TRETINOIN- tretinoin_capsule, liquid filled

Tretinoin induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tretinoin have not been characterized. Following the administration of tretinoin 22. 5 mg/m 2 Absorption Effect of Food Distribution 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 Metabolism Excretion 2 Specific Populations Drug Interaction Studies Clinical Studies and Post Marketing Experience Strong CYP3A inhibitors: Moderate CYP3A Inhibitors: In Vitro Effect of Tretinoin on Transporters: in vitro.

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/RARalpha 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/RARalpha gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated.

The recommended dosage of tretinoin capsules is 22. 2 Discontinue 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. 2 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 The recommended dosage of tretinoin capsules is 22. 5 mg/m 2 Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARalpha 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.

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. gov/medwatch. 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 2 [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. 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 Adverse reactions that occurred in <10% of patients who received tretinoin include: Hepatobiliary disorders: Musculoskeletal and connective tissue disorders: Nervous system disorders: Renal and urinary disorders: Respiratory, thoracic and mediastinal disorders: Infections and infestations: Blood and lymphatic system disorders: Cardiovascular disorders: Ear and labyrinth disorders: General disorders: Metabolism and nutrition disorders: Eye disorders: Gastrointestinal disorders: Vascular disorders: 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.

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.

Lactation 8. 2 Risk Summary [see Clinical Pharmacology ( 12. 1 2 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. 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 IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero Animal Data 2 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. Tretinoin can cause embryo-fetal loss and malformations when administered to a pregnant woman [see Use in Specific Populations ( 8. 1 Pregnancy Testing Contraception Females Males Infertility Males [see Nonclinical Toxicology ( 13. 1 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. 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.

Strong CYP3A Inhibitors and Inducers: 7. 1 Concomitant Use of Products Known to Cause Intracranial Hypertension 7. 2 Vitamin A 7. 3 Anti-fibrinolytic Agents 7. 4 Strong or moderate CYP3A Inhibitors Avoid concomitant use of tretinoin with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin 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 with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible. 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 The concomitant use of vitamin A with tretinoin may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin with vitamin A. 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.

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.
NONCLINICAL TOXICOLOGY
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 2 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 in vivo 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 2
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 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 dagger 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 dagger 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).

Teva Pharmaceuticals USA, Inc.

TRETINOIN- tretinoin_capsule, liquid filled Product manual source documgent