Amnesteem Drug Information

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 patients who can become pregnant 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 patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Amnesteem. Therefore, it is critically important for patients who can become pregnant 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 Ortho-Novum ® 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.

Pregnancy Category X See Boxed CONTRAINDICATIONS AND WARNINGS.

Pediatric Use The use of Amnesteem in pediatric patients less than 12 years of age has not been studied. The use of Amnesteem for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS: General ). Use of Amnesteem in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (≥ 18 years). Results from this study demonstrated that Amnesteem, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. In studies with Amnesteem, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS ). In an open-label clinical trial (N = 217) of a single course of therapy with Amnesteem for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients.

One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values.

Total hip bone mineral densities remained below baseline (range –1.6% to –7.6%) in five of eight patients (62.5%). In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of Amnesteem 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density ).

• Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS. Allergic Reactions Amnesteem is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS: Hypersensitivity ).

The oral LD 50 of isotretinoin is greater than 4000 mg/kg in rats and mice (> 600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects. Amnesteem causes life threatening birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS ). Patients who can become pregnant who present with isotretinoin overdose must be evaluated for pregnancy.

Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month.