ADVERSE REACTIONS SECTION.

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 ToxicityThe most frequently reported adverse events were similar to those described in patients taking high doses of vitamin 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 SyndromeAPL patients treated with tretinoin capsules have experienced 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 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 WholeGeneral 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 DisordersRespiratory 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 DisordersEar 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 DisordersGI 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 DisordersArrhythmias (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 PsychiatricDizziness (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 DisordersRenal insufficiency (11%), dysuria (9%), acute renal failure (3%), micturition frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%).Miscellaneous Adverse EventsIsolated cases of erythema nodosum, basophilia and hyperhistaminemia, Sweets syndrome, organomegaly, hypercalcemia, pancreatitis and myositis have been reported.Additional Adverse Reactions Reported With Tretinoin CapsulesCardiovascularCases of thrombosis (both venous and arterial) involving various sites (eg, cerebrovascular accident, myocardial infarction, renal infarct) have been reported rarely (see PRECAUTIONS: General).HematologicRare cases of thrombocytosis have been reported.SkinGenital ulcerationMiscellaneous Adverse Events Rare cases of vasculitis, predominantly involving the skin, have been reported.

BOXED WARNING SECTION.

WARNINGS. 1. Experienced Physician and InstitutionPatients 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 physician who is experienced in the management of patients with acute leukemia and in facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain 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 SyndromeAbout 25% of patients with APL treated with tretinoin capsules have experienced 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 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 TreatmentDuring tretinoin capsules treatment about 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high WBC at diagnosis (>5x109/L) have an increased risk of further rapid increase in WBC counts. Rapidly evolving leukocytosis is associated with 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 WBC count of >5x109/L or in the case of rapid increase in WBC count for patients leukopenic at start of treatment, and have reported 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 or for patients presenting with WBC count of >5x109/L, or immediately, for patients presenting with WBC count of <5x109/L, if the WBC count reaches >=6x109/L by day 5, or >=10x109/L by day 10, or >=15x109/L by day 28.4. Teratogenic Effects. Pregnancy Category D-see WARNINGSThere is high risk that 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 pregnant woman or 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 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method.Within week prior to the institution of tretinoin capsules therapy, the patient should have blood or urine collected for serum or urine pregnancy test with sensitivity of at least 50 mIU/mL. When possible, tretinoin capsules therapy should be delayed until negative result from this test is obtained. When 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis and Impairment of Fertility. No long-term carcinogenicity studies with tretinoin have been conducted. In short-term carcinogenicity studies, tretinoin at dose of 30 mg/kg/day (about times the human dose on mg/m2 basis) was shown to increase the rate of diethylnitrosamine (DEN)-induced mouse liver adenomas and carcinomas. Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. twofold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to mg/kg/day (about 2/3 the human dose on mg/m2 basis). In 6-week toxicology study in dogs, minimal to marked testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about times the equivalent human dose in mg/m2).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Tretinoin is not cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.. Pharmacokinetics. Tretinoin activity is primarily due to the parent drug. In human pharmacokinetics studies, orally administered drug was well absorbed into the systemic circulation, with approximately two-thirds of the administered radiolabel recovered in the urine. The terminal elimination half-life of tretinoin following initial dosing is 0.5 to hours in patients with APL. There is evidence that tretinoin induces its own metabolism. Plasma tretinoin concentrations decrease on average to one-third of their day values during week of continuous therapy. Mean +- SD peak tretinoin concentrations decreased from 394 +- 89 to 138 +- 139 ng/mL, while area under the curve (AUC) values decreased from 537 +- 191 ng.h/mL to 249 +- 185 ng.h/mL during 45 mg/m2 daily dosing in APL patients. Increasing the dose to correct for this change has not increased response.AbsorptionA single 45 mg/m2 (~80 mg) oral dose to APL patients resulted in mean +- SD peak tretinoin concentration of 347 +- 266 ng/mL. Time to reach peak concentration was between and hours.DistributionThe apparent volume of distribution of tretinoin has not been determined. Tretinoin is greater than 95% bound in plasma, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL.MetabolismTretinoin metabolites have been identified in plasma and urine. Cytochrome P450 enzymes have been implicated in the oxidative metabolism of tretinoin. Metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. In APL patients, daily administration of 45 mg/m2 dose of tretinoin resulted in an approximately tenfold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide after to weeks of continuous dosing, when compared to baseline values.ExcretionStudies with radiolabeled drug have demonstrated that after the oral administration of 2.75 and 50 mg doses of tretinoin, greater than 90% of the radioactivity was recovered in the urine and feces. Based upon data from subjects, approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within days.Special PopulationsThe pharmacokinetics of tretinoin have not been separately evaluated in women, in members of different ethnic groups, or in individuals with renal or hepatic insufficiency.Drug-Drug Interactions In 13 patients who had received daily doses of tretinoin for consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) hour prior to the administration of the tretinoin dose on day 29 led to 72% increase (218 +- 224 vs 375 +- 285 ng.h/mL) in tretinoin mean plasma AUC. The precise cytochrome P450 enzymes involved in these interactions have not been specified; CYP 3A4, 2C8 and 2E have been implicated in various preliminary reports.. Clinical Studies. Tretinoin capsules have been investigated in 114 previously treated APL patients and in 67 previously untreated (de novo) patients in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). All patients received 45 mg/m2/day as divided oral dose for up to 90 days or 30 days beyond the day that CR was reached. Results are shown in the following table:MSKCCNCI Cohort 1NCI Cohort 2Relapsed N=20De Novo n=15Relapsed n=48De Novo n=14Relapsed n=46De Novo+n=38Complete Remission 16 (80%)11 (73%)24 (50%)5 (36%)24 (52%)26 (68%)Median Survival (Mo) 10.8 NR5.8 0.5 8.8 NRMedian Follow-up (Mo) 9.9 42.9 5.6 1.2 8.0 13.1RA-APL Syndrome (20%) (33%) 10 (21%) (43%) NA NANR Not Reached NA Not Available Including chemorefractory patients Including patients who received chemotherapy but failed to enter remissionThe median time to CR was between 40 and 50 days (range: to 120 days). Most patients in these studies received cytotoxic chemotherapy during the remission phase. These results compare to the 30% to 50% CR rate and <=6 month median survival reported for cytotoxic chemotherapy of APL in the treatment of relapse.Ten of 15 pediatric cases achieved CR (8 of 10 males and of females). There were insufficient patients of black, Hispanic or Asian derivation to estimate relative response rates in these groups, but responses were seen in each category. Responses were seen in of patients for whom cytogenetic analysis failed to detect the t(15;17) translocation typically seen in APL. The t(15;17) translocation results in the PML/RAR gene, which appears necessary for this disease. Molecular genetic studies were not conducted in these cases, but it is likely they represent cases with masked translocation giving rise to PML/RAR. Responses to tretinoin have not been observed in cases in which PML/RAR fusion has been shown to be absent.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Tretinoin Capsules are supplied as 10 mg capsules, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with TR with black ink on the yellow side. Supplied in high-density polyethylene, opaque bottles of 100 capsules with child-resistant closure.Bottle of 100..... NDC 10370-268-01Store at 20o to 25C (68o to 77F) [see USP controlled room temperature]. Protect from light.

CLINICAL STUDIES SECTION.

Clinical Studies. Tretinoin capsules have been investigated in 114 previously treated APL patients and in 67 previously untreated (de novo) patients in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). All patients received 45 mg/m2/day as divided oral dose for up to 90 days or 30 days beyond the day that CR was reached. Results are shown in the following table:MSKCCNCI Cohort 1NCI Cohort 2Relapsed N=20De Novo n=15Relapsed n=48De Novo n=14Relapsed n=46De Novo+n=38Complete Remission 16 (80%)11 (73%)24 (50%)5 (36%)24 (52%)26 (68%)Median Survival (Mo) 10.8 NR5.8 0.5 8.8 NRMedian Follow-up (Mo) 9.9 42.9 5.6 1.2 8.0 13.1RA-APL Syndrome (20%) (33%) 10 (21%) (43%) NA NANR Not Reached NA Not Available Including chemorefractory patients Including patients who received chemotherapy but failed to enter remissionThe median time to CR was between 40 and 50 days (range: to 120 days). Most patients in these studies received cytotoxic chemotherapy during the remission phase. These results compare to the 30% to 50% CR rate and <=6 month median survival reported for cytotoxic chemotherapy of APL in the treatment of relapse.Ten of 15 pediatric cases achieved CR (8 of 10 males and of females). There were insufficient patients of black, Hispanic or Asian derivation to estimate relative response rates in these groups, but responses were seen in each category. Responses were seen in of patients for whom cytogenetic analysis failed to detect the t(15;17) translocation typically seen in APL. The t(15;17) translocation results in the PML/RAR gene, which appears necessary for this disease. Molecular genetic studies were not conducted in these cases, but it is likely they represent cases with masked translocation giving rise to PML/RAR. Responses to tretinoin have not been observed in cases in which PML/RAR fusion has been shown to be absent.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Tretinoin capsules are contraindicated in patients with known hypersensitivity to tretinoin capsules, any of its components, or other retinoids. Tretinoin capsules should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule.

DESCRIPTION SECTION.

DESCRIPTION. Tretinoin Capsules are retinoid that induces maturation of acute promyelocytic leukemia (APL) cells in culture. It is available in 10 mg soft gelatin capsule for oral administration. Each capsule also contains butylated hydroxyanisole, edetate disodium, soybean oil, hydrogenated vegetable oils, medium chain triglycerides, soya lecithin, and yellow beeswax. The gelatin capsule shell contains gelatin, glycerin, yellow iron oxide, red iron oxide and titanium dioxide. Capsules are printed with edible black ink, which consist of propylene glycol, iron oxide black, polyvinyl acetate phthalate and polyethylene glycol 400.Chemically, tretinoin is all-trans retinoic acid and is related to retinol (Vitamin A). It is yellow to light orange crystalline powder with molecular weight of 300.44. The structural formula is as follows:. structural-formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The recommended dose is 45 mg/m2/day administered as two evenly divided doses until complete remission is documented. Therapy should be discontinued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.If after initiation of treatment of Tretinoin Capsules the presence of the t(15;17) translocation is not confirmed by cytogenetics and/or by polymerase chain reaction studies and the patient has not responded to tretinoin capsules, alternative therapy appropriate for acute myelogenous leukemia should be considered.Tretinoin Capsules are for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined. All patients should, therefore, receive standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy with tretinoin capsules, unless otherwise contraindicated.

DRUG INTERACTIONS SECTION.

Drug Interactions. Limited clinical data on potential drug interactions are available.Drugs Metabolized By the Hepatic P450 SystemAs tretinoin capsules are metabolized by the hepatic P450 system, there is potential for alteration of pharmacokinetics parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and cyclosporine. To date there are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of tretinoin capsules.Agents Known to Cause Pseudotumor Cerebri/Intracranial Hypertension (Such as Tetracyclines)Tretinoin capsules may cause pseudotumor cerebri/intracranial hypertension. Concomitant administration of tretinoin capsules and agents known to cause pseudotumor cerebri/intracranial hypertension as well might increase the risk of this condition (see WARNINGS).Vitamin AAs with other retinoids, tretinoin capsules must not be administered in combination with vitamin because symptoms of hypervitaminosis could be aggravated.Anti-fibrinolytic Agents (Such as Tranexamic Acid, Aminocaproic Acid, or Aprotinin)Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with tretinoin capsules and anti-fibrinolytic agents. Therefore, caution should be exercised when administering tretinoin capsules concomitantly with these agents (see PRECAUTIONS: General).Effect of FoodNo data on the effect of food on the absorption of tretinoin capsules are available. The absorption of retinoids as class has been shown to be enhanced when taken together with food.

GENERAL PRECAUTIONS SECTION.

General. Tretinoin capsules have potentially significant toxic side effects in APL patients. Patients undergoing therapy should be closely observed for signs of respiratory compromise and/or leukocytosis (see boxed WARNINGS). Supportive care appropriate for APL patients, eg, prophylaxis for bleeding, prompt therapy for infection, should be maintained during therapy with tretinoin capsules.There is risk of thrombosis (both venous and arterial) which may involve any organ system, during the first month of treatment (see ADVERSE REACTIONS). Therefore, caution should be exercised when treating patients with the combination of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin (see Drug Interactions).The ability to drive or operate machinery might be impaired in patients treated with tretinoin capsules, particularly if they are experiencing dizziness or severe headache.Microdosed progesterone preparations (minipill) may be an inadequate method of contraception during treatment with tretinoin capsules.

GERIATRIC USE SECTION.

Geriatric Use. Of the total number of subjects in clinical studies of tretinoin capsules, 21.4% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Tretinoin capsules are indicated for the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RAR gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated. Tretinoin capsules are for the induction of remission only. The optimal consolidation or maintenance regimens have not been defined, but all patients should receive an accepted form of remission consolidation and/or maintenance therapy for APL after completion of induction therapy with tretinoin capsules.

LABORATORY TESTS SECTION.

Laboratory Tests. The patients hematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently.

MECHANISM OF ACTION SECTION.

Mechanism of Action. Tretinoin is not cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

NURSING MOTHERS SECTION.

Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from tretinoin capsules in nursing infants, mothers should discontinue nursing prior to taking this drug.

OVERDOSAGE SECTION.

OVERDOSAGE. In case of overdose with Tretinoin, reversible signs of hypervitaminosis (headache, nausea, vomiting, mucocutaneous symptoms) can appear. The maximal tolerated dose in patients with myelodysplastic syndrome or solid tumors was 195 mg/m2/day. The maximal tolerated dose in pediatric patients was lower at 60 mg/m2/day. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have quickly resolved without apparent residual effects.There is no specific treatment in the case of an overdose; however, it is important that the patient be treated in special hematological unit.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL. Tretinoin CapsulesNDC 10370-268-0110 mg100 count. bottle-label.

PATIENT MEDICATION INFORMATION SECTION.

Patient Information. WARNING TO FEMALE PATIENTSYOU MUST NOT BECOME PREGNANT DURING TRETINOIN TREATMENT.There is an extremely high risk that deformed baby will result if you become pregnant while taking tretinoin capsules, in any amount, for even short periods of time. Potentially any exposed fetuses can be affected. There is also an increased risk of miscarriage. Premature births may also occur.Effective contraception (birth control) should be discussed with your doctor. Two forms of reliable contraception must be used during therapy, and must be continued for one month after tretinoin treatment has stopped. If directed by your doctor, two forms of reliable contraception must also be used simultaneously for at least one month before beginning therapy. It is recommended that you either abstain from sexual intercourse or use two reliable kinds of birth control at the same time. Birth control must be used even if you think you cannot become pregnant, unless you have had hysterectomy.If you are pregnant or become pregnant while on tretinoin therapy or during the month after treatment has stopped, immediately contact your doctor to discuss the desirability of continuing the pregnancy.YOU MUST NOT TAKE TRETINOIN CAPSULES IF YOU ARE NURSING MOTHER.Tretinoin capsules should not be taken by nursing mothers since it is not known whether it is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tretinoin, mothers should discontinue nursing prior to taking this drug.General guidelines for taking your medication...Call your doctor if you have any questions or experience any severe or troubling symptoms.Tretinoin capsules do not need to be refrigerated. However, do not expose the capsules to sunlight or excessive heat.Be sure to take your medication as prescribed by your doctor. Read the prescription label on the package carefully. If there is anything you dont understand, ask your doctor or pharmacist to explain it to you.Keep tretinoin capsules and all medications out of the reach of children.Store at 68o to 77oF (20 to 25C) Protect from light.Manufactured for:Par PharmaceuticalChestnut Ridge, NY 10977Made in FranceRevised: 01/17 OS268A-01-82-02. Call your doctor if you have any questions or experience any severe or troubling symptoms.. Tretinoin capsules do not need to be refrigerated. However, do not expose the capsules to sunlight or excessive heat.. Be sure to take your medication as prescribed by your doctor. Read the prescription label on the package carefully. If there is anything you dont understand, ask your doctor or pharmacist to explain it to you.. Keep tretinoin capsules and all medications out of the reach of children.

PEDIATRIC USE SECTION.

Pediatric Use. There are limited clinical data on the pediatric use of tretinoin capsules. Of 15 pediatric patients (age range: to 16 years) treated with tretinoin capsules, the incidence of complete remission was 67%. Safety and effectiveness in pediatric patients below the age of year have not been established. Some pediatric patients experience severe headache and pseudotumor cerebri, requiring analgesic treatment and lumbar puncture for relief. Increased caution is recommended in the treatment of pediatric patients. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable toxicity; however, the efficacy and safety of tretinoin capsules at doses lower than 45 mg/m2/day have not been evaluated in the pediatric population.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Tretinoin activity is primarily due to the parent drug. In human pharmacokinetics studies, orally administered drug was well absorbed into the systemic circulation, with approximately two-thirds of the administered radiolabel recovered in the urine. The terminal elimination half-life of tretinoin following initial dosing is 0.5 to hours in patients with APL. There is evidence that tretinoin induces its own metabolism. Plasma tretinoin concentrations decrease on average to one-third of their day values during week of continuous therapy. Mean +- SD peak tretinoin concentrations decreased from 394 +- 89 to 138 +- 139 ng/mL, while area under the curve (AUC) values decreased from 537 +- 191 ng.h/mL to 249 +- 185 ng.h/mL during 45 mg/m2 daily dosing in APL patients. Increasing the dose to correct for this change has not increased response.AbsorptionA single 45 mg/m2 (~80 mg) oral dose to APL patients resulted in mean +- SD peak tretinoin concentration of 347 +- 266 ng/mL. Time to reach peak concentration was between and hours.DistributionThe apparent volume of distribution of tretinoin has not been determined. Tretinoin is greater than 95% bound in plasma, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL.MetabolismTretinoin metabolites have been identified in plasma and urine. Cytochrome P450 enzymes have been implicated in the oxidative metabolism of tretinoin. Metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. In APL patients, daily administration of 45 mg/m2 dose of tretinoin resulted in an approximately tenfold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide after to weeks of continuous dosing, when compared to baseline values.ExcretionStudies with radiolabeled drug have demonstrated that after the oral administration of 2.75 and 50 mg doses of tretinoin, greater than 90% of the radioactivity was recovered in the urine and feces. Based upon data from subjects, approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within days.Special PopulationsThe pharmacokinetics of tretinoin have not been separately evaluated in women, in members of different ethnic groups, or in individuals with renal or hepatic insufficiency.Drug-Drug Interactions In 13 patients who had received daily doses of tretinoin for consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) hour prior to the administration of the tretinoin dose on day 29 led to 72% increase (218 +- 224 vs 375 +- 285 ng.h/mL) in tretinoin mean plasma AUC. The precise cytochrome P450 enzymes involved in these interactions have not been specified; CYP 3A4, 2C8 and 2E have been implicated in various preliminary reports.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Tretinoin capsules have potentially significant toxic side effects in APL patients. Patients undergoing therapy should be closely observed for signs of respiratory compromise and/or leukocytosis (see boxed WARNINGS). Supportive care appropriate for APL patients, eg, prophylaxis for bleeding, prompt therapy for infection, should be maintained during therapy with tretinoin capsules.There is risk of thrombosis (both venous and arterial) which may involve any organ system, during the first month of treatment (see ADVERSE REACTIONS). Therefore, caution should be exercised when treating patients with the combination of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin (see Drug Interactions).The ability to drive or operate machinery might be impaired in patients treated with tretinoin capsules, particularly if they are experiencing dizziness or severe headache.Microdosed progesterone preparations (minipill) may be an inadequate method of contraception during treatment with tretinoin capsules.. Laboratory Tests. The patients hematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently.. Drug Interactions. Limited clinical data on potential drug interactions are available.Drugs Metabolized By the Hepatic P450 SystemAs tretinoin capsules are metabolized by the hepatic P450 system, there is potential for alteration of pharmacokinetics parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and cyclosporine. To date there are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of tretinoin capsules.Agents Known to Cause Pseudotumor Cerebri/Intracranial Hypertension (Such as Tetracyclines)Tretinoin capsules may cause pseudotumor cerebri/intracranial hypertension. Concomitant administration of tretinoin capsules and agents known to cause pseudotumor cerebri/intracranial hypertension as well might increase the risk of this condition (see WARNINGS).Vitamin AAs with other retinoids, tretinoin capsules must not be administered in combination with vitamin because symptoms of hypervitaminosis could be aggravated.Anti-fibrinolytic Agents (Such as Tranexamic Acid, Aminocaproic Acid, or Aprotinin)Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with tretinoin capsules and anti-fibrinolytic agents. Therefore, caution should be exercised when administering tretinoin capsules concomitantly with these agents (see PRECAUTIONS: General).Effect of FoodNo data on the effect of food on the absorption of tretinoin capsules are available. The absorption of retinoids as class has been shown to be enhanced when taken together with food.. Carcinogenesis, Mutagenesis and Impairment of Fertility. No long-term carcinogenicity studies with tretinoin have been conducted. In short-term carcinogenicity studies, tretinoin at dose of 30 mg/kg/day (about times the human dose on mg/m2 basis) was shown to increase the rate of diethylnitrosamine (DEN)-induced mouse liver adenomas and carcinomas. Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. twofold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to mg/kg/day (about 2/3 the human dose on mg/m2 basis). In 6-week toxicology study in dogs, minimal to marked testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about times the equivalent human dose in mg/m2).. Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from tretinoin capsules in nursing infants, mothers should discontinue nursing prior to taking this drug.. Pediatric Use. There are limited clinical data on the pediatric use of tretinoin capsules. Of 15 pediatric patients (age range: to 16 years) treated with tretinoin capsules, the incidence of complete remission was 67%. Safety and effectiveness in pediatric patients below the age of year have not been established. Some pediatric patients experience severe headache and pseudotumor cerebri, requiring analgesic treatment and lumbar puncture for relief. Increased caution is recommended in the treatment of pediatric patients. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable toxicity; however, the efficacy and safety of tretinoin capsules at doses lower than 45 mg/m2/day have not been evaluated in the pediatric population.. Geriatric Use. Of the total number of subjects in clinical studies of tretinoin capsules, 21.4% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS SECTION.

WARNINGS. Pregnancy Category - 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 pregnant woman. Tretinoin causes fetal resorptions and 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, mg/kg/day in rats, mg/kg/day in hamsters, and at dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and times the human dose, respectively, on mg/m2 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 month following discontinuation of therapy. Contraception must be used even when there is history of infertility or menopause, unless 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) TranslocationInitiation 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/RAR 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) SyndromeIn up to 25% of patients with APL treated with tretinoin capsules, syndrome occurs which can be fatal (see boxed WARNINGS and ADVERSE REACTIONS).Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Capsules TreatmentSee boxed WARNINGS .Pseudotumor CerebriRetinoids, 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.LipidsUp 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 ResultsElevated 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 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.

LABOR & DELIVERY SECTION.

8.2 Lactation. There are no data on the presence of tretinoin in human milk, the effects on the breastfeed child or the effects on milk production. Because of the potential for serious adverse reactions from tretinoin capsules in breastfed infants, advise women not to breastfed during treatment with tretinoin capsules and for week after the last dose.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules: 10 mg, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with TR with black ink on the yellow side.. Capsules: 10 mg.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Use in Females and Males of Reproductive Potential. Tretinoin capsules can cause embryo-fetal loss and malformations when administered to pregnant woman [see Use in Specific Populations (8.1 )].Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have negative pregnancy test within week prior to initiating tretinoin capsules with sensitivity of at least 50 mIU/mL.ContraceptionFemalesAdvise females of reproductive potential to abstain continuously from sexual intercourse or to use two effective methods of contraception. Counsel patients to use two effective methods of contraception during treatment with tretinoin capsules and for month after the last dose. Two methods of effective contraception is indicated even where there has been history of infertility, unless due to hysterectomy. Refer females of reproductive potential to qualified provider of contraceptive methods, if needed.MalesAdvise males with female partners of reproductive potential to use effective contraception during and after treatment with tretinoin capsules and for week after the last dose.InfertilityMalesBased on testicular toxicities observed in dogs, tretinoin capsules may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of effect on fertility is unknown.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Embryo-Fetal ToxicityAdvise female patients of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to use methods of effective contraception during treatment with tretinoin capsules and for month after the last dose [see Use in Specific Populations (8.3)].Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for week after the last dose [see Use in Specific Populations (8.3)].Differentiation SyndromeAdvise patients that tretinoin capsules can cause differentiation syndrome. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [see Warnings and Precautions (5.2)].Patients Without t(15;17) Translocation or PML/RAR FusionAdvise patients that tretinoin capsules are not recommended for use in patients without t(15;17) translocation or PML/RAR fusion [see Warnings and Precautions (5.3)].LeukocytosisInform patients that rapidly evolving leukocytosis, which can be life-threatening, can occur during treatment with tretinoin capsules [see Warnings and Precautions (5.4)].Intracranial HypertensionAdvise patients that tretinoin capsules can cause intracranial hypertension, especially in pediatric patients. Ask patients to immediately report any symptoms suggestive of intracranial hypertension, such as headache, nausea, vomiting, and visual disturbances [see Warnings and Precautions (5.5)].Lipid AbnormalitiesInform patients that hypercholesterolemia and/or hypertriglyceridemia can occur during treatment with tretinoin capsules. Advise patients on the need for monitoring fasting triglycerides and cholesterol [see Warnings and Precautions (5.6)].HepatotoxicityAdvise patients that tretinoin capsules can cause elevated liver function tests. Advise patients on the need for monitoring of liver function tests [see Warnings and Precautions (5.7)].Thromboembolic Events Inform patients that venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct can occur during treatment with tretinoin capsules [see Warnings and Precautions (5.8)].LactationAdvise women not to breastfeed during treatment with tretinoin capsules and for week after the last dose [see Use in Specific Populations (8.2)]. Administration InstructionsAdvise patients to swallow tretinoin capsules whole with water. Advise patients not to chew, dissolve, or open capsules. Advise patients not to take missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. Advise patients that if vomiting occurs after tretinoin capsules administration, that they should not take an additional dose, but continue with the next scheduled dose [see Dosage and Administration (2.2)].Effects on Ability to Drive and Use MachinesAdvise patients that the ability to drive or operate machinery might be impaired when treated with tretinoin capsules, particularly if patients are experiencing dizziness or severe headache.Manufactured for:Par Pharmaceutical Chestnut Ridge, NY 10977Made in FranceRevised: 03/2023.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No 2-year carcinogenicity studies in rodents have been conducted with tretinoin. In carcinogenicity study, female B5D2F1 mice pretreated with carcinogen diethylnitrosamine (DEN, intraperitoneal 50 mg/kg and 100 mg/kg) received dietary supplement of all-trans-retinoic acid (tretinoin) for 12 months. Tretinoin at dose of 30 mg/kg/day in the diet (about times the human dose on mg/m2 basis) was shown to increase the rate of DEN-induced mouse hepatocellular carcinomas. Tretinoin in combination with 50 mg/kg of DEN also increased the incidence of hemangiomas and hemangiosarcomas.Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. 2-fold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to mg/kg/day (about 2/3 the human dose on mg/m2 basis). In 6-week toxicology study in dogs, testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about times the equivalent human dose in mg/m2).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tretinoin capsules have not been characterized.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], tretinoin capsules can cause embryo-fetal loss and malformations when administered to pregnant woman. Tretinoin capsules are retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin was teratogenic and embryotoxic in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on mg/m2 basis (see Data). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In theU.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataHuman Data Trentoin capsules are retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids have been documented in humans. Reported malformations include abnormalities of the central nervous system, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero.Animal DataTretinoin causes fetal resorptions and 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, mg/kg/day in rats, mg/kg/day in hamsters, and at dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and times the human dose, respectively, on mg/m2 basis).

SPL UNCLASSIFIED SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Acute Promyelocytic LeukemiaThe safety of tretinoin capsules was evaluated in patients with APL who received tretinoin capsules at dose of 22.5 mg/m2 orally twice daily [see Clinical Studies (14)].The most common adverse reactions (>=30%) were headache, fever, skin/mucous membrane dryness, bone pain, malaise, shivering, upper respiratory tract disorders, dyspnea, hemorrhage, infections, nausea/vomiting, rash, peripheral edema, leukocytosis, pain, gastrointestinal hemorrhage, chest discomfort, abdominal pain.Table summarizes the adverse reactions for patients with APL.Table 1. Adverse Reactions (>= 10%) Occurring in Patients with APL Who Received Tretinoin CapsulesAdverse Reaction Tretinoin Capsules All Grades (%) Nervous system disorders Headache 86 Dizziness 20 Paresthesias 17 Anxiety 17 Insomnia 14 Depression 14 Confusion 11 General disorders Fever 83 Skin/mucous membrane dryness 77 Malaise 66 Shivering 63 Peripheral edema 52 Pain 37 Chest discomfort 32 Edema 29 Mucositis 26 Weight increase 23 Anorexia 17 Weight decrease 17 Musculoskeletal and connective tissue disorders Bone pain 77 Myalgia 14 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders 63 Dyspnea 60 Respiratory insufficiency 26 Pleural effusion 20 Rales 14 Expiratory wheezing 14 Pneumonia 14 Vascular disorders Hemorrhage 60 Gastrointestinal hemorrhage 34 Flushing 23 Hypotension 14 Hypertension 11 Phlebitis 11 Infections and infestations Infections 58 Gastrointestinal disorders Nausea/vomiting 57 Abdominal pain 31 Other gastrointestinal disorders 26 Diarrhea 23 Constipation 17 Dyspepsia 14 Abdominal distention 11 Skin and subcutaneous tissue disorders Rash 54 Pruritus 20 Increased sweating 20 Alopecia 14 Skin changes 14 Blood and lymphatic system disorders Leukocytosis 49 Differentiation syndrome1 26 Disseminated intravascular coagulation 26 Ear and labyrinth disorders Earache or feeling of fullness in the ears 23 Cardiac disorders Arrhythmias 23 Eye disorders Visual disturbances 17 Ocular disorders 17 Renal and urinary disorders Renal insufficiency 111Differentiation syndrome can be associated with other commonly reported eventssuch as fever, leukocytosis, dyspnea, pneumonia, pleural effusion, pericardial effusion,hypotension, edema, weight gain, and renal failure.Adverse reactions that occurred in <10% of patients who received tretinoin capsules include:Hepatobiliary disorders: Hepatosplenomegaly (9%), hepatitis (3%), unspecified liver disorder (3%).Musculoskeletal and connective tissue disorders: Flank pain (9%), bone inflammation (3%).Nervous system disorders: Agitation (9%), cerebral hemorrhage (9%), intracranial hypertension (9%), hallucination (6%), 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, stroke, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, and slow speech (3% each).Renal and urinary disorders: Dysuria (9%), acute renal failure, micturition frequency, renal tubular necrosis, and enlarged prostate (3% each).Respiratory, thoracic and mediastinal disorders: Lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma, pulmonary edema, larynx edema, and unspecified pulmonary disease (3% each).Infections and infestations: Cellulitis (8%).Blood and lymphatic system disorders: Lymph disorders (6%).Cardiovascular disorders: Cardiac failure (6%), cardiac arrest, myocardial infarction, enlarged heart, heart murmur, myocarditis, pericarditis, and secondary cardiomyopathy (3% each).Ear and labyrinth disorders: Hearing loss and other unspecified auricular disorders (6%), irreversible hearing loss (<1%).General disorders: Face edema (6%), pallor (6%), hypothermia (3%).Metabolism and nutrition disorders: Fluid imbalance (6%), acidosis (3%).Eye disorders: Changed visual acuity (6%), visual field defects (3%).Gastrointestinal disorders: Ascites, ulcer (3% each).Vascular disorders: Ischemia and pulmonary hypertension (3% each).. Hepatobiliary disorders: Hepatosplenomegaly (9%), hepatitis (3%), unspecified liver disorder (3%).. Musculoskeletal and connective tissue disorders: Flank pain (9%), bone inflammation (3%).. Nervous system disorders: Agitation (9%), cerebral hemorrhage (9%), intracranial hypertension (9%), hallucination (6%), 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, stroke, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, and slow speech (3% each).. Renal and urinary disorders: Dysuria (9%), acute renal failure, micturition frequency, renal tubular necrosis, and enlarged prostate (3% each).. Respiratory, thoracic and mediastinal disorders: Lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma, pulmonary edema, larynx edema, and unspecified pulmonary disease (3% each).. Infections and infestations: Cellulitis (8%).. Blood and lymphatic system disorders: Lymph disorders (6%).. Cardiovascular disorders: Cardiac failure (6%), cardiac arrest, myocardial infarction, enlarged heart, heart murmur, myocarditis, pericarditis, and secondary cardiomyopathy (3% each).. Ear and labyrinth disorders: Hearing loss and other unspecified auricular disorders (6%), irreversible hearing loss (<1%).. General disorders: Face edema (6%), pallor (6%), hypothermia (3%).. Metabolism and nutrition disorders: Fluid imbalance (6%), acidosis (3%).. Eye disorders: Changed visual acuity (6%), visual field defects (3%).. Gastrointestinal disorders: Ascites, ulcer (3% each).. Vascular disorders: Ischemia and pulmonary hypertension (3% each).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], tretinoin capsules can cause embryo-fetal loss and malformations when administered to pregnant woman. Tretinoin capsules are retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin was teratogenic and embryotoxic in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on mg/m2 basis (see Data). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In theU.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataHuman Data Trentoin capsules are retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids have been documented in humans. Reported malformations include abnormalities of the central nervous system, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero.Animal DataTretinoin causes fetal resorptions and 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, mg/kg/day in rats, mg/kg/day in hamsters, and at dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and times the human dose, respectively, on mg/m2 basis).. 8.2 Lactation. There are no data on the presence of tretinoin in human milk, the effects on the breastfeed child or the effects on milk production. Because of the potential for serious adverse reactions from tretinoin capsules in breastfed infants, advise women not to breastfed during treatment with tretinoin capsules and for week after the last dose.. 8.3 Use in Females and Males of Reproductive Potential. Tretinoin capsules can cause embryo-fetal loss and malformations when administered to pregnant woman [see Use in Specific Populations (8.1 )].Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have negative pregnancy test within week prior to initiating tretinoin capsules with sensitivity of at least 50 mIU/mL.ContraceptionFemalesAdvise females of reproductive potential to abstain continuously from sexual intercourse or to use two effective methods of contraception. Counsel patients to use two effective methods of contraception during treatment with tretinoin capsules and for month after the last dose. Two methods of effective contraception is indicated even where there has been history of infertility, unless due to hysterectomy. Refer females of reproductive potential to qualified provider of contraceptive methods, if needed.MalesAdvise males with female partners of reproductive potential to use effective contraception during and after treatment with tretinoin capsules and for week after the last dose.InfertilityMalesBased on testicular toxicities observed in dogs, tretinoin capsules may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of effect on fertility is unknown.. 8.4 Pediatric Use. Safety and effectiveness of tretinoin capsules have been established in pediatric patients year of age and older and the information on this use is discussed throughout the labeling. The maximum tolerated dose is lower in pediatric patients compared to adults. Some pediatric patients experience severe headache and intracranial hypertension, which required management with an analgesic and lumbar puncture. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable adverse reactions.Safety and effectiveness in pediatric patients less than year of age have not been established.. 8.5 Geriatric Use. Across clinical studies of tretinoin capsules, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

VETERINARY INDICATIONS SECTION.

5.7 Hepatotoxicity. Elevated liver function test results occurred in 50% to 60% of patients during treatment with tretinoin capsules. Most of these abnormalities resolved without interruption of tretinoin capsules or after completion of treatment. Monitor liver function test at baseline and during treatment as clinically indicated. Consider withholding tretinoin capsules if liver function test results increase to greater than times the upper limit of normal values until resolution.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Patients Without t(15;17) Translocation or PML/RAR Fusion: tretinoin capsules may be initiated based on morphological diagnosis of APL. Confirm diagnosis by detection of the t(15;17) translocation or PML/RAR fusion. (5.3)Leukocytosis: Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated. (5.4)Intracranial Hypertension: Tretinoin capsules has been associated with benign intracranial hypertension, especially in pediatric patients. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. (5.5)Lipid Abnormalities: Patients experienced hypercholesterolemia and/or hypertriglyceridemia, which may be reversible upon completion of treatment. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment. (5.6)Hepatotoxicity: Monitor liver function test results at baseline and during treatment as clinically indicated. (5.7)Thromboembolic Events: Venous and arterial events have been reported; these events may occur during the first month of treatment with tretinoin capsules. (5.8, 7.4) Patients Without t(15;17) Translocation or PML/RAR Fusion: tretinoin capsules may be initiated based on morphological diagnosis of APL. Confirm diagnosis by detection of the t(15;17) translocation or PML/RAR fusion. (5.3). Leukocytosis: Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated. (5.4). Intracranial Hypertension: Tretinoin capsules has been associated with benign intracranial hypertension, especially in pediatric patients. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. (5.5). Lipid Abnormalities: Patients experienced hypercholesterolemia and/or hypertriglyceridemia, which may be reversible upon completion of treatment. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment. (5.6). Hepatotoxicity: Monitor liver function test results at baseline and during treatment as clinically indicated. (5.7). Thromboembolic Events: Venous and arterial events have been reported; these events may occur during the first month of treatment with tretinoin capsules. (5.8, 7.4). 5.1 Embryo-Fetal Toxicity. Tretinoin capsules can cause embryo-fetal loss and malformations when administered to pregnant woman. Tretinoin capsules are retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on mg/m2 basis.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective methods of contraception during treatment with tretinoin capsules and for month following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for week following the last dose [see Use in Specific Populations (8.1, 8.3)].. 5.2 Differentiation Syndrome. Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules [see Adverse Reactions (6.1)]. Symptoms include 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 been accompanied by impaired myocardial contractility and episodic hypotension and it has been observed with or without concomitant leukocytosis. This syndrome generally occurs during the first month of treatment, as early as following the first dose. Endotracheal intubation and mechanical ventilation were required in some cases due to progressive hypoxemia and several patients have died with multi-organ failure. At the first signs or symptoms of this syndrome, immediately administer dexamethasone 10 mg intravenously every 12 hours until signs and symptoms have abated for at least days and initiate hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe differentiation syndrome until resolution [see Adverse Reactions (6.1)].. 5.3 Patients Without t(15;17) Translocation or PML/RAR Fusion. Tretinoin capsules may be initiated based on the morphological diagnosis of acute promyelocytic leukemia (APL). Confirm the diagnosis of APL by detection of the t(15;17) translocation using cytogenetic studies or PML/RAR fusion using molecular diagnostic techniques. Tretinoin capsules not recommended for use in patients without these genetic markers [see Indications and Usage (1)]. 5.4 Leukocytosis. Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules [see Adverse Reactions (6.1)]. Patients who present with baseline white blood cell count (WBC) 5 109/L have an increased risk. Patients who receive chemotherapy with tretinoin capsules may be at reduced risk. Rapidly evolving leukocytosis is associated with higher risk of life-threatening complications. Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated.. 5.5 Intracranial Hypertension. Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Evaluate patients with these symptoms for intracranial hypertension, and, if present, institute appropriate care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate.The concomitant use of other products (e.g., tetracyclines) that can cause intracranial hypertension may increase the risk. Avoid concomitant use of tretinoin capsules with other products that can cause intracranial hypertension [see Drug Interactions (7.2)].. 5.6 Lipid Abnormalities. Hypercholesterolemia and/or hypertriglyceridemia has occurred in up to 60% of patients who received tretinoin capsules. These changes may be reversible upon completion of treatment. The clinical consequences of increased 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.Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment.. 5.7 Hepatotoxicity. Elevated liver function test results occurred in 50% to 60% of patients during treatment with tretinoin capsules. Most of these abnormalities resolved without interruption of tretinoin capsules or after completion of treatment. Monitor liver function test at baseline and during treatment as clinically indicated. Consider withholding tretinoin capsules if liver function test results increase to greater than times the upper limit of normal values until resolution.. 5.8 Thromboembolic Events. Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules [see Adverse Reactions (6.2)]. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk. Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin [see Drug Interactions (7.4)].