Tretinoin

1 INDICATIONS AND USAGE Tretinoin capsules are indicated for the induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL) characterized by the presence of the t(15;17) translocation or PML/RARα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. Tretinoin capsules are a retinoid indicated for induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL), characterized by presence of t(15;17) translocation or presence of PML/RARα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission. ( 2.2 ) • Discontinue 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. ( 2.2 ) 2.1 Important Safety Information Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules [see Use in Specific Populations (8.3)] . 2.2 Recommended Dosage The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission is documented. Discontinue tretinoin capsules 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARα fusion has not been identified [see Warnings and Precautions (5.3)] . Take tretinoin capsules with a meal. Swallow tretinoin capsules whole with water. Do not chew, dissolve, or open capsule. Do not take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. If vomiting occurs after tretinoin capsules administration, do not take an additional dose, but continue with the next scheduled dose.

2.1 Important Safety Information Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules [see Use in Specific Populations (8.3)] .

2.2 Recommended Dosage The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission is documented. Discontinue tretinoin capsules 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARα fusion has not been identified [see Warnings and Precautions (5.3)] . Take tretinoin capsules with a meal. Swallow tretinoin capsules whole with water. Do not chew, dissolve, or open capsule. Do not take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. If vomiting occurs after tretinoin capsules administration, do not take an additional dose, but continue with the next scheduled dose.

3 DOSAGE FORMS AND STRENGTHS Tretinoin Capsules are available as: 10 mg: Pink, oval, soft-gelatin capsules printed with black ‘T 10’ filled with yellow to orange, opaque, viscous suspension. Capsules: 10 mg ( 3 )

4 CONTRAINDICATIONS Tretinoin capsules are contraindicated in patients with a known hypersensitivity to tretinoin capsules, any of its components, or other retinoids. Reactions have included rash, pruritus, face edema, and dyspnea. [see Adverse Reactions ( 6.1 )]. Hypersensitivity to tretinoin capsules, any of its components, or other retinoids (4)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Differentiation Syndrome [see Warnings and Precautions ( 5.2 )] • Leukocytosis [see Warnings and Precautions ( 5.4 )] • Intracranial hypertension [see Warnings and Precautions ( 5.5 )] • Lipid abnormalities [see Warnings and Precautions ( 5.6 )] • Hepatotoxicity [see Warnings and Precautions ( 5.7 )] • Thromboembolic events [see Warnings and Precautions ( 5.8 )] The most common adverse reactions (≥30%) are 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 ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Leukemia The safety of tretinoin capsules was evaluated in patients with APL who received tretinoin capsules at a dose of 22.5 mg/m 2 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 1 summarizes the adverse reactions for patients with APL. Table 1. Adverse Reactions (≥ 10%) Occurring in Patients with APL Who Received Tretinoin Capsules Adverse 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 syndrome 1 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 11 1 Differentiation syndrome can be associated with other commonly reported events such 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, ap …

7 DRUG INTERACTIONS • Strong CYP3A Inhibitors and Inducers: Avoid coadministration with strong CYP3A inhibitors and inducers. ( 7.1 ) • Concomitant Use of Products Known to Cause Intracranial Hypertension : Avoid concomitant use with other products that can cause intracranial hypertension. ( 7.2 ) • Vitamin A : Avoid concomitant use with vitamin A. ( 7.3 ) • Anti-fibrinolytic Agents : Avoid concomitant use with anti-fibrinolytic agents. ( 7.4 ) 7.1 Effects of Other Drugs on Tretinoin Capsules Strong or moderate CYP3A Inhibitors Avoid concomitant use of tretinoin capsules with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin capsules more frequently for adverse reactions. Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Strong CYP3A Inducers Concomitant use of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible. 7.2 Concomitant Use of Products Known to Cause Intracranial Hypertension Intracranial hypertension has been reported in patients who received tretinoin capsules and concomitant use of other products that can cause intracranial hypertension, such as tetracyclines, may increase the risk. Avoid concomitant use of tretinoin capsules with other products agents that can cause intracranial hypertension [see Warnings and Precautions ( 5.5 )] . 7.3 Vitamin A The concomitant use of vitamin A with tretinoin capsules may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin capsules with vitamin A. 7.4 Anti-fibrinolytic Agents Fatal thrombotic complications have been reported in patients who have received tretinoin capsules and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin capsules with anti-fibrinolytic agents [see Warnings and Precautions ( 5.8 )].

7.1 Effects of Other Drugs on Tretinoin Capsules Strong or moderate CYP3A Inhibitors Avoid concomitant use of tretinoin capsules with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin capsules more frequently for adverse reactions. Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Strong CYP3A Inducers Concomitant use of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible.

7.2 Concomitant Use of Products Known to Cause Intracranial Hypertension Intracranial hypertension has been reported in patients who received tretinoin capsules and concomitant use of other products that can cause intracranial hypertension, such as tetracyclines, may increase the risk. Avoid concomitant use of tretinoin capsules with other products agents that can cause intracranial hypertension [see Warnings and Precautions ( 5.5 )] .

7.3 Vitamin A The concomitant use of vitamin A with tretinoin capsules may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin capsules with vitamin A.

7.4 Anti-fibrinolytic Agents Fatal thrombotic complications have been reported in patients who have received tretinoin capsules and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin capsules with anti-fibrinolytic agents [see Warnings and Precautions ( 5.8 )].

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based 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 a pregnant woman. Tretinoin capsules are a 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 a mg/m 2 basis (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.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. Data Human Data Tretinoin capsules are a 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 Data 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). 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 1 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 a pregnant woman [see Use in Specific Populations ( 8.1 ) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test within 1 week prior to initiating tretinoin capsules with a sensitivity of at least 50 mIU/mL. Contraception Females Advise 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 1 month after the last dose. Two methods of effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Refer females of reproductive potential to a qualified provider of contraceptive methods, if needed. Males Advise males with female partners of reproductive potential to use effective contraception during and after treatment with tretinoin capsules and for 1 week after the last dose. Infertility Males Based 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 1 year of age and older and the inform …

12.1 Mechanism of Action Tretinoin 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 a 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.

11 DESCRIPTION Tretinoin, USP is a retinoid. The chemical name is all-trans retinoic acid. The molecular formula is C 20 H 28 O 2 and the molecular weight is 300.44 g/mol. The structural formula is: It is a yellow to yellow-orange, crystalline powder with melting point at about 182°C (with decomposition). Tretinoin, USP is very sparingly soluble in water. Tretinoin is available as capsules containing 10 mg tretinoin for oral use. Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, refined soybean oil and yellow wax. The ingredients in the capsule shell include gelatin, glycerin, sorbitol, red iron oxide, titanium dioxide. The ingredients in the edible imprinting ink include ammonium hydroxide, black iron oxide, propylene glycol and shellac. The ingredients in the processing aid Phosal 53 include lecithin, caprylic/capric triglycerides, ethanol, sunflower mono/diglycerides, oleic acid, ascorbyl palmitate and tocopherol. structure

10 OVERDOSAGE In case of overdose with tretinoin capsules, reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. 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 a special hematological unit.

16 HOW SUPPLIED/STORAGE AND HANDLING 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 • Cartons of 30 capsules (10 capsules each blister pack x 3), NDC 0904-6867-04 • Bottles of 100 capsules, NDC 0904-6867-60 (discontinued) CARTONS - WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 20oC to 25oC (68oF to 77oF); [see USP Controlled Room Temperature]. Keep bottle tightly closed. Protect from light.