Amnesteem Drug Information

Amnesteem is indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, Amnesteem is reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. Limitations of Use: If a second course of Amnesteem treatment is needed, it is not recommended before a two-month waiting period because the patient's acne may continue to improve following a 15 to 20-week course of treatment.

Evaluations Prior to Prescribing and Use of Amnesteem

In patients who can get pregnant, only prescribe Amnesteem after verification and documentation that they are not pregnant. For the detailed requirements prior to prescribing Amnesteem, see Use in Specific Populations. Table 1: Amnesteem: Recommended Divided Doses (0.5 mg/kg/day dosage) Table 2: Amnesteem: Recommended Divided Doses (1 mg/kg/day dosage) To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid.

Swallow capsules whole. Do not split, crush, chew, or suck on the capsules. During treatment, the dosage may be adjusted according to response of the disease and/or adverse reactions, 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 dosage adjustments up to 2 mg/kg/day for Amnesteem in divided doses with food, as tolerated (see Table 3). Table 3: Amnesteem: Recommended Divided Doses (2 mg/kg/day dosage) The safety and effectiveness of once daily dosing with Amnesteem has not been established and is not recommended. If a dose of Amnesteem is missed, just skip that dose.

Do not take two doses of Amnesteem at the same time.

Recommended Duration of Use

A course of treatment is 15 to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, may discontinue Amnesteem. After a period of 2 months or more off treatment, and if warranted by persistent or recurring severe nodular acne, may initiate a second course of Amnesteem in patients who have completed skeletal growth.

The use of another course of Amnesteem treatment is not recommended before a two-month waiting period because the patient's acne may continue to improve after a 15 to 20-week course of treatment. 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 dosages, has not been studied, and is not recommended.

The effect of long-term use of Amnesteem on bone loss is unknown.

• The following adverse reactions with Amnesteem are described in more detail in other sections of the labeling:
• Embryo-Fetal Toxicity
• Psychiatric Disorders
• Intracranial Hypertension (Pseudotumor Cerebri)
• Serious Skin Reactions
• Pancreatitis
• Lipid Abnormalities
• Hearing Impairment
• Hepatotoxicity
• Inflammatory Bowel Disease
• Musculoskeletal Abnormalities
• Ocular Abnormalities
• Hypersensitivity Reactions The following adverse reactions, presented alphabetically by body system, associated with the use of Amnesteem were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. Adverse Reactions with a Dose Relationship Cheilitis and hypertriglyceridemia were dose related. Body as a Whole Allergic reactions, dry mouth, edema, fatigue, irritability, lymphadenopathy, pain, systemic hypersensitivity, vasculitis, weight loss. Cardiovascular Palpitation, stroke, tachycardia, vascular thrombotic disease Endocrine/Metabolism and Nutritional Alterations in blood sugar levels, decreased appetite, hypertriglyceridemia, weight fluctuation. Gastrointestinal Abdominal pain, bleeding and inflammation of the gums, colitis, constipation, diarrhea, esophageal ulceration, esophagitis, ileitis, nausea, hepatitis, inflammatory bowel disease, other nonspecific gastrointestinal symptoms, pancreatitis, vomiting. Hematologic Anemia, neutropenia including severe neutropenia, rare reports of agranulocytosis, thrombocytopenia. Infections and Infestations Infections (including disseminated herpes simplex, hordeolum, nasopharyngitis, upper respiratory tract infections). Laboratory Abnormalities
• The following lab test values were increased: alkaline phosphatase, ALT, AST, bilirubin, cholesterol, CPK, fasting blood glucose, gamma-glutamyltransferase, LDH, LDL, platelet counts, sedimentation rate, triglycerides, and uric acid (hyperuricemia).
• The following lab test values were decreased: high density lipoprotein (HDL), RBC parameters, and WBC counts.
• Urine findings included increased microscopic or gross hematuria, proteinuria, white cells. Musculoskeletal and Connective Tissue Arthritis, calcification of tendons and ligaments; decreases in bone mineral density; elevations of CPK/rare reports of rhabdomyolysis musculoskeletal symptoms (sometimes severe) including arthralgia, back pain, extremity pain, musculoskeletal pain or stiffness, myalgia, neck pain; other types of bone abnormalities; premature epiphyseal closure; skeletal hyperostosis; tendonitis; and transient chest pain. Neurological Dizziness, drowsiness, intracranial hypertension (pseudotumor cerebri), headache, insomnia, lethargy, malaise, nervousness, paresthesia, seizures, syncope, stroke, and weakness. Psychiatric Aggression, auditory hallucinations, anger, depression, emotional instability, insomnia, irritability, panic attack, psychosis, suicidal ideation, suicide, suicide attempts, violent behaviors. In some patients who reported depression, their depression subsided with discontinuation of Amnesteem treatment but recurred with reinstitution of Amnesteem treatment. Reproductive System Abnormal menses, sexual dysfunction that may continue after discontinuation of treatment (including erectile dysfunction, decreased libido, decreased vaginal lubrication, and vaginal dryness). Respiratory Bronchospasm (with or without a history of asthma), epistaxis, nasal dryness, respiratory infection, voice alteration. Skin and Subcutaneous Tissue Abnormal wound healing (delayed healing or exuberant granulation tissue with crusting), acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), contact dermatitis, dermatitis, dry mouth, dry nose, dry skin, epistaxis, erythema, eruptive xanthomas, erythema multiforme, flushing, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), skin fragility, Stevens-Johnson syndrome, sunburn, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including granulomatosis with polyangiitis), wound healing abnormal (delayed healing or exuberant granulation tissue with crusting). Senses Hearing: hearing impairment, tinnitus. Ocular: asthenopia, blurred vision, cataracts, color vision disorder, conjunctivitis, corneal opacities, decreased night vision which may persist, dry eyes, eye irritation, eye pruritis, eyelid inflammation, increased lacrimation, keratitis, ocular hyperemia, optic neuritis, photophobia, reduced visual acuity, visual disturbances. Renal and Urinary Glomerulonephritis, nonspecific urogenital findings. Most common adverse reactions are (incidence ≥ 5%): dry lips, dry skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, increased creatine kinase, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, reduced visual acuity. To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Vitamin A Avoid concomitant use of Amnesteem with supplements containing vitamin A. Amnesteem is closely related to vitamin A. Therefore, concomitant use of Amnesteem with vitamin A may lead to Amnesteem-related adverse reactions.

Tetracyclines

Avoid concomitant use of Amnesteem with tetracyclines. Amnesteem use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use with tetracyclines.

Oral Contraceptives It is not known if there is an interaction between Amnesteem with oral contraceptives that do not contain norethindrone and ethinyl estradiol. Amnesteem did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with norethindrone and ethinyl estradiol oral contraceptive.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that documents pregnancies in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after Amnesteem treatment immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). Risk Summary Amnesteem is contraindicated during pregnancy because isotretinoin can cause fetal harm when administered to a pregnant patient.

There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. If Amnesteem is used during pregnancy, or if the patient becomes pregnant while taking Amnesteem, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking Amnesteem, immediately discontinue Amnesteem and refer the patient to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Data Human Data Major congenital malformations that have been documented following Amnesteem exposure include malformations of the face, eyes, ears, skull, central nervous system (CNS), cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency.

In some cases, death has occurred as a result of the malformations. Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy.

• Pediatric Use The safety and effectiveness of Amnesteem for the treatment of severe recalcitrant nodular acne have been established in non-pregnant pediatric patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional treatment, including systemic antibiotics. Use of Amnesteem in this age group for this indication is supported by evidence from a clinical trial comparing 103 pediatric patients (13 to 17 years) to 197 adults (both with severe recalcitrant nodular acne). Results from this study demonstrated that Amnesteem, at a dosage of 1 mg/kg/day given in two divided doses, was similarly effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. The safety and effectiveness of Amnesteem in pediatric patients less than 12 years of age have not been established. Adverse Reactions in Pediatric Patients In trials with Amnesteem, adverse reactions reported in pediatric patients aged 12 to 17 years old 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. Back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Evaluate the musculoskeletal system in pediatric patients 12 years of age and older who present with these symptoms during or after a course of Amnesteem. Consider discontinuing Amnesteem if any significant abnormality is found. Effects on Bone Mineral Density in Pediatric Patients In an open-label clinical trial (N = 217) of a single course of treatment with Amnesteem for adolescents with severe recalcitrant nodular acne, BMD at several skeletal sites were assessed:
• One patient had a decrease in lumbar spine BMD > 4% based on unadjusted data; 16 (8%) patients had decreases in lumbar spine BMD > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index).
• Nine patients (5%) had a decrease in total hip BMD > 5% based on unadjusted data. Twenty-one (11%) patients had decreases in total hip BMD > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the patients with decreased BMD for up to 11 months thereafter demonstrated increasing BMD in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine BMD measurements below baseline values. Total hip BMD remained below baseline range patients (63%). In a separate open-label extension trial of 10 patients including those ages 13 to 17 years, who started a second course of Amnesteem 4 months after the first course, two patients showed a decrease in mean lumbar spine BMD up to 3.3%. Epiphyseal Closure There have been spontaneous literature reports of premature epiphyseal closure in acne patients who received the recommended dosage of Amnesteem. The effect of multiple courses of Amnesteem on epiphyseal closure is unknown.

• Amnesteem is contraindicated in:
• Pregnancy.
• Patients with hypersensitivity to isotretinoin (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components (anaphylaxis and other allergic reactions have occurred). Amnesteem is contraindicated in:
• Pregnancy
• Patients with hypersensitivity to isotretinoin (or Vitamin A) or any of its components

Isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. Evaluate patients who can become pregnant who present with an isotretinoin overdosage for pregnancy. Because an overdosage would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, instruct male patients treated with Amnesteem to use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for 1 month after the overdose.

Instruct all patients with Amnesteem overdose not donate blood for at least 1 month. If an overdose occurs, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.