FDA label 48843426-ed9d-86f2-e063-6294a90a425f

WARNINGS Pregnancy Category D – See Boxed WARNINGS Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys, and may be expected to cause fetal harm when administered to a pregnant woman. Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m 2 basis). There are no adequate and well-controlled studies in pregnant women. Although experience with humans administered tretinoin is extremely limited, increased spontaneous abortions and major human fetal abnormalities related to the use of other retinoids have been documented in humans. Reported defects include abnormalities of the CNS, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. Cases of IQ scores less than 85, with or without obvious CNS abnormalities, have also been reported. All fetuses exposed during pregnancy can be affected and at the present time there is no antepartum means of determining which fetuses are and are not affected. Effective contraception must be used by all females during tretinoin therapy and for 1 month following discontinuation of therapy. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Whenever contraception is required, it is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing or terminating the pregnancy. Patients Without the t(15;17) Translocation Initiation of therapy with tretinoin may be based on the morphological diagnosis of acute promyelocytic leukemia. Confirmation of the diagnosis of APL should be sought by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RARα fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to tretinoin has not been demonstrated; therefore, patients who lack the genetic marker should be considered for alternative treatment. Retinoic Acid-APL (RA-APL) Syndrome In up to 25% of patients with APL treated with tretinoin, a syndrome occurs which can be fatal (see boxed WARNINGS and ADVERSE REACTIONS ). Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Treatment See boxed WARNINGS . Pseudotumor Cerebri Retinoids, including tretinoin, have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in pediatric patients. The concomitant use of other agents known to cause pseudotumor cerebri/intracranial hypertension, such as tetracyclines, might increase the risk of this condition (see PRECAUTIONS: Drug Interactions ). [ 2 ] Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be evaluated for pseudotumor cerebri, and, if present, appropriate care should be instituted in concert with neurological assessment. Lipids Up to 60% of patients experienced hypercholesterolemia and/or hypertriglyceridemia, which were reversible upon completion of treatment. The clinical consequences of temporary elevation of triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Elevated Liver Function Test Results Elevated liver function test results occur in 50% to 60% of patients during treatment. Liver function test results should be carefully monitored during treatment and consideration be given to a temporary withdrawal of tretinoin if test results reach >5 times the upper limit of normal values. However, the majority of these abnormalities resolve without interruption of tretinoin or after completion of treatment.

ADVERSE REACTIONS Virtually all patients experience some drug-related toxicity, especially headache, fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require interruption of therapy. Some of the adverse events are common in patients with APL, including hemorrhage, infections, gastrointestinal hemorrhage, disseminated intravascular coagulation, pneumonia, septicemia, and cerebral hemorrhage. The following describes the adverse events, regardless of drug relationship, that were observed in patients treated with tretinoin. Typical Retinoid Toxicity The most frequently reported adverse events were similar to those described in patients taking high doses of vitamin A and included headache (86%), fever (83%), skin/mucous membrane dryness (77%), bone pain (77%), nausea/vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), increased sweating (20%), visual disturbances (17%), ocular disorders (17%), alopecia (14%), skin changes (14%), changed visual acuity (6%), bone inflammation (3%), visual field defects (3%). RA-APL Syndrome APL patients treated with tretinoin have experienced a potentially fatal syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension and has been observed with or without concomitant leukocytosis. Some patients have expired due to progressive hypoxemia and multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of tretinoin. The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first signs of the syndrome appear to reduce morbidity and mortality. Treatment with dexamethasone, 10 mg intravenously administered every 12 hours for 3 days or until resolution of symptoms, should be initiated without delay at the first suspicion of symptoms (one or more of the following: fever, dyspnea, weight gain, abnormal chest auscultatory findings or radiographic abnormalities). Sixty percent or more of patients treated with tretinoin may require high-dose steroids because of these symptoms. The majority of patients do not require termination of tretinoin therapy during treatment of the syndrome. Body as a Whole General disorders related to tretinoin administration and/or associated with APL included malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), myalgia (14%), flank pain (9%), cellulitis (8%), face edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders (6%), acidosis (3%), hypothermia (3%), ascites (3%). Respiratory System Disorders Respiratory system disorders were commonly reported in APL patients administered tretinoin. The majority of these events are symptoms of the RA-APL syndrome (see boxed WARNINGS ). Respiratory system adverse events included upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing (14%), lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), pulmonary edema (3%), larynx edema (3%), unspecified pulmonary disease (3%). Ear Disorders Ear disorders were consistently reported, with earache or feeling of fullness in the ears reported by 23% of the patients. Hearing loss and other unspecified auricular disorders were observed in 6% of patients, with infrequent (<1%) reports of irreversible hearing loss. Gastrointestinal Disorders GI disorders included GI hemorrhage (34%), abdominal pain (31%), other gastrointestinal disorders (26%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatosplenomegaly (9%), hepatitis (3%), ulcer (3%), unspecified liver disorder (3%). Cardiovascular and Heart Rate and Rhythm Disorders Arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy. Central and Peripheral Nervous System Disorders and Psychiatric Dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), cerebral hemorrhage (9%), intracranial hypertension (9%), agitation (9%), hallucination (6%) and for 3% of patients: abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, slow speech. Urinary System Disorders Renal insufficiency (11%), dysuria (9%), acute renal failure (3%), micturition frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%). Miscellaneous Adverse Events Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, Sweet’s syndrome, organomegaly, hypercalcemia, pancreatitis and myositis have been reported. Additional Adverse Reactions Reported With Tretinoin Cardiovascular Cases of thrombosis (both venous and arterial) involving various sites (eg, cerebrovascular accident, myocardial infarction, renal infarct) have been reported rarely (see PRECAUTIONS: General ). Hematologic Rare cases of thrombocytosis have been reported. [ 6 ] Skin Genital ulceration [ 7 ] Miscellaneous Adverse Events Rare cases of vasculitis, predominantly involving the skin, have been reported. [ 8 ] To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.