Sotret 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 Sotret 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 Sotret 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 Sotret 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 Sotret therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotretinoin therapy.
Isotretinoin capsule 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 Sotret immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).
Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Sotret should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.
Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with isotretinoin capsules. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin capsules 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 isotretinoin capsules 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 isotretinoin capsules.5
Blood lipid determinations should be performed before Sotret is given and then at intervals until the lipid response to Sotret 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 Sotret therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Sotret therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).
Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 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 1.0 mg/kg/day, respectively, after normalization for total body surface area).
Impaired hearing has been reported in patients taking isotretinoin capsules; 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 Sotret treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).
Clinical hepatitis considered to be possibly or probably related to isotretinoin capsules 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 Sotret, the drug should be discontinued and the etiology further investigated.
Isotretinoin capsules have 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 isotretinoin capsules treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Sotret immediately (see ADVERSE REACTIONS: Gastrointestinal).
Effects of multiple courses of Sotret 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 isotretinoin 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 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 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 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13 to 18 years, who started a second course of isotretinoin 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 isotretinoin population. While causality to Sotret has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Sotret be given at the recommended doses for no longer than the recommended duration.
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