FDA label 63fe1606-e9c8-b3d9-e053-2991aa0acd8f

WARNINGS 1. Experienced Physician and Institution Patients with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to tretinoin capsules. Tretinoin capsules should therefore be administered only to patients with APL under the strict supervision of a physician who is experienced in the management of patients with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity, including respiratory compromise. Use of tretinoin capsules requires that the physician concludes that the possible benefit to the patient outweighs the following known adverse effects of the therapy. 2. Retinoic Acid-APL Syndrome About 25% of patients with APL treated with tretinoin capsules have experienced a syndrome called the retinoic acid-APL (RA-APL) 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. It has been observed with or without concomitant leukocytosis. Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several patients have expired with multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of tretinoin capsules. The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously administered every 12 hours for 3 days or until the resolution of symptoms) should be immediately initiated, irrespective of the leukocyte count. The majority of patients do not require termination of tretinoin capsules therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, temporary interruption of tretinoin capsules therapy should be considered. 3. Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Capsules Treatment During tretinoin capsules treatment about 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high WBC at diagnosis (>5x10 9 /L) have an increased risk of a further rapid increase in WBC counts. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, treatment with high-dose steroids should be initiated immediately. Some investigators routinely add chemotherapy to tretinoin capsules treatment in the case of patients presenting with a WBC count of >5x10 9 /L or in the case of a rapid increase in WBC count for patients leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consideration could be given to adding full-dose chemotherapy (including an anthracycline if not contraindicated) to the tretinoin capsules therapy on day 1 or 2 for patients presenting with a WBC count of >5x10 9 /L, or immediately, for patients presenting with a WBC count of <5x10 9 /L, if the WBC count reaches ≥6x10 9 /L by day 5, or ≥10x10 9 /L by day 10, or ≥15x10 9 /L by day 28. 4. Teratogenic Effects. Pregnancy Category D–see WARNINGS There is a high risk that a severely deformed infant will result if tretinoin capsules are administered during pregnancy. If, nonetheless, it is determined that tretinoin capsules represent the best available treatment for a pregnant woman or a woman of childbearing potential, it must be assured that the patient has received full information and warnings of the risk to the fetus if she were to be pregnant and of the risk of possible contraception failure and has been instructed in the need to use two reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method. Within 1 week prior to the institution of tretinoin capsules therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL. When possible, tretinoin capsules therapy should be delayed until a negative result from this test is obtained. When a delay is not possible, the patient should be placed on two reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of tretinoin capsules treatment.

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 capsules 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 capsules 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 capsules 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 capsules 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 capsules, a syndrome occurs which can be fatal (see boxed WARNINGS and ADVERSE REACTIONS ). Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Capsules Treatment See boxed WARNINGS . Pseudotumor Cerebri Retinoids, including tretinoin capsules, 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 ). 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 capsules if test results reach >5 times the upper limit of normal values. However, the majority of these abnormalities resolve without interruption of tretinoin capsules or after completion of treatment.

ADVERSE REACTIONS Virtually all patients experience some drug-related toxicity, especially head ache, 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 capsules. 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 capsules 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 capsules. 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 capsules may require high-dose steroids because of these symptoms. The majority of patients do not require termination of tretinoin capsules therapy during treatment of the syndrome. Body as a Whole General disorders related to tretinoin capsules 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 capsules. 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 Capsules 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. Skin Genital ulceration Miscellaneous Adverse Events Rare cases of vasculitis, predominantly involving the skin, have been reported.