Tretinoin

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 Teva at 1-888-838-2872 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 was evaluated in patients with APL who received tretinoin 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 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 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 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). 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Erythema nodosum, basophilia and hyperhistaminemia, Sweet’s Syndrome, organomegaly, hypercalcemia, pancreatitis, myositis, thrombosis (both venous and arterial), thrombocytosis, genital ulceration and vasculitis, predominantly involving the skin.

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

11 DESCRIPTION Tretinoin, USP is a retinoid that induces maturation of acute promyelocytic leukemia (APL) cells in culture. It is available in a 10 mg gelatin capsule for oral administration. Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, hydrogenated vegetable oil, polysorbate 80, soybean oil, vitamin E, and white wax (beeswax). The ingredients in the capsule shell include black iron oxide, red iron oxide, titanium dioxide and yellow iron oxide. The ingredients in the edible imprinting ink include D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, iron oxide black, propylene glycol and shellac glaze. Chemically, tretinoin, USP is all- trans retinoic acid and is related to retinol (Vitamin A) and has the following chemical name: 3,7-Dimethyl-9-(2,6,6-trimethyl-1- cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a yellow to light orange crystalline powder, and has the following structural formula: structural formula

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.

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 )

10 OVERDOSAGE In case of overdose with tretinoin, 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.

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 Strong CYP3A Inhibitors The coadministration of tretinoin with ketoconazole, a strong CYP3A4 inhibitor, increased tretinoin plasma concentration, which may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of tretinoin with strong CYP3A inhibitors if possible. Monitor patients taking a strong CYP3A inhibitor with tretinoin more frequently for adverse reactions. Strong CYP3A Inducers The coadministration of tretinoin with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid coadministration 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 and concomitant use of other products that can cause intracranial hypertension, such as tetracyclines, may increase the risk. Avoid concomitant use of tretinoin 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 may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin with vitamin A. 7.4 Anti-fibrinolytic Agents Fatal thrombotic complications have been reported in patients who have received tretinoin and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin with anti-fibrinolytic agents [see Warnings and Precautions ( 5.8 )] .

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tretinoin have not been characterized. 12.3 Pharmacokinetics Following the administration of tretinoin 22.5 mg/m 2 orally twice daily, the mean ± SD peak tretinoin concentrations after the first dose was 394 ± 89 and after 1 week of continuous treatment was 138 ± 139 ng/mL, while area under the curve (AUC) after the first dose was 537 ± 191 ng·h/mL and after 1 week of continuous treatment was 249 ± 185 ng·h/mL. Absorption Time to reach peak concentration was between 1 and 2 hours. The absolute bioavailability of tretinoin was approximately 50%. Effect of Food The effect of food on the absorption of tretinoin has not been characterized. Food increases the absorption of retinoids, as a class. Distribution The apparent volume of distribution of tretinoin has not been determined. Protein binding is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL. Elimination The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. Metabolism Tretinoin induced its own metabolism with plasma concentrations after 1 week of continuous therapy decreased to one-third of their day 1 values. Tretinoin is metabolized by cytochrome P450 enzymes, CYP3A4, 2C8, and 2E and undergoes glucuronidation by UGT2B7. Metabolites include 9-cis retinoic acid, 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. Excretion Following administration of radiolabeled tretinoin 2.75 mg and 50 mg (0.53 to 9.6 times the approved recommended dosage based on 1.7 m 2 ), approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within 6 days. Specific Populations The effect of age, sex, race, renal impairment, and hepatic impairment on the pharmacokinetics of tretinoin is unknown. Drug Interaction Studies Clinical Studies Coadministration of ketoconazole (strong CYP3A inhibitor) increased tretinoin AUC by 72%. In Vitro Studies Effect of Tretinoin on Transporters: Tretinoin does not inhibit P-gp and BCRP in vitro .

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.

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

12.3 Pharmacokinetics Following the administration of tretinoin 22.5 mg/m 2 orally twice daily, the mean ± SD peak tretinoin concentrations after the first dose was 394 ± 89 and after 1 week of continuous treatment was 138 ± 139 ng/mL, while area under the curve (AUC) after the first dose was 537 ± 191 ng·h/mL and after 1 week of continuous treatment was 249 ± 185 ng·h/mL. Absorption Time to reach peak concentration was between 1 and 2 hours. The absolute bioavailability of tretinoin was approximately 50%. Effect of Food The effect of food on the absorption of tretinoin has not been characterized. Food increases the absorption of retinoids, as a class. Distribution The apparent volume of distribution of tretinoin has not been determined. Protein binding is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL. Elimination The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. Metabolism Tretinoin induced its own metabolism with plasma concentrations after 1 week of continuous therapy decreased to one-third of their day 1 values. Tretinoin is metabolized by cytochrome P450 enzymes, CYP3A4, 2C8, and 2E and undergoes glucuronidation by UGT2B7. Metabolites include 9-cis retinoic acid, 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. Excretion Following administration of radiolabeled tretinoin 2.75 mg and 50 mg (0.53 to 9.6 times the approved recommended dosage based on 1.7 m 2 ), approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within 6 days. Specific Populations The effect of age, sex, race, renal impairment, and hepatic impairment on the pharmacokinetics of tretinoin is unknown. Drug Interaction Studies Clinical Studies Coadministration of ketoconazole (strong CYP3A inhibitor) increased tretinoin AUC by 72%. In Vitro Studies Effect of Tretinoin on Transporters: Tretinoin does not inhibit P-gp and BCRP in vitro .

20230228

12

3 DOSAGE FORMS AND STRENGTHS Capsules: 10 mg, two-piece hard gelatin capsule with brown opaque cap and dark yellow opaque body, filled with yellow viscous oily suspension. Imprinted in black ink with stylized barr 808. Capsules: 10 mg

Tretinoin Tretinoin TRETINOIN TRETINOIN BUTYLATED HYDROXYANISOLE EDETATE DISODIUM GELATIN HYDROGENATED SOYBEAN OIL POLYSORBATE 80 SOYBEAN OIL ALPHA-TOCOPHEROL WHITE WAX FERROSOFERRIC OXIDE FERRIC OXIDE RED TITANIUM DIOXIDE FERRIC OXIDE YELLOW D&C YELLOW NO. 10 ALUMINUM LAKE FD&C BLUE NO. 1 ALUMINUM LAKE FD&C BLUE NO. 2--ALUMINUM LAKE FD&C RED NO. 40 PROPYLENE GLYCOL SHELLAC dark yellow barr;808

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No 2-year carcinogenicity studies in rodents have been conducted with tretinoin. In a carcinogenicity study, female B5D2F1 mice pretreated with a 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 a dose of 30 mg/kg/day in the diet (about 2 times the human dose on a mg/m 2 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. A 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 a clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m 2 basis). In a 6-week toxicology study in dogs, testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m 2 ).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No 2-year carcinogenicity studies in rodents have been conducted with tretinoin. In a carcinogenicity study, female B5D2F1 mice pretreated with a 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 a dose of 30 mg/kg/day in the diet (about 2 times the human dose on a mg/m 2 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. A 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 a clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m 2 basis). In a 6-week toxicology study in dogs, testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m 2 ).

ANDA077684

Tretinoin

Tretinoin

0555-0808

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 0555-0808-02 Tretinoin Capsules 10 mg Rx Only 100 Capsules 10 mg

17 PATIENT COUNSELING INFORMATION Embryo-Fetal Toxicity Advise female patients of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a 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 2 methods of effective contraception during treatment with tretinoin capsules and for 1 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 1 week after the last dose [see Use in Specific Populations ( 8.3 )] . Differentiation Syndrome Advise 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/RARα Fusion Advise patients that tretinoin capsules are not recommended for use in patients without t(15;17) translocation or PML/RARα fusion [see Warnings and Precautions ( 5.3 )] . Leukocytosis Inform patients that rapidly evolving leukocytosis, which can be life-threatening, can occur during treatment with tretinoin capsules [see Warnings and Precautions ( 5.4 )] . Intracranial Hypertension Advise 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 Abnormalities Inform 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 )] . Hepatotoxicity Advise 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 )] . Lactation Advise women not to breastfeed during treatment with tretinoin capsules and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )] . Administration Instructions Advise patients to swallow tretinoin capsules whole with water. Advise patients not to chew, dissolve, or open capsules. Advise patients not to take a 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 Machines Advise 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. Brands listed are the trademarks of their respective owners. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. C 2/2023

14 CLINICAL STUDIES The efficacy of tretinoin has been evaluated in 114 previously treated patients and in 67 previously untreated (“de novo”) patients with APL 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). Patients received tretinoin 22.5 mg/m 2 orally twice daily for up to 90 days following the first dose or 30 days following achievement of complete remission. Efficacy results are shown Table 2. Table 2. Efficacy Results in a Controlled Clinical Trial (MSKCC) and Compassionate Use MSKCC NCI Cohort 1 NCI Cohort 2 Relapsed N = 20 De Novo n = 15 Relapsed* N = 48 De Novo n = 14 Relapsed n = 46 De Novo † n = 38 Complete Remission 16 (80%) 11 (73%) 24 (50%) 5 (36%) 24 (52%) 26 (68%) Median Survival (months) 10.8 NR 5.8 0.5 8.8 NR Median Follow-up (months) 9.9 42.9 5.6 1.2 8.0 13.1 NR = Not Reached NA = Not Available *Including 9 chemorefractory patients † Including 8 patients who received chemotherapy but failed to enter remission The median time to complete remission was between 40 and 50 days (range: 2 to 120 days). Most patients received cytotoxic chemotherapy during the remission phase. Ten of 15 pediatric cases achieved complete remission (8 of 10 males and 2 of 5 females).

8.5 Geriatric Use Across clinical studies of tretinoin, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

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 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 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. Females of reproductive potential must have a negative pregnancy test within 1 week prior to initiating tretinoin 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 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 has been established in pediatric patients 1 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 a 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 1 year of age have not been established.

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , tretinoin can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin is 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 is 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 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 can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin is 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 is 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 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 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. Females of reproductive potential must have a negative pregnancy test within 1 week prior to initiating tretinoin 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 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 has been established in pediatric patients 1 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 a 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 1 year of age have not been established. 8.5 Geriatric Use Across clinical studies of tretinoin, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Tretinoin Capsules, 10 mg are available as two-piece hard gelatin capsule with brown opaque cap and dark yellow opaque body, filled with yellow viscous oily suspension. Imprinted in black ink with stylized barr 808. Available in bottles of 100 capsules (NDC 0555-0808-02). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Keep this and all medications out of the reach of children. Protect from light.

WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME Tretinoin can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin and for 1 week after the last dose [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 , 8.3 )] . Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin for moderate and severe Differentiation Syndrome until resolution [see Warnings and Precautions ( 5.2 )] . WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning . Embryo-Fetal Toxicity: Tretinoin can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin and for 1 week after the last dose. ( 5.1 , 8.1 , 8.3 ) Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin for moderate and severe Differentiation Syndrome until resolution. ( 5.2 )