Acitretin

INDICATIONS AND USAGE Acitretin Capsules, USP are indicated for the treatment of severe psoriasis in adults. Because of significant adverse effects associated with its use, Acitretin Capsules, USP should be prescribed only by those knowledgeable in the systemic use of retinoids. In females of reproductive potential, Acitretin Capsules, USP should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments (see boxed CONTRAINDICATIONS AND WARNINGS — Acitretin Capsules, USP can cause severe birth defects). Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses, when clinically indicated, have produced efficacy results similar to the initial course of therapy.

DOSAGE AND ADMINISTRATION There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with acitretin capsules. A number of the more common side effects are dose-related. Individualization of dosage is required to achieve sufficient therapeutic response while minimizing side effects. Therapy with acitretin capsules should be initiated at 25 to 50 mg per day, given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may be given dependent upon an individual patient’s response to initial treatment. Relapses may be treated as outlined for initial therapy. When acitretin capsules are used with phototherapy, the prescriber should decrease the phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS: General ). Females who have taken TEGISON (etretinate) must continue to follow the contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the US; for information, call Alembic Pharmaceuticals Limited at 1-866-210-9797 . Information for Pharmacists Acitretin capsules must only be dispensed in no more than a monthly supply. An acitretin capsules Medication Guide must be given to the patient each time acitretin capsules are dispensed, as required by law.

CONTRAINDICATIONS Pregnancy See boxed CONTRAINDICATIONS AND WARNINGS . Acitretin capsules are contraindicated in patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values (see boxed WARNINGS: Hepatotoxicity , WARNINGS: Lipids and Possible Cardiovascular Effects , and PRECAUTIONS ). An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin capsules is also contraindicated (see PRECAUTIONS: Drug Interactions ). Since both acitretin capsules and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri ). Acitretin capsules are contraindicated in cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids .

ADVERSE REACTIONS Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and central nervous systems. Many of the clinical adverse reactions reported to date with administration of acitretin resemble those of the hypervitaminosis A syndrome. Adverse Events/Postmarketing Reports In addition to the events listed in the tables for the clinical trials, the following adverse events have been identified during postapproval use of acitretin. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Acute myocardial infarction, thromboembolism (see WARNINGS ), stroke. Immune System Disorders Hypersensitivity, including angioedema and urticaria (see CONTRAINDICATIONS ). Nervous System Myopathy with peripheral neuropathy has been reported during therapy with acitretin. Both conditions improved with discontinuation of the drug. Psychiatric Aggressive feelings and/or suicidal thoughts have been reported. These events, including self-injurious behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking acitretin. Since other factors may have contributed to these events, it is not known if they are related to acitretin (see PRECAUTIONS ). Reproductive Vulvo-vaginitis due to Candida albicans . Skin and Appendages Thinning of the skin, skin fragility, and scaling may occur all over the body, particularly on the palms and soles; nail fragility is frequently observed. Madarosis and exfoliative dermatitis/erythroderma have been reported (see WARNINGS ). Vascular Disorders: Capillary leak syndrome (see WARNINGS ). Clinical Trials During clinical trials with acitretin, 513 of 525 (98%) subjects reported a total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely, primarily because of adverse experiences involving the mucous membranes and skin. Three subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung cancer); the other subject died of an acute myocardial infarction, considered remotely related to drug therapy. In clinical trials, acitretin was associated with elevations in liver function test results or triglyceride levels and hepatitis. The tables below list by body system and frequency the adverse events reported during clinical trials of 525 subjects with psoriasis. Table 3: Adverse Events Frequently Reported during Clinical Trials Percent of Subjects Reporting (N = 525) Body System >75% 50% to 75% 25% to 50% 10% to 25% CNS Rigors Eye Disorders Xerophthalmia Mucous Membranes Cheilitis Rhinitis Dry mouth Epistaxis Musculoskeletal Arthralgia Spinal hyperostosis (progression of existing lesions) Skin and Appendages Alopecia Skin peeling Dry skin Nail disorder Pruritus Erythematous rash Hyperesthesia Paresthesia Paronychia Skin atrophy Sticky skin Table 4: Adverse Events Less Frequently Reported during Clinical Trials (Some of Which May Bear No Relationship to Therapy) Percent of Subjects Reporting (N = 525) Body System 1% to 10% <1% Body as a Whole Anorexia Edema Fatigue Hot Flashes Increased appetite Alcohol intolerance Dizziness Fever Influenza-like symptoms Malaise Moniliasis Muscle weakness Weight increase Cardiovascular Flushing Chest pain Cyanosis Increased bleeding time Intermittent claudication Peripheral ischemia CNS (also see Psychiatric) Headache Pain Abnormal gait Migraine Neuritis Pseudotumor cerebri (intracranial hypertension) Eye Disorders Abnormal/ blurred vision Blepharitis Conjunctivitis/ irritation Corneal epithelial abnormality Decreased night vision/night blindness Eye abnormality Eye pain Photophobia Abnormal lacrimation Chalazion Conjunctival hemorrhage Corneal ulceration Diplopia Ectropion Itchy eyes and lids Papilledema Recurrent sties Subepithelial corne …

Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS : Drug Interactions ): In studies of in vivo pharmacokinetic drug interactions, no interaction was seen between acitretin and cimetidine, digoxin, phenprocoumon, or glyburide. Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-life, see below) can be formed with concurrent ingestion of acitretin and ethanol. In a 2-way crossover trial, all 10 subjects formed etretinate with concurrent ingestion of a single 100-mg oral dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol, approximately 1.4 g per kg body weight). A mean peak etretinate concentration of 59 ng per mL (range: 22 to 105 ng per mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate in this trial was comparable to a single 5-mg oral dose of etretinate. There was no detectable formation of etretinate when a single 100-mg oral dose of acitretin was administered without concurrent ethanol ingestion, although the formation of etretinate without concurrent ethanol ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS ). Of 93 evaluable psoriatic subjects on acitretin therapy in several foreign trials (10 to 80 mg per day), 16% had measurable etretinate levels (>5 ng per mL). Etretinate has a much longer elimination half-life compared with that of acitretin. In one trial the apparent mean terminal half-life after 6 months of therapy was approximately 120 days (range: 84 to 168 days). In another trial of 47 subjects treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng per mL) 2.1 to 2.9 years after therapy was discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue. Progestin-only Contraceptives: It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin preparations. 1 Microdosed “minipill” progestin preparations are not recommended for use with acitretin. It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.

Drug Interactions: Ethanol: Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics ). Glyburide: In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended (see CLINICAL PHARMACOLOGY : Pharmacokinetics and DOSAGE AND ADMINISTRATION ). Hormonal Contraceptives: It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin “minipill” preparations. Microdosed “minipill” progestin preparations are not recommended for use with acitretin (see CLINICAL PHARMACOLOGY : Pharmacokinetic Drug Interactions ). It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy . Methotrexate: An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated (see CONTRAINDICATIONS ). Phenytoin: If acitretin is given concurrently with phenytoin, …

DESCRIPTION Acitretin, USP (micronized), a retinoid, is available in 10 mg, 17.5 mg, and 25 mg gelatin capsules for oral administration. Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a metabolite of etretinate and is related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow crystalline powder. The structural formula is: C 21 H 26 O 3 M.W. 326.43 Each capsule contains acitretin, USP (micronized) 10 mg, 17.5 mg, and 25 mg. Inactive ingredients are crospovidone, microcrystalline cellulose, poloxamer, povidone, sodium ascorbate and sodium lauryl sulfate. The 10 mg, 17.5, and 25 mg gelatin capsule shells contain gelatin and titanium dioxide. The 10 mg and 25 mg capsule shells also contain D&C yellow no. 10, FD&C blue no. 1, and FD&C red no. 40. The 17.5 mg capsule shells also contain red iron oxide and yellow iron oxide. The 25 mg gelatin capsule shells also contain FD&C yellow no. 6. The edible imprinting ink contains black iron oxide, D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, propylene glycol and shellac glaze. Meets USP Dissolution Test 2 . Acitretin Structural Formula

OVERDOSAGE In the event of acute overdosage, acitretin capsules must be withdrawn at once. Symptoms of overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral toxicity (LD 50 ) of acitretin in both mice and rats was greater than 4,000 mg per kg. In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25-mg capsules (525-mg single dose). He vomited several hours later but experienced no other ill effects. All female patients of childbearing potential who have taken an overdose of acitretin capsules must: 1) Have a pregnancy test at the time of overdose; 2) Be counseled as per the boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth defects and contraceptive use for at least 3 years’ duration after the overdose.

HOW SUPPLIED Acitretin Capsules USP are available as follows: 10 mg: Two-piece hard gelatin capsule with light green opaque cap and white opaque body filled with yellow powder, imprinted in black ink with TEVA on the cap and 1135 on the body, available in bottles of 30 capsules (NDC 0093-1135-56). 17.5 mg: Two-piece hard gelatin capsule with yellow opaque cap and yellow opaque body filled with yellow powder, imprinted in black ink with TEVA on the cap and 1138 on the body, available in bottles of 30 capsules (NDC 0093-1138-56). 25 mg: Two-piece hard gelatin capsule with light green opaque cap and yellow opaque body filled with yellow powder, imprinted in black ink with TEVA on the cap and 1136 on the body, available in bottles of 30 capsules (NDC 0093-1136-56). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required). PROTECT FROM LIGHT. AVOID EXPOSURE TO HIGH TEMPERATURES AND HUMIDITY AFTER THE BOTTLE IS OPENED. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.