Medication

INDICATIONS AND USAGE Severe Recalcitrant Nodular Acne Amnesteem is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition, 2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Amnesteem should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics . In addition, Amnesteem is indicated only for those female patients who are not pregnant, because Amnesteem can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS ). A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients. 1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Amnesteem. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density , Hyperostosis , and Premature Epiphyseal Closure ).

DOSAGE AND ADMINISTRATION Amnesteem should be administered with a meal (see PRECAUTIONS: Information for Patients ). The recommended dosage range for Amnesteem is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5 and 1 mg/kg/day, 8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects — some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Amnesteem with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions. The safety of once daily dosing with Amnesteem has not been established. Once daily dosing is not recommended. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Amnesteem, even in low doses, has not been studied, and is not recommended. It is important that Amnesteem be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Amnesteem on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density , Hyperostosis , and Premature Epiphyseal Closure ). Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS ). Table 4. Amnesteem Dosing by Body Weight (Based on Administration with Food) Body Weight Total mg/day kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg 40 50 60 70 80 90 100 88 110 132 154 176 198 220 20 25 30 35 40 45 50 40 50 60 70 80 90 100 80 100 120 140 160 180 200 INFORMATION FOR PHARMACISTS Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to obtain an authorization and the “do not dispense to patient after” date. Amnesteem must only be dispensed in no more than a 30 day supply. REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM. An Amnesteem Medication Guide must be given to the patient each time Amnesteem is dispensed, as required by law. This Amnesteem Medication Guide is an important part of the risk management program for the patient.

ADVERSE REACTIONS Clinical Trials and Post-marketing Surveillance The adverse reactions listed below reflect the experience from investigational studies of Amnesteem, and the post-marketing experience. The relationship of some of these events to Amnesteem therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Amnesteem are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage and eyes). Dose Relationship Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS ). Body as a Whole: allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity ), edema, fatigue, lymphadenopathy, weight loss Cardiovascular: palpitation, tachycardia, vascular thrombotic disease, stroke Endocrine/Metabolic: hypertriglyceridemia (see WARNINGS: Lipids ), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests ) Gastrointestinal: inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease ), hepatitis (see WARNINGS: Hepatotoxicity ), pancreatitis (see WARNINGS: Lipids ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms Hematologic: allergic reactions (see PRECAUTIONS: Hypersensitivity ), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients ). See PRECAUTIONS: Laboratory Tests for other hematological parameters Musculoskeletal: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal ), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PRECAUTIONS: Information for Patients ), transient pain in the chest (see PRECAUTIONS: Information for Patients ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests ) Neurological: pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri ), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness Psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders ), emotional instability Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. Reproductive System: abnormal menses Respiratory: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration Skin and Appendages: acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas, 7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson Syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS: Hypersensitivity ) abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PRECAUTIONS: Information for Patients ) Special Senses: Hearing: hearing impairment (see WARNINGS: Hearing Impairment ), tinnitus Vision: corneal opacities (see WARNINGS: Corneal Opacities ), decreased night vision which may persist (see WARNINGS: Decreased Night Vision ), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances Urinary System: glomerulonephritis (see PRECAUTIONS: Hypersensitivity ), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters) Laboratory Elevation of plasma triglycerides (see WARNINGS: Lipids ), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity ) Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests ), hyperuricemia Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PRECAUTIONS: Information for Patients ), elevated sedimentation rates, elevated platelet counts, thrombocytopenia White cells in the urine, proteinuria, microscopic or gross hematuria

Drug Interactions Vitamin A: Because of the relationship of Amnesteem to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with Amnesteem and tetracyclines should be avoided because Amnesteem use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Amnesteem therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Amnesteem. Therefore, it is critically important for female patients of childbearing potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS ). Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum ® 7/7/7 Tablets as an oral contraceptive agent, Amnesteem at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. St. John’s Wort: Amnesteem use is associated with depression in some patients (see WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric ). 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. Phenytoin: Amnesteem has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Amnesteem. Therefore, caution should be exercised when using these drugs together. Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Amnesteem. Therefore, caution should be exercised when using these drugs together.