Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 24 October 2017

Indication(s)

INDICATIONS AND USAGE SORIATANE is indicated for the treatment of severe psoriasis in adults. Because of significant adverse effects associated with its use, SORIATANE should be prescribed only by those knowledgeable in the systemic use of retinoids. In females of reproductive potential, SORIATANE 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 — SORIATANE 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.

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Advisory information

contraindications
CONTRAINDICATIONS Pregnancy: See boxed CONTRAINDICATIONS AND WARNINGS. SORIATANE is 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 SORIATANE is also contraindicated (see PRECAUTIONS: Drug Interactions). Since both SORIATANE and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri). SORIATANE is contraindicated in cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids.
Special warnings and precautions
PRECAUTIONS A description of the Do Your P.A.R.T. materials is provided below. The main goals of the materials are to explain the program requirements, to reinforce the educational messages, and to assess program effectiveness. The Do Your P.A.R.T. booklet includes: •The Do Your P.A.R.T. Patient Brochure: information on the program requirements, risks of acitretin, and the types of contraceptive methods •The Contraception Counseling Referral Form for female patients who want to receive free contraception counseling reimbursed by the manufacturer •The Patient Agreement/Informed Consent for Female Patients form •Medication Guide The Do Your P.A.R.T. program also includes a voluntary patient survey for women of childbearing potential to assess the effectiveness of the SORIATANE Pregnancy Prevention Program Do Your P.A.R.T. Do Your P.A.R.T. Program materials are available at www.soriatane.com or may be requested by calling 1-888-784-3335 (1-888-STIEFEL). Information for Patients: (See Medication Guide for all patients and Patient Agreement/Informed Consent for Female Patients at end of professional labeling). Patients should be instructed to read the Medication Guide supplied as required by law when SORIATANE is dispensed. Females of Reproductive Potential: SORIATANE can cause severe birth defects. Female patients must not be pregnant when therapy with SORIATANE is initiated, they must not become pregnant while taking SORIATANE and for at least 3 years after stopping SORIATANE, so that the drug can be eliminated to below a blood concentration that would be associated with an increased incidence of birth defects. Because this threshold has not been established for acitretin in humans and because elimination rates vary among patients, the duration of posttherapy contraception to achieve adequate elimination cannot be calculated precisely (see boxed CONTRAINDICATIONS AND WARNINGS). Females of reproductive potential should also be advised that they must not ingest beverages or products containing ethanol while taking SORIATANE and for 2 months after SORIATANE has been discontinued. This allows for elimination of the acitretin which can be converted to etretinate in the presence of alcohol. Female patients should be advised that any method of birth control can fail, including tubal ligation, and that microdosed progestin “minipill” preparations are not recommended for use with SORIATANE (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions). Data from one patient who received a very low-dosed progestin contraceptive (levonorgestrel 0.03 mg) had a significant increase of the progesterone level after 3 menstrual cycles during acitretin treatment.2 Female patients should be advised to contact their physician, women’s health centers, pharmacies, or hospital emergency rooms for information about how to obtain Emergency Contraception if sexual intercourse occurs without using 2 effective forms of contraception simultaneously. A 24-hour, toll-free number (1-800-739-6700) is also available for patients to receive automated birth control and emergency contraception information. Female patients should sign a consent form prior to beginning therapy with SORIATANE (see boxed CONTRAINDICATIONS AND WARNINGS). Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective case report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive SORIATANE prior to or during nursing because of the potential for serious adverse reactions in nursing infants. All Patients: Depression and/or other psychiatric symptoms such as aggressive feelings or thoughts of self-harm 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 SORIATANE. Since other factors may have contributed to these events, it is not known if they are related to SORIATANE. Patients should be counseled to stop taking SORIATANE and notify their prescriber immediately if they experience psychiatric symptoms. Patients should be advised that a transient worsening of psoriasis is sometimes seen during the initial treatment period. Patients should be advised that they may have to wait 2 to 3 months before they get the full benefit of SORIATANE, although some patients may achieve significant improvements within the first 8 weeks of treatment as demonstrated in clinical trials. Decreased night vision has been reported during therapy with SORIATANE. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored (see WARNINGS and ADVERSE REACTIONS). Patients should be advised that they may experience decreased tolerance to contact lenses during the treatment period and sometimes after treatment has stopped. Patients should not donate blood during and for at least 3 years following therapy because SORIATANE can cause birth defects and women of childbearing potential must not receive blood from patients being treated with SORIATANE. Because of the relationship of SORIATANE to vitamin A, patients should be advised against taking vitamin A supplements in excess of minimum recommended daily allowances to avoid possible additive toxic effects. Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical UV exposure) because the effects of UV light are enhanced by retinoids. Patients should be advised that they must not give their SORIATANE to any other person. For Prescribers: SORIATANE has not been studied in and is not indicated for treatment of acne. Phototherapy: Significantly lower doses of phototherapy are required when SORIATANE is used because effects on the stratum corneum induced by SORIATANE can increase the risk of erythema (burning) (see DOSAGE AND ADMINISTRATION). 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 SORIATANE 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 SORIATANE (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, the protein binding of phenytoin may be reduced. Tetracyclines: Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see CONTRAINDICATIONS and WARNINGS: Pseudotumor Cerebri). Vitamin A and Oral Retinoids: Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A. Other: There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction. Laboratory Tests: If significant abnormal laboratory results are obtained, either dosage reduction with careful monitoring or treatment discontinuation is recommended, depending on clinical judgment. Blood Sugar: Some patients receiving retinoids have experienced problems with blood sugar control. In addition, new cases of diabetes have been diagnosed during retinoid therapy, including diabetic ketoacidosis. In diabetics, blood-sugar levels should be monitored very carefully. Lipids: In clinical trials, the incidence of hypertriglyceridemia was 66%, hypercholesterolemia was 33%, and that of decreased HDL was 40%. Pretreatment and follow-up measurements should be obtained under fasting conditions. It is recommended that these tests be performed weekly or every other week until the lipid response to SORIATANE has stabilized (see WARNINGS). Liver Function Tests: Elevations of AST (SGOT), ALT (SGPT), or LDH were experienced by approximately 1 in 3 patients treated with SORIATANE. It is recommended that these tests be performed prior to initiation of therapy with SORIATANE, at 1- to 2-week intervals until stable, and thereafter at intervals as clinically indicated (see CONTRAINDICATIONS and boxed WARNINGS). Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: A carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg per kg per day administered 7 days per week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. An 80-week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum recommended human therapeutic dose based on a mg-per-m2 comparison. Mutagenesis: Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays. Impairment of Fertility: In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg per kg per day (approximately one-half the maximum recommended therapeutic dose based on a mg-per-m2 comparison). Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg per kg per day). No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg per day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men.4-6 No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured.4,5 Pregnancy: Teratogenic Effects: (see boxed CONTRAINDICATIONS AND WARNINGS). In a study in which acitretin was administered to male rats only at a dosage of 5 mg per kg per day for 10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were observed in the progeny (see boxed CONTRAINDICATIONS AND WARNINGS for information about male use of SORIATANE). Nonteratogenic Effects: In rats dosed at 3 mg per kg per day (approximately one-half the maximum recommended therapeutic dose based on a mg-per-m2 comparison), slightly decreased pup survival and delayed incisor eruption were noted. At the next lowest dose tested, 1 mg per kg per day, no treatment-related adverse effects were observed. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. No clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic retinoids, including etretinate, a metabolite of SORIATANE. A causal relationship between these effects and SORIATANE has not been established. While it is not known that these occurrences are more severe or more frequent in children, there is special concern in pediatric patients because of the implications for growth potential (see WARNINGS: Hyperostosis). Geriatric Use: Clinical trials of SORIATANE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A 2-fold increase in acitretin plasma concentrations was seen in healthy elderly subjects compared with young subjects, although the elimination half-life did not change (see CLINICAL PHARMACOLOGY: Special Populations).
Adverse reactions
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 SORIATANE 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 SORIATANE. 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 SORIATANE. 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 SORIATANE. Since other factors may have contributed to these events, it is not known if they are related to SORIATANE (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 SORIATANE, 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, SORIATANE 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 corneal lesions Gastrointestinal Abdominal pain Diarrhea Nausea Tongue disorder Constipation Dyspepsia Esophagitis Gastritis Gastroenteritis Glossitis Hemorrhoids Melena Tenesmus Tongue ulceration Liver and Biliary Hepatic function abnormal Hepatitis Jaundice Mucous Membranes Gingival bleeding Gingivitis Increased saliva Stomatitis Thirst Ulcerative stomatitis Altered saliva Anal disorder Gum hyperplasia Hemorrhage Pharyngitis Musculoskeletal Arthritis Arthrosis Back pain Hypertonia Myalgia Osteodynia Peripheral joint hyperostosis (progression of existing lesions) Bone disorder Olecranon bursitis Spinal hyperostosis (new lesions) Tendonitis Psychiatric Depression Insomnia Somnolence Anxiety Dysphonia Libido decreased Nervousness Reproductive Atrophic vaginitis Leukorrhea Respiratory Sinusitis Coughing Increased sputum Laryngitis Skin and Appendages Abnormal skin odor Abnormal hair texture Bullous eruption Cold/clammy skin Dermatitis Increased sweating Infection Psoriasiform rash Purpura Pyogenic granuloma Rash Seborrhea Skin fissures Skin ulceration Sunburn Acne Breast pain Cyst Eczema Fungal infection Furunculosis Hair discoloration Herpes simplex Hyperkeratosis Hypertrichosis Hypoesthesia Impaired healing Otitis media Otitis externa Photosensitivity reaction Psoriasis aggravated Scleroderma Skin nodule Skin hypertrophy Skin disorder Skin irritation Sweat gland disorder Urticaria Verrucae Special Senses/ Other Earache Taste perversion Tinnitus Ceruminosis Deafness Taste loss Urinary Abnormal urine Dysuria Penis disorder Laboratory: Therapy with SORIATANE induces changes in liver function tests in a significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 subjects treated with SORIATANE. In most subjects, elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of treatment. In subjects receiving SORIATANE during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% (see WARNINGS). Transient, usually reversible elevations of alkaline phosphatase have been observed. Table 5 lists the laboratory abnormalities reported during clinical trials. Table 5. Abnormal Laboratory Test Results Reported during Clinical Trials Percent of Subjects Reporting Body System 50% to 75% 25% to 50% 10% to 25% 1% to 10% Electrolytes Increased: –Phosphorus –Potassium –Sodium Decreased: –Phosphorus –Potassium –Sodium Increased and decreased: –Magnesium Increased and decreased: –Calcium –Chloride Hematologic Increased: –Reticulocytes Decreased: –Hematocrit –Hemoglobin –WBC Increased: –Haptoglobin –Neutrophils –WBC Increased: –Bands –Basophils –Eosinophils –Hematocrit –Hemoglobin –Lymphocytes –Monocytes Decreased: –Haptoglobin –Lymphocytes –Neutrophils –Reticulocytes Increased or decreased: –Platelets –RBC Hepatic Increased: –Cholesterol –LDH –SGOT –SGPT Decreased: –HDL cholesterol Increased: –Alkaline phosphatase –Direct bilirubin –GGTP Increased: –Globulin –Total bilirubin –Total protein Increased and decreased: –Serum albumin Miscellaneous Increased: –Triglycerides Increased: –CPK –Fasting blood sugar Decreased: –Fasting blood sugar –High occult blood Increased and decreased: –Iron Renal Increased: –Uric acid Increased: –BUN –Creatinine Urinary WBC in urine Acetonuria Hematuria RBC in urine Glycosuria Proteinuria

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with SORIATANE. 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 SORIATANE 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 SORIATANE is 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 Stiefel at 1-888-784-3335 (1-888-STIEFEL). Information for Pharmacists: SORIATANE must only be dispensed in no more than a monthly supply. A SORIATANE Medication Guide must be given to the patient each time SORIATANE is dispensed, as required by law.
Pregnancy and lactation
Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective case report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive SORIATANE prior to or during nursing because of the potential for serious adverse reactions in nursing infants.

Interactions

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 SORIATANE. It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.

More information

Category Value
Authorisation number NDA019821
Agency product number LCH760E9T7
Orphan designation No
Product NDC 0145-3817,0145-0091,0145-0090
Date Last Revised 09-10-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 894861
Marketing authorisation holder Stiefel Laboratories Inc
Warnings CONTRAINDICATIONS AND WARNINGS: Pregnancy SORIATANE must not be used by females who are pregnant, or who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy. SORIATANE also must not be used by females who may not use reliable contraception while undergoing treatment and for at least 3 years following discontinuation of treatment. Acitretin is a metabolite of etretinate (TEGISON), and major human fetal abnormalities have been reported with the administration of acitretin and etretinate. Potentially, any fetus exposed can be affected. Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been associated with the formation of etretinate, which has a significantly longer elimination half-life than acitretin. Because the longer elimination half-life of etretinate would increase the duration of teratogenic potential for female patients, ethanol must not be ingested by female patients of childbearing potential either during treatment with SORIATANE or for 2 months after cessation of therapy. This allows for elimination of acitretin, thus removing the substrate for transesterification to etretinate. The mechanism of the metabolic process for conversion of acitretin to etretinate has not been fully defined. It is not known whether substances other than ethanol are associated with transesterification. Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats at oral doses of 0.6, 3, and 15 mg per kg, respectively. These doses are approximately 0.2, 0.3, and 3 times the maximum recommended therapeutic dose, respectively, based on a mg-per-m2 comparison. Major human fetal abnormalities associated with acitretin and/or etretinate administration have been reported including meningomyelocele; meningoencephalocele; multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges; malformations of hip, ankle, and forearm; low-set ears; high palate; decreased cranial volume; cardiovascular malformation; and alterations of the skull and cervical vertebrae. SORIATANE should be prescribed only by those who have special competence in the diagnosis and treatment of severe psoriasis, are experienced in the use of systemic retinoids, and understand the risk of teratogenicity. Because of the teratogenicity of SORIATANE, a program called the Do Your P.A.R.T. program, Pregnancy Prevention Actively Required During and After Treatment, has been developed to educate women of childbearing potential and their healthcare providers about the serious risks associated with acitretin and to help prevent pregnancies from occurring with the use of this drug and for 3 years after its discontinuation. The Do Your P.A.R.T. program requirements are described below and program materials are available at www.soriatane.com or may be requested by calling 1-888-784-3335 (1-888-STIEFEL) (see also PRECAUTIONS section). Important Information for Women of Childbearing Potential: SORIATANE should be considered only for women with severe psoriasis unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments. Females of reproductive potential must not be given a prescription for SORIATANE until pregnancy is excluded. SORIATANE is contraindicated in females of reproductive potential unless the patient meets ALL of the following conditions: • Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU per mL before receiving the initial prescription for SORIATANE. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue therapy with SORIATANE. The second pregnancy test (a confirmation test) should be done during the first 5 days of the menstrual period immediately preceding the beginning of therapy with SORIATANE. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of contraception [birth control] simultaneously). If the second pregnancy test is negative, initiation of treatment with SORIATANE should begin within 7 days of the specimen collection. SORIATANE should be limited to a monthly supply. • Must have a pregnancy test with a sensitivity of at least 25 mIU per mL repeated every month during treatment with SORIATANE. The patient must have a negative result from a urine or serum pregnancy test before receiving a prescription for SORIATANE. To encourage compliance with this recommendation, a monthly supply of the drug should be prescribed. For at least 3 years after discontinuing therapy with SORIATANE, a pregnancy test must be repeated every 3 months. • Must have selected and have committed to use 2 effective forms of contraception (birth control) simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has undergone a hysterectomy or is clearly postmenopausal. • Patients must use 2 effective forms of contraception (birth control) simultaneously for at least 1 month prior to initiation of therapy with SORIATANE, during therapy with SORIATANE, and for at least 3 years after discontinuing therapy with SORIATANE. A Contraception Counseling Referral Form is available so that patients can receive an initial free contraception counseling session and pregnancy testing. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis by the prescriber during therapy with SORIATANE and every 3 months for at least 3 years following discontinuation of SORIATANE. Effective forms of contraception include both primary and secondary forms of contraception. Primary forms of contraception include: tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and injectable/implantable/insertable/topical hormonal birth control products. Secondary forms of contraception include condoms (with or without spermicide), diaphragms and cervical caps (which must be used with a spermicide), and vaginal sponges (contains spermicide). Any birth control method can fail. Therefore, it is critically important that women of childbearing potential use 2 effective forms of contraception (birth control) simultaneously. 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 SORIATANE. It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy. Prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John’s wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John’s wort (see PRECAUTIONS). • Must have signed a Patient Agreement/Informed Consent for Female Patients that contains warnings about the risk of potential birth defects if the fetus is exposed to SORIATANE, about contraceptive failure, about the fact that they must not ingest beverages or products containing ethanol while taking SORIATANE and for 2 months after treatment with SORIATANE has been discontinued, and about preventing pregnancy while taking SORIATANE and for at least 3 years after discontinuing SORIATANE. If pregnancy does occur during therapy with SORIATANE or at any time for at least 3 years following discontinuation of SORIATANE, the prescriber and patient should discuss the possible effects on the pregnancy. The available information is as follows: Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated during pregnancy. The risk of severe fetal malformations is well established when systemic retinoids are taken during pregnancy. Pregnancy must also be prevented after stopping acitretin therapy, while the drug is being eliminated to below a threshold blood concentration that would be associated with an increased incidence of birth defects. Because this threshold has not been established for acitretin in humans and because elimination rates vary among patients, the duration of posttherapy contraception to achieve adequate elimination cannot be calculated precisely. It is strongly recommended that contraception be continued for at least 3 years after stopping treatment with acitretin, based on the following considerations: • In the absence of transesterification to form etretinate, greater than 98% of the acitretin would be eliminated within 2 months, assuming a mean elimination half-life of 49 hours. • In cases where etretinate is formed, as has been demonstrated with concomitant administration of acitretin and ethanol, • greater than 98% of the etretinate formed would be eliminated in 2 years, assuming a mean elimination half-life of 120 days. • greater than 98% of the etretinate formed would be eliminated in 3 years, based on the longest demonstrated elimination half-life of 168 days. However, etretinate was found in plasma and subcutaneous fat in one patient reported to have had sporadic alcohol intake, 52 months after she stopped acitretin therapy.2 • Severe birth defects have been reported where conception occurred during the time interval when the patient was being treated with acitretin and/or etretinate. In addition, severe birth defects have also been reported when conception occurred after the mother completed therapy. These cases have been reported both prospectively (before the outcome was known) and retrospectively (after the outcome was known). The events below are listed without distinction as to whether the reported birth defects are consistent with retinoid-induced embryopathy or not. • There have been 318 prospectively reported cases involving pregnancies and the use of etretinate, acitretin, or both. In 238 of these cases, the conception occurred after the last dose of etretinate (103 cases), acitretin (126), or both (9). Fetal outcome remained unknown in approximately one-half of these cases, of which 62 were terminated and 14 were spontaneous abortions. Fetal outcome is known for the other 118 cases and 15 of the outcomes were abnormal (including cases of absent hand/wrist, clubfoot, GI malformation, hypocalcemia, hypotonia, limb malformation, neonatal apnea/anemia, neonatal ichthyosis, placental disorder/death, undescended testicle, and 5 cases of premature birth). In the 126 prospectively reported cases where conception occurred after the last dose of acitretin only, 43 cases involved conception at least 1 year but less than 2 years after the last dose. There were 3 reports of abnormal outcomes out of these 43 cases (involving limb malformation, GI tract malformations, and premature birth). There were only 4 cases where conception occurred at least 2 years after the last dose but there were no reports of birth defects in these cases. • There is also a total of 35 retrospectively reported cases where conception occurred at least 1 year after the last dose of etretinate, acitretin, or both. From these cases there are 3 reports of birth defects when the conception occurred at least 1 year but less than 2 years after the last dose of acitretin (including heart malformations, Turner’s Syndrome, and unspecified congenital malformations) and 4 reports of birth defects when conception occurred 2 or more years after the last dose of acitretin (including foot malformation, cardiac malformations [2 cases], and unspecified neonatal and infancy disorder). There were 3 additional abnormal outcomes in cases where conception occurred 2 or more years after the last dose of etretinate (including chromosome disorder, forearm aplasia, and stillbirth). • 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 Stiefel at 1-888-784-3335 (1-888-STIEFEL). • Patients should not donate blood during and for at least 3 years following the completion of therapy with SORIATANE because women of childbearing potential must not receive blood from patients being treated with SORIATANE. Important Information for Males Taking SORIATANE: Patients should not donate blood during and for at least 3 years following therapy with SORIATANE because women of childbearing potential must not receive blood from patients being treated with SORIATANE. • Samples of seminal fluid from 3 male patients treated with acitretin and 6 male patients treated with etretinate have been assayed for the presence of acitretin. The maximum concentration of acitretin observed in the seminal fluid of these men was 12.5 ng per mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be 125 ng, which is 1/200,000 of a single 25 mg capsule. Thus, although it appears that residual acitretin in seminal fluid poses little, if any, risk to a fetus while a male patient is taking the drug or after it is discontinued, the no-effect limit for teratogenicity is unknown and there is no registry for birth defects associated with acitretin. The available data are as follows: There have been 25 cases of reported conception when the male partner was taking acitretin. The pregnancy outcome is known in 13 of these 25 cases. Of these, 9 reports were retrospective and 4 were prospective (meaning the pregnancy was reported prior to knowledge of the outcome)3. For All Patients: A SORIATANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT EACH TIME SORIATANE IS DISPENSED, AS REQUIRED BY LAW. boxed warning table.jpg