WARNINGS

Psychiatric Disorders Amnesteem may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.

No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric).

Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin.

Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need.

Therefore, prior to initiation of Amnesteem therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary.

Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment.

Patients should stop Amnesteem and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit.

Discontinuation of Amnesteem therapy may be insufficient; further evaluation may be necessary.

While such monitoring may be helpful, it may not detect all patients at risk.

Patients may report mental health problems or family history of psychiatric disorders.

These reports should be discussed with the patient and/or the patient’s family.

A referral to a mental health professional may be necessary.

The physician should consider whether Amnesteem therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Amnesteem therapy.

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

Concomitant treatment with tetracyclines should therefore be avoided.

Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances.

Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue Amnesteem immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).

Serious Skin Reactions There have been post-marketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use.

These events may be serious and result in death, life-threatening events, hospitalization or disability.

Patients should be monitored closely for severe skin reactions and discontinuation of Amnesteem should be considered if warranted.

Pancreatitis Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels.

In rare instances, fatal hemorrhagic pancreatitis has been reported.

Amnesteem should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

Lipids Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Amnesteem.

Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Amnesteem in clinical trials.

In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels.

In clinical trials, the effects on triglycerides, HDL and cholesterol were reversible upon cessation of Amnesteem therapy.

Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Amnesteem.5 Blood lipid determinations should be performed before Amnesteem is given and then at intervals until the lipid response to Amnesteem is established, which usually occurs within 4 weeks.

Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Amnesteem therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder).

If Amnesteem therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).

The cardiovascular consequences of hypertriglyceridemia associated with Amnesteem are unknown.

Animal Studies In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age.

Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

Hearing Impairment Impaired hearing has been reported in patients taking Amnesteem; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued.

Mechanism(s) and causality for this event have not been established.

Patients who experience tinnitus or hearing impairment should discontinue Amnesteem treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).

Hepatotoxicity Clinical hepatitis considered to be possibly or probably related to Amnesteem therapy has been reported.

Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug.

If normalization does not readily occur or if hepatitis is suspected during treatment with Amnesteem, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease Amnesteem has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders.

In some instances, symptoms have been reported to persist after Amnesteem treatment has been stopped.

Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Amnesteem immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal Bone Mineral Density Effects of multiple courses of Amnesteem on the developing musculoskeletal system are unknown.

There is some evidence that long-term, high dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system.

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 PRECAUTIONS: Pediatric Use).

Spontaneous reports of osteoporosis, osteopenia, bone fractures and delayed healing of bone fractures have been seen in the Amnesteem population.

While causality to Amnesteem has not been established, an effect cannot be ruled out.

Longer term effects have not been studied.

It is important that Amnesteem be given at the recommended doses for no longer than the recommended duration.

Hyperostosis A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day.

Additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses.

The skeletal effects of multiple Amnesteem treatment courses for acne are unknown.

In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of Amnesteem given in two divided doses.

Hyperostosis may require a longer time frame to appear.

The clinical course and significance remain unknown.

Premature Epiphyseal Closure There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Amnesteem.

The effect of multiple courses of Amnesteem on epiphyseal closure is unknown.

Vision Impairment Visual problems should be carefully monitored.

All Amnesteem patients experiencing visual difficulties should discontinue Amnesteem treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).

Corneal Opacities Corneal opacities have occurred in patients receiving Amnesteem for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization.

The corneal opacities that have been observed in clinical trial patients treated with Amnesteem have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses).

Decreased Night Vision Decreased night vision has been reported during Amnesteem therapy and in some instances the event has persisted after therapy was discontinued.

Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.