Although an effect of Zenatane on bone loss is not established, physicians should use caution when prescribing Zenatane to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. 

Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Zenatane or following cessation of therapy with Zenatane while involved in these activities. While causality to Zenatane has not been established, an effect must not be ruled out. 

Information for Patients 

See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS. 

  * Patients must be instructed to read the Medication Guide supplied as required by law when Zenatane is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE REMS patient educational materials. All patients must sign the Patient Enrollment Form for Patients who cannot get Pregnant.
  * Patients who can become pregnant must be instructed that they must not be pregnant when Zenatane therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Zenatane, while taking Zenatane, and for one month after Zenatane has been stopped, unless they commit to continuous abstinence from not having any sexual contact with a partner that could result in pregnancy. They should also sign a second Patient Enrollment Form for Patients who can get Pregnant prior to beginning Zenatane therapy. Patients who can become pregnant should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Zenatane prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS). 
  * Zenatane is found in the semen of male patients taking Zenatane, but the amount delivered to a a patient who can become pregnant would be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete, and two had other possible explanations for the defects observed.
  * 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 Zenatane treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment 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 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 Zenatane 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 Zenatane treatment 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 Zenatane therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Zenatane therapy.
  * Patients must be informed that some patients, while taking Zenatane or soon after stopping Zenatane, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking Zenatane have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on Zenatane becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take Zenatane. Some people have had other signs of depression while taking Zenatane. 
  * Patients must be informed that they must not share Zenatane with anyone else because of the risk of birth defects and other serious adverse events. 
  * Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant patient whose fetus must not be exposed to Zenatane.
  * Patients should be reminded to take Zenatane with a meal (see DOSAGEAND ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. 
  * Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. 
  * Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Zenatane therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS:  Skin and Appendages). 
  * Patients should be advised to avoid prolonged exposure to UV rays or sunlight. 
  * Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy. 
  * Patients should be informed that approximately 16% of patients treated with Zenatane in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Zenatane, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare post marketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests:  CPK). 
  * Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Zenatane developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Zenatane. Consideration should be given to discontinuation of Zenatane if any significant abnormality is found. 
  * Neutropenia and rare cases of agranulocytosis have been reported. Zenatane should be discontinued if clinically significant decreases in white cell counts occur. 
  * Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. Zenatane should be discontinued if clinically significant skin reactions occur. 



Hypersensitivity 

Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.