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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.

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.

• 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 (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 (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 are described elsewhere in the labeling: • Differentiation Syndrome [see ( 5.2 )] • Leukocytosis [see ( 5.4 )] • Intracranial hypertension [see (5.5)] • Lipid abnormalities [see ( 5.6 )] • Hepatotoxicity [see ( 5.7 )] • Thromboembolic events [see (5 .8 )] The most common (≥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 , contact Par Health at 1-800-828-9393 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 (≥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 for patients with APL. Table 1....

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 ( 6.1 )]. Hypersensitivity to tretinoin capsules, any of its components, or other retinoids