you should take phenytoin. You will need to allow some time between receiving your feedings and taking phenytoin.

Phenytoin may help control your condition but will not cure it. Continue to take phenytoin even if you feel well. Do not stop taking phenytoin without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. If you suddenly stop taking phenytoin, your seizures may worsen. Your doctor will probably decrease your dose gradually.

Phenytoin may be used with other seizure medicines. Keep using all of your seizure medicines unless your doctor tells you otherwise. Do not change brands or dosage forms of phenytoin without first checking with your doctor. Different products may not work the same way. If you refill your medicine and it looks different, check with your pharmacist.

Phenytoin common side effects include dizziness, ataxia, nausea, gum hyperplasia and rash (which can occur in 10% of patients). Phenytoin has major effects on metabolism of other medications, and patients should be provided specific advice about other medications that can be used during long term phenytoin therapy.

Normal phenytoin level

Phenytoin is available in oral and intravenous (IV) formulations. The oral form is completely absorbed after ingestion. Its absorption is rapid with peak plasma concertation at 1.5 to 3 hours for the immediate release formulation and 4 to 12 hours for the extended-release formulation. However, due to its effects of reducing gastrointestinal (GI) motility and its poor water solubility, absorption tends to be delayed in oral overdose with peak concentrations occurring at up to 24 to 48 hours ²⁾.

Due to its poor water solubility, parenteral phenytoin is mixed with propylene glycol and alcohol and is only recommended for IV use. It needs to be administered slowly to prevent the adverse effects of rapid propylene glycol toxicity, usually over 45 minutes to an hour. Peak phenytoin concentrations occur 20 to 35 minutes after the completion of the infusion. Fosphenytoin is a water-soluble prodrug of phenytoin that can be administered intramuscularly (IM) or IV but needs to be converted enzymatically by phosphatase in the body to the active phenytoin compound. Intravenous fosphenytoin peaks within minutes, but the active phenytoin takes 34 to 42 minutes after completion of the IV infusion to reach peak plasma concentrations. If given by intramuscular route peak is delayed to 1.5 to 3.0 hours. Therefore, neither route results in rapid seizure control in status epilepticus.

Phenytoin has a narrow therapeutic window, between 10-20 mg/L. Serum concentrations of phenytoin are monitored by measuring the total phenytoin concentration. However, phenytoin is generally 90% bound to plasma proteins (mostly albumin), and only its unbound form is pharmacologically active. A greater fraction of the drug is unbound in neonates and pregnant patient, a patient with hypoalbuminemia of any cause (renal failure, hepatic failure, malnutrition) and uremia. Patients with decreased protein binding capacity may display symptoms of toxicity despite normal total phenytoin levels. Phenytoin is distributed in all tissues and becomes firmly tissue-bound with a large volume of distribution. The level of unbound phenytoin may be calculated using the corrected Winter-Tozer formula:

• Corrected Phenytoin Levels (mg/dl): Serum Phenytoin Level (milligrams/Liter)
• (0.25 x albumin [grams/deciliter]) +0.1

Some literature may use 0.29 as the albumin coefficient to improve accuracy depending on whether the sample was run at room temperature or body temperature.

Corrected Phenytoin Levels in patients with:

Hypoalbuminemia (mg/dl):

• Serum Phenytoin Level (milligrams/Liter)
• (0.20 x albumin [grams/deciliter]) +0.1

One to 5% of phenytoin is excreted unchanged in the urine. The remainder is metabolized by the hepatic P450 enzyme system, predominantly CYP2C9 and CYP 2C19, and induces CYP3A4, which account for many of its drug-drug interactions. All its metabolites are inactive. At plasma concentrations less than 10 mg/L, elimination follows first-order kinetics, and the rate of elimination is proportional to the drug concentration. With increasing plasma concentrations, the half-life increases as the kinetics approach zero-order. Following saturation of the system, elimination follows zero order kinetics with the same amount of drug eliminated for a given amount of time, irrespective of plasma concentration. Subsequently, the normal average half-life of 22 hours can become significantly prolonged with marked overdose.

Phenytoin mechanism of action

Phenytoin is a voltage-gated, sodium channel blocker, stabilizing the inactive state of the sodium channel and prolonging the neuronal refractory period. Phenytoin acts on the sodium channels on both neuronal and cardiac tissue. In the central nervous system, it targets neurons with high-frequency activity (as observed in seizures), with the majority of its actions on the motor cortex. Phenytoin is believed to be based upon stablization of neuronal membranes caused by an increase in the efflux and decrease in the influx of sodium ions across GABA regulated sodium channels. This prevents the spread of a seizure’s focal point and reduces the activity of brain stem regions responsible for the tonic phase of a tonic-clonic seizure. In cardiac tissue, phenytoin shortens cardiac action potentials and prolongs the refractory period between them.

Phenytoin special precautions

Before taking phenytoin:

• tell your doctor and pharmacist if you are allergic to phenytoin, other hydantoin medications such as ethotoin (Peganone) or fosphenytoin (Cerebyx), or any other medications. Also tell your doctor if you are allergic to carbamazepine (Carbatrol, Equetro, Tegretol, others), or if your doctor chose not to treat you with carbamazepine because laboratory testing showed that you have an inherited risk factor that makes it more likely that you will have an allergic reaction to carbamazepine. This risk factor may also increase the chance that you will have an allergic reaction to phenytoin.
• tell your doctor if you are taking delavirdine (Rescriptor). Your doctor will probably tell you not to take phenytoin if you are taking this medication.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: albendazole (Albenza); amiodarone (Nexterone, Pacerone); anticoagulants (‘blood thinners’) such as warfarin (Coumadin, Jantoven); antifungal medications such as fluconazole (Diflucan), ketoconazole (Nizoral), itraconazole (Onmel, Sporanox), miconazole (Oravig), posaconazole (Noxafil), and voriconazole (Vfend); certain antivirals such as efavirenz (Sustiva, in Atripla), indinavir (Crixivan), lopinavir (in Kaletra), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); bleomycin; capecitabine (Xeloda); carboplatin; chloramphenicol; chlordiazepoxide (Librium, in Librax); chlorpropamide (Diabinese); cholesterol medications such as atorvastatin (Lipitor, in Caduet), fluvastatin (Lescol), and simvastatin (Zocor, in Vytorin); cisplatin; clozapine (Fazaclo, Versacloz); cyclosporine (Gengraf, Neoral, Sandimmune); diazepam (Valium); digoxin (Lanoxin); disulfiram (Antabuse); doxorubicin (Doxil); doxycycline (Doryx, Vibramycin); fluorouracil; fluoxetine (Prozac, Sarafem, in Symbyax, others); fluvoxamine (Luvox); folic acid; fosamprenavir (Lexiva); furosemide (Lasix); H2 antagonists such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac); hormonal contraceptives (birth control pills, patches, rings, or injections); hormone replacement therapy (HRT); irinotecan (Camptosar); isoniazid (Laniazid, in Rifamate, in Rifater); medications for mental illness and nausea; other medications for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol, others), ethosuximide (Zarontin), felbamate (Felbatol), lamotrigine (Lamictal), methsuximide (Celontin), oxcarbazepine (Trilepta), phenobarbital, topiramate (Topamax), and valproic acid (Depakene); methadone (Dolophine, Methadose); methotrexate (Otrexup, Rasuvo); methylphenidate (Daytrana, Concerta, Metadate, Ritalin); mexiletine; nifedipine (Adalat, Afeditab), nimodipine (Nymalize), nisoldipine (Sular); omeprazole (Prilosec); oral steroids such as dexamethasone, methylprednisolone (Medrol), prednisolone, and prednisone (Rayos); paclitaxel (Abraxane, Taxol); paroxetine (Paxil, Pexeva); praziquantel (Biltricide); quetiapine (Seroquel); quinidine (in Nuedexta); reserpine ; rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); salicylate pain relievers such as aspirin, choline magnesium trisalicylate, choline salicylate, diflunisal, magnesium salicylate (Doan’s, others), and salsalate; sertraline (Zoloft); sucralfate (Carafate); sulfa antibiotics; teniposide (Vumon); theophylline (Elixophyllin, Theo-24); ticlopidine; tolbutamide; trazodone; verapamil (Calan, Verelan, in Tarka); vigabatrin (Sabril); and vitamin D. Your doctor may need to change the doses of your medications or monitor you more carefully for side effects.
• tell your doctor if you are taking antacids that contain calcium, magnesium, or aluminum (Maalox, Mylanta, Tums, others). Your doctor may tell you to allow some time to pass between taking the antacid and taking phenytoin.
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have ever developed a liver problem while taking phenytoin. Your doctor will probably tell you not to take phenytoin again.
• tell your doctor if you drink or have ever drunk large amounts of alcohol and if you have or have ever had diabetes, porphyria (condition in which certain natural substances build up in the body and may cause stomach pain, changes in thinking or behavior, or other symptoms), or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You should not become pregnant while you are taking phenytoin. Talk to your doctor about effective birth control methods that you can use during your treatment. If you become pregnant while taking phenytoin, call your doctor. Phenytoin may harm the fetus.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking phenytoin.
• you should know that this medication may cause dizziness and problems with coordination. Do not drive a car or operate machinery until you know how this medication affects you.
• talk to your doctor about the safe use of alcohol while you are taking this medication.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking phenytoin. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as phenytoin to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as phenytoin, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or to end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.
• talk to your doctor about the best way to care for your teeth, gums, and mouth during your treatment with phenytoin. It is very important that you care for your mouth properly to decrease the risk of gum damage caused by phenytoin.

Tell your doctor right away if you or your child develop a fever, rash, swollen, painful, or tender lymph glands in the neck, armpit, or groin, unusual bleeding or bruising, or yellow eyes or skin after using Phenytoin. These may be symptoms of a serious and life-threatening condition called drug reaction with eosinophilia and systemic symptoms (DRESS).

Phenytoin may cause liver damage. Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin.

Phenytoin can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
Avoid contact sports or other situations where bruising or injury could occur.

Phenytoin may decrease bone mineral density. A low bone mineral density can cause weak bones or osteoporosis. If you or your child have any questions about this ask your doctor.

Phenytoin may affect blood sugar levels. If you or your child notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

Phenytoin may cause some people 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. If you, your child, or your caregiver notice any of these side effects, tell your or your child’s doctor right away.

In some patients (usually younger patients), tenderness, swelling, or bleeding of the gums (gingival hyperplasia) may appear soon after phenytoin treatment is started. To help prevent this, brush and floss your teeth carefully and regularly and massage your gums. Also, see your dentist every 6 months to have your teeth cleaned. If you have any questions about how to take care of your teeth and gums, or if you notice any tenderness, swelling, or bleeding of your gums, check with your doctor or dentist.

Before you have any medical tests, tell the medical doctor in charge that you or your child are taking Phenytoin. The results of some tests may be affected by Phenytoin.

Phenytoin may cause drowsiness, trouble thinking, or trouble in controlling movements. Do not drive or do anything else that could be dangerous until you know how Phenytoin affects you.

Avoid drinking alcohol while you are using Phenytoin.

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 or vitamin supplements.

Phenytoin in pregnancy

US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal malformations) and other developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple animal species at clinically relevant doses. There are no controlled data in human pregnancy.

• An increased risk of congenital abnormalities (“fetal hydantoin syndrome”) has been associated with the use of phenytoin in epileptic women during pregnancy.
• The overall incidence of neonate malformations for offspring of mothers treated with anti-seizure medications is approximately 10%, or 2 to 3 fold the incidence in the general population (although a definite causal relationship has not been established).
• Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took Phenytoin alone or in combination with other antiepileptic drugs during pregnancy.
• There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

Using phenytoin while you are pregnant can harm your unborn baby. When ingested by pregnant women, a range of vascular and skeletal anomalies have been reported ³⁾. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Phenytoin in breastfeeding

There are no adequate studies in women for determining infant risk when using phenytoin during breastfeeding. Weigh the potential benefits against the potential risks before taking phenytoin while breastfeeding.

• Because of the low levels of phenytoin in breastmilk, amounts ingested by the infant are small and usually cause no difficulties when used alone except for rare idiosyncratic reactions. Breastfeeding during monotherapy does not appear to adversely affect infant growth or development.
• Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.
• In one case report, maternal phenytoin dosage requirements decreased as breastfeeding was discontinued.

Phenytoin 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 phenytoin, 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 phenytoin with any of the following medicines is not recommended. Your doctor may decide not to treat you with phenytoin or change some of the other medicines you take.

• Artemether
• Atazanavir
• Boceprevir
• Cobicistat
• Daclatasvir
• Darunavir
• Dasabuvir
• Delamanid
• Delavirdine
• Doravirine
• Elbasvir
• Elvitegravir
• Grazoprevir
• Isavuconazonium
• Lorlatinib
• Lurasidone
• Maraviroc
• Ombitasvir
• Paritaprevir
• Piperaquine
• Praziquantel
• Ranolazine
• Rilpivirine
• Ritonavir
• Telaprevir
• Tenofovir Alafenamide

Using phenytoin 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.

• Abemaciclib
• Abiraterone Acetate
• Acalabrutinib
• Afatinib
• Alfentanil
• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Phosphate
• Amiodarone
• Apazone
• Apixaban
• Apremilast
• Aprepitant
• Aripiprazole
• Axitinib
• Beclamide
• Bedaquiline
• Benzhydrocodone
• Bictegravir
• Bosutinib
• Brexpiprazole
• Brigatinib
• Buprenorphine
• Bupropion
• Cabozantinib
• Calcifediol
• Calcium Carbonate
• Carbamazepine
• Cariprazine
• Ceritinib
• Chlorpheniramine
• Cisatracurium
• Clarithromycin
• Clofazimine
• Clozapine
• Cobimetinib
• Codeine
• Copanlisib
• Crizotinib
• Cyclophosphamide
• Dabigatran Etexilate
• Dasatinib
• Deferasirox
• Deflazacort
• Desogestrel
• Diazepam
• Diazoxide
• Dienogest
• Digoxin
• Dihydrocodeine
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Dolutegravir
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Dronedarone
• Drospirenone
• Duvelisib
• Eliglustat
• Encorafenib
• Enzalutamide
• Eravacycline
• Erdafitinib
• Erlotinib
• Eslicarbazepine Acetate
• Estradiol
• Ethinyl Estradiol
• Ethosuximide
• Ethynodiol
• Etonogestrel
• Etravirine
• Everolimus
• Exemestane
• Ezogabine
• Fentanyl
• Fluvastatin
• Fosaprepitant
• Fosnetupitant
• Fostamatinib
• Gefitinib
• Gestodene
• Gilteritinib
• Glasdegib
• Glecaprevir
• Halothane
• Hemin
• Hydrocodone
• Ibrutinib
• Idelalisib
• Ifosfamide
• Imatinib
• Infliximab
• Irinotecan
• Irinotecan Liposome
• Itraconazole
• Ivabradine
• Ivacaftor
• Ivosidenib
• Ixabepilone
• Ixazomib
• Ketoconazole
• Lacosamide
• Lamotrigine
• Lapatinib
• Larotrectinib
• Ledipasvir
• Letermovir
• Levonorgestrel
• Lidocaine
• Linagliptin
• Lopinavir
• Macimorelin
• Macitentan
• Magaldrate
• Magnesium Carbonate
• Magnesium Hydroxide
• Magnesium Oxide
• Magnesium Trisilicate
• Manidipine
• Meperidine
• Mestranol
• Methadone
• Methotrexate
• Miconazole
• Midostaurin
• Mifepristone
• Naloxegol
• Neratinib
• Netupitant
• Nifedipine
• Nilotinib
• Nimodipine
• Nintedanib
• Norethindrone
• Norgestimate
• Norgestrel
• Olaparib
• Orlistat
• Osimertinib
• Oxcarbazepine
• Oxycodone
• Paclitaxel
• Palbociclib
• Paliperidone
• Panobinostat
• Pazopanib
• Pentazocine
• Perampanel
• Pibrentasvir
• Ponatinib
• Posaconazole
• Quetiapine
• Regorafenib
• Reserpine
• Ribociclib
• Rifampin
• Rivaroxaban
• Rocuronium
• Roflumilast
• Rolapitant
• Romidepsin
• Saquinavir
• Sertraline
• Simeprevir
• Sofosbuvir
• Sonidegib
• Sorafenib
• Stiripentol
• St John’s Wort
• Sufentanil
• Tacrolimus
• Tamoxifen
• Tasimelteon
• Temsirolimus
• Tezacaftor
• Theophylline
• Thiotepa
• Ticagrelor
• Tofacitinib
• Tolvaptan
• Trabectedin
• Tramadol
• Triclabendazole
• Ulipristal
• Valbenazine
• Vandetanib
• Velpatasvir
• Vemurafenib
• Venetoclax
• Vilazodone
• Vincristine
• Vincristine Sulfate Liposome
• Vinflunine
• Vorapaxar
• Voriconazole
• Vortioxetine
• Voxilaprevir

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

• Acetaminophen
• Acetazolamide
• Acyclovir
• Amitriptyline
• Amprenavir
• Aripiprazole Lauroxil
• Atorvastatin
• Betamethasone
• Bexarotene
• Bleomycin
• Busulfan
• Capecitabine
• Carboplatin
• Caspofungin
• Chloramphenicol
• Cimetidine
• Ciprofloxacin
• Cisplatin
• Clobazam
• Clopidogrel
• Colesevelam
• Cortisone
• Cyclosporine
• Dexamethasone
• Dicumarol
• Digitoxin
• Diltiazem
• Disopyramide
• Disulfiram
• Doxepin
• Doxifluridine
• Felbamate
• Fluconazole
• Fludrocortisone
• Fluorouracil
• Fluoxetine
• Fluvoxamine
• Folic Acid
• Fosamprenavir
• Ginkgo
• Imipramine
• Isoniazid
• Levodopa
• Levomethadyl
• Levothyroxine
• Lithium
• Methoxsalen
• Methsuximide
• Midazolam
• Nafimidone
• Nelfinavir
• Nilutamide
• Nisoldipine
• Ospemifene
• Pancuronium
• Paroxetine
• Phenprocoumon
• Piperine
• Prednisolone
• Prednisone
• Progabide
• Quinidine
• Quinine
• Remacemide
• Rifapentine
• Risperidone
• Rufinamide
• Sabeluzole
• Shankhapulshpi
• Simvastatin
• Sirolimus
• Sulfamethizole
• Sulfamethoxazole
• Sulfaphenazole
• Sulthiame
• Tegafur
• Telithromycin
• Tenidap
• Tiagabine
• Ticlopidine
• Ticrynafen
• Tirilazad
• Tizanidine
• Tolbutamide
• Topiramate
• Trazodone
• Triamcinolone
• Trimethoprim
• Tubocurarine
• Valacyclovir
• Valproic Acid
• Vecuronium
• Verapamil
• Vigabatrin
• Viloxazine

Other Interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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

• Enteral Nutrition
• Ethanol

Other Medical Problems

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

• Acute hepatoxicity (liver problem) from previous phenytoin use—Should not be used in patients with this condition.
• Bone problems (eg, osteomalacia, osteoporosis) or
• Depression or mental illness, history of or
• Diabetes or
• Heart disease or
• Lymphadenopathy (lymph node problems) or
• Porphyria (an enzyme problem) or
• Vitamin D deficiency—Use with caution. May make these conditions worse.
• Hypoalbuminemia (low albumin in the blood) or
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal from the body.

Phenytoin uses

Phenytoin is used to control seizures (convulsions) in the treatment of epilepsy. Phenytoin is also used to prevent and treat seizures that occur during brain surgery.

• Seizures (non-emergent use): Control of generalized tonic-clonic and complex partial (psychomotor, temporal lobe) seizures; prevention and treatment of seizures occurring during or following neurosurgery (capsule, chewable tablet, and injection only).
• Status epilepticus (injection only): Treatment of generalized tonic-clonic status epilepticus.

Off Label Uses

• Prevention of early (within 1 week) posttraumatic seizures following traumatic brain injury

Data from a randomized, double-blind, placebo-controlled trial in patients with serious head trauma supports the use of phenytoin to prevent posttraumatic seizures in patients who recently (within 1 week) experienced a traumatic brain injury. Phenytoin did not reduce the incidence of late (≥day 8) posttraumatic seizures.

Based on the Brain Trauma Foundation’s Guidelines for the Management of Severe Traumatic Brain Injury and the American Association of Neurology (AAN) Practice Parameter for Antiepileptic Drug Prophylaxis in Severe Traumatic Brain Injury, phenytoin is effective and recommended to decrease the risk of posttraumatic seizures occurring within the first 7 days of traumatic brain injury.

Phenytoin is also used to control irregular heartbeat. Phenytoin is now rarely used to suppress ventricular arrhythmias in patients unresponsive to lidocaine. Talk to your doctor about the risks of using phenytoin for your condition.

Phenytoin dose

The dose of phenytoin 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 phenytoin. If your dose is different, do not change it unless your doctor tells you to do so.

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

For seizures:

For oral dosage form (extended-release capsules):

• Adults—At first, 100 milligrams (mg) 3 times a day or 300 mg once a day. Your doctor may increase your dose as needed. For patients in the clinic or hospital (except with a history of liver or kidney disease), a loading dose of 1000 mg is divided into three doses (400 mg, 300 mg, 300 mg) and given every 2 hours. Then, normal maintenance dose may be started 24 hours after the loading dose.
• Children older than 6 years of age—300 mg per day. Your doctor may adjust your dose as needed.
• Children 6 years of age and younger—Dose is based on body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in 2 or 3 divided doses per day. The doctor may adjust the dose as needed.

For oral dosage form (suspension):

• Adults—At first, 5 milliliters (mL) or one teaspoonful 3 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 25 mL per day.
• Children older than 6 years of age—300 mg per day. Your doctor may adjust your dose as needed.
• Children 6 years of age and younger—Dose is based on age and body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in 2 or 3 divided doses per day. Your doctor may adjust your dose as needed.

For oral dosage form (tablets):

• Adults—At first, 100 milligrams (mg) 3 times a day. Your doctor may adjust your dose as needed.
• Children older than 6 years of age—300 mg per day, given in 2 or 3 divided doses per day. Your doctor may adjust your dose as needed.
• Children 6 years of age and younger—Dose is based on age and body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in 2 or 3 divided doses per day. The doctor may adjust the dose as needed.

What should I do if I forget a dose?

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

Phenytoin side effects

Phenytoin may cause an increase in your blood sugar. Talk to your doctor about the symptoms of high blood sugar and what to do if you experience these symptoms.

Taking phenytoin may increase the risk that you will develop osteomalacia (weakening and softening of the bones) and problems with your lymph nodes including Hodgkin’s disease (cancer that begins in the lymph system). Talk to your doctor about the risks of using this medication to treat your condition.

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

• difficulty falling asleep or staying asleep
• uncontrollable eye movements
• abnormal body movements
• loss of coordination
• confusion
• slowed thinking
• slurred speech
• headache
• constipation
• unwanted hair growth
• coarsening of facial features
• enlargement of lips
• overgrowth of gums
• pain or curving of the penis

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

• swollen lymph glands
• blisters
• joint pain
• nausea
• vomiting
• yellowing of the skin or eyes
• pain in upper right part of the stomach
• excessive tiredness
• unusual bruising or bleeding
• loss of appetite
• flu-like symptoms
• fever, sore throat, rash, mouth ulcers, or easy bruising, or facial swelling
• swelling of the face, eyes, throat, tongue, or lips
• dizziness, tiredness, irregular heartbeat, or chest pain

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

Phenytoin overdose symptoms may include the following:

• uncontrollable eye movements
• loss of coordination
• slow or slurred speech
• uncontrollable shaking of a part of the body
• nausea
• vomiting
• difficulty understanding reality
• coma (loss of consciousness for a period of time)
• confusion
• convulsions (occasionally)
• dizziness
• fever
• low blood pressure
• muscle rigidity or spasms
• sleepiness
• side-to-side eye movement (nystagmus)
• slurred speech
• swollen gums
• tremor (unintentional trembling)
• unsteadiness

Phenytoin toxicity

Phenytoin displays its main signs of toxicity on the nervous and cardiovascular systems. Overdose on oral phenytoin causes mainly neurotoxicity and only very rarely causes cardiovascular toxicity. On the other hand, cardiovascular toxicity is the main side effect of parenteral administration ⁴⁾.

Neurotoxicity

The neurotoxic effects are concentration dependent and can range from mild nystagmus to ataxia, slurred speech, vomiting, lethargy and eventually coma and death. Paradoxically, at very high concentrations, phenytoin can lead to seizures. Symptoms correlate well with the unbound plasma phenytoin concentration. However, this laboratory value is seldom obtained. The following is a loose correlation of side effects with total plasma phenytoin concentrations (the value obtained in most laboratories):

• Less than 10 mg/L: Rare side effects
• Ten to 20 mg/L: Occasional mild horizontal nystagmus on lateral gaze
• Twenty to 30 mg/L: Nystagmus
• Thirty to 40 mg/L: Ataxia, slurred speech, tremor, nausea, and vomiting
• Forty to 50 mg/L: Lethargy, confusion, hyperactivity
• Greater than 50 mg/L: Coma and seizures

Seizures are very rare and usually occur at very high serum concentrations. The presence of seizures in a patient with suspected phenytoin overdose should prompt the search for other coingestants.

Cardiac Toxicity

Phenytoin is a Vaughn Williams Class IB antiarrhythmic; although, it is almost never used as an antiarrhythmic anymore. Its effects on the cardiac voltage-gated sodium channels can lead to dysrhythmias as well as SA and AV nodal blocks although such effects have rarely been reported following ingestion of the oral form. In the intravenous form, the main toxicity is believed to be from its parenteral vehicle: propylene glycol. Propylene glycol is a cardiac depressant, and rapid infusions can lead to bradycardia, hypotension, and asystole. Care must be taken so that intravenous formulations of phenytoin are not administered at a rate faster than 50 mg per minute.

Other Toxicities

“Purple Glove syndrome” is a rare side effect that can occur with intravenous administration of phenytoin. It is characterized by worsening distal limb edema and discoloration which can lead to extensive skin necrosis and limb ischemia. Phenytoin hypersensitivity has also been reported, generally occurring one week to 1 month after initiation of therapy. It is characterized by a fever, rash and different internal organ involvement (hepatitis, myocarditis, pneumonitis). Chronic intake of phenytoin can lead to folate deficiency, peripheral neuropathy or a lupus-like syndrome although these effects have not been reported from acute overdoses.

Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere in the United States. This hotline number will let you talk to experts in poisoning. They will give you further instructions.

This is a free and confidential service. All local poison control centers in the United States use this national number. You should call if you have any questions about poisoning or poison prevention. It does NOT need to be an emergency. You can call for any reason, 24 hours a day, 7 days a week.

Take the pill container with you to the hospital, if possible.

Risk factors for phenytoin toxicity

The different risk factors for phenytoin toxicity are as follows:

Change in Medications

Phenytoin toxicity can occur from an increase in the daily dose of phenytoin, changes in the formulations or brands as well as changes in the frequency of administration. It can also occur when patients are started on new medications that interact with the metabolism or binding capacity of phenytoin to plasma proteins. Due to its metabolism by CYP450 liver enzymes, multiple drug interactions can occur.

Change in Physiology

New disease states can lead to changes in the phenytoin plasma concentration. Liver cirrhosis can lead to a decrease in serum albumin as well as a decreased metabolism of phenytoin by the CYP450 pathway, both leading to increased amounts of free phenytoin in the serum. Kidney disease can also lead to hypoalbuminemia as well as uremia which decreases the percentage of bound phenytoin in the plasma. Malnutrition, malignancy, and pregnancy are other causes for phenytoin toxicity in a patient on chronic therapy without any changes in dose.

Acute Ingestion

Acute ingestion leading to overdose can be intentional or unintentional. There have also been reports of crack cocaine being adultered with phenytoin, which can lead to an unintentional overdose

Chronic Toxicity

One of the more common manifestations of chronic phenytoin ingestion is gingival hyperplasia. The cause of phenytoin-induced gingival enlargement is likely due to the direct effects of the drug and its metabolites on the gingival fibroblasts. Other factors which can contribute to phenytoin-induced gingival enlargement include adrenocortical axis suppression, alterations in the metabolism of calcium, low serum folic acid levels, and suppression of the immune system.

DRESS Syndrome

Drug reaction with eosinophilia and systemic symptoms, or DRESS syndrome, has been associated with chronic phenytoin use. This rare syndrome may occur in one out of 1000 to 10,000 users of any of the aromatic anticonvulsants, including phenytoin, carbamazepine, and lamotrigine. Onset is typically within two months of initiation of therapy and is triggered by metabolites of each agent inducing a type-IV hypersensitivity. Symptoms typically include high fever, a macular rash, and pharyngitis, and it is often mistaken early in the course for streptococcal pharyngitis. Multi-organ system involvement lymphadenopathy, liver injury, acute kidney injury and occasional encephalitis may occur. A peripheral blood smear shows eosinophilia and atypical lymphocytosis, often confusing the diagnosis with acute mononucleosis. Fatalities in the unrecognized case can be as high as 10%. Immediately discontinuation of phenytoin and the initiation of steroid treatment is key to preventing progression. A skin biopsy may be needed to confirm the diagnosis. A substitute anticonvulsant, from a non-aromatic class, should be used in place of phenytoin.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Phenytoin has been associated with both Stevens-Johnson syndrome, and its more severe manifestation toxic epidermal necrolysis (TEN). Once thought to be idiopathic, these life-threatening dermopathies have been linked to genetic variants of the human lymphocyte antigen system, and in CYP genetic variants. Mostly in Asia, patients who carry the HLAB*1502 and CYP2C9*3 genes are at high risk. If the presence of a skin and a mucosal rash is seen, immediate discontinuation of phenytoin is mandatory. Genetic testing may be advised before switching to another aromatic anticonvulsant.

Phenytoin toxicity symptoms

Phenytoin toxicity symptoms may include the following:

• uncontrollable eye movements
• loss of coordination
• slow or slurred speech
• uncontrollable shaking of a part of the body
• nausea
• vomiting
• difficulty understanding reality
• coma (loss of consciousness for a period of time)
• confusion
• convulsions (occasionally)
• dizziness
• fever
• low blood pressure
• muscle rigidity or spasms
• sleepiness
• side-to-side eye movement (nystagmus)
• slurred speech
• swollen gums
• tremor (unintentional trembling)
• unsteadiness

Phenytoin toxicity treatment

There is no specific antidote for phenytoin toxicity, and the hallmark of treatment is supportive care. Your health care provider will measure and monitor the your vital signs, including temperature, pulse, breathing rate, and blood pressure. Blood tests will be done to check phenytoin levels. Symptoms will be treated as appropriate. You may receive:

• Activated charcoal
• Airway support, including oxygen, breathing tube through the mouth (intubation), and ventilator (breathing machine)
• Blood and urine tests
• Chest x-ray
• EKG (electrocardiogram, or heart tracing)
• Fluids through the vein (intravenous or IV)
• Laxative
• Medicines to treat symptoms

The management of phenytoin toxicity should initially proceed along the lines of accepted treatment of general overdoses. The airway should be assessed, and advanced airway management initiated in patients that cannot maintain their airway or respiratory drive. The circulation should be assessed and abnormalities in vital signs addressed. Hypotension can be treated with an initial bolus of isotonic solution. If unresponsive to fluid administration, vasopressors can be initiated with norepinephrine or dopamine being preferred. Bradycardia can also be managed according to standard advanced cardiac life support protocols including atropine, epinephrine and if needed, transcutaneous or transvenous pacing. Consultation with a medical toxicologist is highly recommended ⁵⁾.

Other symptoms of overdose can be managed according to standards of care. Antiemetics can be administered in cases of nausea and vomiting. Seizures can be controlled by following the normal seizure protocols with benzodiazepines as the first like medications followed by phenobarbital or levetiracetam for persistent or recurrent seizures.

Activated charcoal reliably binds phenytoin and prevents absorption. In acute ingestions, one dose of activated charcoal may be of benefit especially in large acute overdoses as phenytoin slows GI (gastrointestinal) motility and absorption is delayed. Activated charcoal is also of benefit in acute ingestions of extended-release tablets. Activated charcoal is not recommended if there is a depressed mental state. The role of multi-dose activated charcoal is controversial. Some studies have shown increased clearance rates although no clinical benefit or improvement in patient outcomes could be demonstrated. Induced emesis, gastric lavage, and whole bowel irrigation are not recommended for phenytoin overdose.

Despite high-plasma protein binding by phenytoin, the drug can be removed by hemodialysis with moderate effectiveness. However, clinical benefits are controversial. Due to the high-risk nature of hemodialysis, the effectiveness of supportive treatment, and the self-limited nature of acute overdoses, hemodialysis is rarely recommended and should only be used in extreme situations after consultation with a medical toxicologist. One guideline by the EXTRIP group advises the consideration of hemodialysis in cases of coma, and possibly in incapacitating ataxia; however, no specific serum concentration threshold can be used as a sole reason to perform dialysis.

Phenytoin toxicity prognosis

How well a person does depends on the severity of the overdose and how quickly treatment is received. If there has been prolonged coma and shock (damage to multiple internal organs), a more serious outcome is possible.

Deaths are rare from phenytoin ingestion alone. Most reported cases involve ingestion of other substances along with phenytoin. Fatal cases of single phenytoin ingestions typically involve serum concentrations of greater than 125 mg/L.

Disposition of patients is made on an individual basis. Patients requiring ventilatory support, hemodynamically unstable patients or patients with abnormal ECGs should be admitted to a monitored setting. Patients with mild to moderate overdoses, normal mentation, normal ECGs without any hypotension, bradycardia, or arrhythmias can be safely admitted to a bed without cardiac monitoring.

Serum phenytoin levels should be repeated and trended. Decreasing levels of serum phenytoin in a patient that can ambulate without assistance and has someone at home who can assist with activities of daily living until all symptoms of toxicity have resolved may be safely discharged home. Adequate follow-up should be arranged. All patients with intentional overdoses should receive a psychiatric consultation while hospitalized.