TRETINOIN Drug Interactions: What You Need to Know

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 )]</span>.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 )]</span>.

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)

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 have 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 )

5.1 Embryo-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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.2 Differentiation Syndrome Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.3 Patients 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 are not recommended for use in patients without these genetic markers <span class="opacity-50 text-xs">[see Indications and Usage ( 1 )]</span> .

5.4 Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Patients who present with a baseline white blood cell count (WBC) &gt; 5 × 10 9 /L have an increased risk. Patients who receive chemotherapy with tretinoin capsules may be at a reduced risk. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated.

5.5 Intracranial Hypertension Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Evaluate patients with these symptoms for intracranial hypertension, and, if present, institute appropriate care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. The concomitant use of other products (e.g., tetracyclines) that can cause intracranial hypertension may increase the risk. Avoid concomitant use of tretinoin capsules with other products that can cause intracranial hypertension <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.6 Lipid Abnormalities Hypercholesterolemia and/or hypertriglyceridemia has occurred in up to 60% of patients who received tretinoin capsules. These changes may be reversible upon completion of treatment. The clinical consequences of increased triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment.

5.7 Hepatotoxicity Elevated liver function test results occurred in 50% to 60% of patients during treatment with tretinoin capsules. Most of these abnormalities resolved without interruption of tretinoin capsules or after completion of treatment. Monitor liver function test at baseline and during treatment as clinically indicated. Consider withholding tretinoin capsules if liver function test results increase to greater than 5 times the upper limit of normal values until resolution.

5.8 Thromboembolic Events Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk. Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 )]</span> .

5.1 Embryo-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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.2 Differentiation Syndrome Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.3 Patients 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 are not recommended for use in patients without these genetic markers <span class="opacity-50 text-xs">[see Indications and Usage ( 1 )]</span> .

5.4 Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Patients who present with a baseline white blood cell count (WBC) &gt; 5 × 10 9 /L have an increased risk. Patients who receive chemotherapy with tretinoin capsules may be at a reduced risk. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated.

5.5 Intracranial Hypertension Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Evaluate patients with these symptoms for intracranial hypertension, and, if present, institute appropriate care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. The concomitant use of other products (e.g., tetracyclines) that can cause intracranial hypertension may increase the risk. Avoid concomitant use of tretinoin capsules with other products that can cause intracranial hypertension <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.6 Lipid Abnormalities Hypercholesterolemia and/or hypertriglyceridemia has occurred in up to 60% of patients who received tretinoin capsules. These changes may be reversible upon completion of treatment. The clinical consequences of increased triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment.

5.8 Thromboembolic Events Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk. Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 )]</span> .