Tretinoin 10 mg Capsule, 30-count — NDC 72162-1220-3 (Billing 72162-1220-03)

5 WARNINGS AND PRECAUTIONS Patients Without t(15;17) Translocation or PML/RARα Fusion: tretinoin capsules may be initiated based on morphological diagnosis of APL. Confirm diagnosis by detection of the t(15;17) translocation or PML/RARα 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 )

5.1Embryo-Fetal Toxicity 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 has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m 2 basis.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use 2 effective methods of contraception during treatment with tretinoin capsules and for 1 month following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

5.2Differentiation 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 3 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 )] .

5.3Patients Without t(15;17) Translocation or PML/RARα 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/RARα fusion using molecular diagnostic techniques. Tretinoin capsules not recommended for use in patients without these genetic markers [see Indications and Usage ( 1 )] .

5.4Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tre… [Excerpted — this section continues on DailyMed.]

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 Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 (%) N ervous 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, aphasia, asterixis, cerebellar edema,… [Excerpted — this section continues on DailyMed.]

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 )

7.1Effects of Other Drugs on Tretinoin Capsules Strong CYP3A Inhibitors The coadministration of tretinoin capsules 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 capsules with strong CYP3A inhibitors if possible. Monitor patients taking a strong CYP3A inhibitor with tretinoin capsules more frequently for adverse reactions.

Strong CYP3A Inducers The coadministration of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid coadministration with strong CYP3A inducers if possible.

7.2Concomitant 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 )] .

7.3Vitamin 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.

7.4Anti-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 )].

7.1Effects of Other Drugs on Tretinoin Capsules Strong CYP3A Inhibitors The coadministration of tretinoin capsules 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 capsules with strong CYP3A inhibitors if possible. Monitor patients taking a strong CYP3A inhibitor with tretinoin capsules more frequently for adverse reactions.

Strong CYP3A Inducers The coadministration of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid coadministration with strong CYP3A inducers if possible.

7.2Concomitant 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 )] .

7.3Vitamin 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.

7.4Anti-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 )].