Version May 2024
Patients with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to tretinoin capsules. Tretinoin capsules should, therefore, be administered only to patients with APL under the strict supervision of a physician who is experienced in the management of patients with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity, including respiratory compromise. Use of tretinoin capsules requires that the physician concludes that the possible benefit to the patient outweighs the following known adverse reactions in therapy.
Approximately 25% of patients with APL treated with tretinoin capsules have experienced a syndrome called the retinoic acid-APL (RA-APL) syndrome, characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multiorgan failure. This syndrome occasionally has been accompanied by impaired myocardial contractility and episodic hypotension. It has been observed with or without concomitant leukocytosis. Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several patients have expired with multiorgan failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of tretinoin capsules.
The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings, or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously administered every 12 hours for 3 days or until the resolution of symptoms) should be immediately initiated, irrespective of the leukocyte count. The majority of patients do not require termination of tretinoin capsules therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, temporary interruption of tretinoin capsules therapy should be considered.
During tretinoin capsules treatment, about 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high WBC at diagnosis (>5 × 109/L) have an increased risk of a further rapid increase in WBC. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.
If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, treatment with high-dose steroids should be initiated immediately. Some investigators routinely add chemotherapy to tretinoin capsules treatment in the case of patients presenting with a WBC of >5 × 109/L or in the case of a rapid increase in WBC for patients leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consideration could be given to adding full-dose chemotherapy (including an anthracycline if not contraindicated) to the tretinoin capsules therapy on day 1 or 2 for patients presenting with a WBC of >5 × 109/L, or immediately, for patients presenting with a WBC of <5 × 109/L, if the WBC reaches ≥6 × 109/L by day 5, or ≥10 × 109/L by day 10, or ≥15 × 109/L by day 28.
Pregnancy (Category D): There is a high risk that a severely deformed infant will result if tretinoin capsules are administered during pregnancy. If, nonetheless, it is determined that tretinoin capsules represent the best available treatment for a pregnant woman or a woman of childbearing potential, it must be assured that the patient has received full information and warnings of the risk to the fetus if she were to be pregnant and of the risk of possible contraception failure and has been instructed in the need to use 2 reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method.
Within 1 week prior to the institution of tretinoin capsules therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 milliunits/mL. When possible, tretinoin capsules therapy should be delayed until a negative result from this test is obtained. When a delay is not possible, the patient should be placed on 2 reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of tretinoin capsules treatment.
Note: Acute promyelocytic leukemia (APL) induction treatment with tretinoin should be initiated early; discontinue if pending cytogenetic analysis does not confirm t(15;17) translocation or the presence of the PML/RARα fusion protein. In patients presenting with WBC ≥5,000/mm3 or serum creatinine >1.39 mg/dL, consider systemic corticosteroids (eg, dexamethasone, prednisone) for prophylaxis of differentiation syndrome (Ref).
Acute promyelocytic leukemia:
Remission induction: Note: For non–high-risk APL patients (WBC ≤10,000/mm3), induction therapy consists of tretinoin with arsenic trioxide, although tretinoin with anthracycline-based chemotherapy is an option when arsenic trioxide cannot be used. For patients with high-risk APL (WBC >10,000/mm3), induction therapy generally consists of tretinoin and anthracycline-based chemotherapy ± arsenic trioxide (Ref).
Manufacturer's labeling: Oral: 45 mg/m2/day in 2 equally divided doses until documentation of complete remission (CR); discontinue 30 days after CR or after 90 days of treatment, whichever occurs first.
Tretinoin with arsenic trioxide: Oral: 45 mg/m2/day in 2 equally divided doses until <5% blasts in marrow and no abnormal promyelocytes or complete remission, up to a maximum of 60 or 85 days; refer to protocol(s) for further information (Ref).
Tretinoin with idarubicin: Oral: 45 mg/m2/day in 2 equally divided doses until complete hematologic remission (Ref).
Tretinoin with daunorubicin and cytarabine: Oral: 45 mg/m2/day in 2 equally divided doses until complete remission or 90 days (Powell 2010) or until complete hematologic remission (Ref).
Tretinoin with arsenic trioxide and gemtuzumab ozogamicin: Oral: 45 mg/m2/day in 2 equally divided doses until <5% blasts in marrow and no abnormal promyelocytes (Ref).
Tretinoin with gemtuzumab ozogamicin: Oral: 45 mg/m2/day in 2 equally divided doses until complete remission (Ref).
Consolidation therapy (off-label use):
Tretinoin with arsenic trioxide: Oral: 45 mg/m2/day in 2 equally divided doses days 1 to 14 every 28 days for 7 cycles (Ref) or for 2 weeks every 28 days for 7 cycles (Ref).
Tretinoin with idarubicin/mitoxantrone: Oral: 45 mg/m2/day in 2 equally divided doses for 15 days each month for 3 months (in combination with idarubicin [courses 1 and 3] and mitoxantrone [course 2]) (Ref).
Tretinoin and daunorubicin after arsenic trioxide: Oral: 45 mg/m2/day in 2 equally divided doses for 7 days of each cycle (in combination with daunorubicin for 2 cycles; begin after 2 arsenic trioxide consolidation cycles) (Ref).
Maintenance therapy (off-label use): Oral: 45 mg/m2/day in 2 equally divided doses for 15 days every 3 months (in combination with mercaptopurine and methotrexate) for 2 years (Ref) or 45 mg/m2/day in 2 equally divided doses for 7 days every other week (± mercaptopurine and methotrexate) for 1 year (Ref). Note: For non–high-risk patients (WBC ≤10,000/mm3) receiving chemotherapy-free therapy, maintenance therapy is not needed (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment: Liver function tests >5 × ULN: Consider temporarily withholding treatment. Most liver function test abnormalities will resolve without interruption of treatment or after completion of tretinoin therapy.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status. If dose reduction for toxicity is recommended in the prescribing information, the dose should be increased back to the initial or previously tolerated dose only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
Differentiation syndrome: Regardless of the leukocyte count, at the first signs suggestive of APL differentiation syndrome (eg, unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings, radiographic abnormalities), immediately initiate corticosteroid therapy with dexamethasone 10 mg IV every 12 hours for 3 days or until the symptoms resolve, then taper off over 2 weeks (Ref); consider interrupting tretinoin until resolution of hypoxia, although most patients do not require termination of tretinoin therapy during treatment of differentiation syndrome.
Leukocytosis with signs/symptoms of differentiation syndrome: Initiate treatment with high-dose corticosteroids immediately.
Refer to adult dosing.
(For additional information see "All-trans retinoic acid (systemic tretinoin): Pediatric drug information")
Note: Frequency, number of doses, timing of doses during cycles/phases, and concomitant therapy may vary; refer to individual protocols.
Acute promyelocytic leukemia (APL): Limited data available (Ref):
Children and Adolescents:
Note: Daily doses should be rounded to the nearest 10 mg (ie, if <5 mg round down; if ≥5 mg round up); if necessary, the morning dose may differ from the evening dose.
Remission induction: Oral: 25 mg/m2/day in 2 divided doses days 1 to 30 (in combination with idarubicin) (Ref). Induction treatment of APL with tretinoin should be initiated early; discontinue if pending cytogenetic analysis does not confirm t(15;17) translocation or the presence of the PML/RARα fusion protein.
Consolidation 1: Oral: 25 mg/m2/day in 2 divided doses on days 1 to 14 of a 35-day cycle; repeat once for a total of 2 cycles (in combination with arsenic trioxide) (Ref).
Consolidation 2: Oral: 25 mg/m2/day in 2 divided doses on days 1 to 14 (in combination with IV cytarabine [high-dose], intrathecal cytarabine, and mitoxantrone) (Ref).
Consolidation 3: Oral: 25 mg/m2/day in 2 divided doses on days 1 to 14 (in combination with intrathecal cytarabine and idarubicin) (Ref).
Consolidation 4 (only for high-risk APL): Oral: 25 mg/m2/day in 2 divided doses on days 1 to 14 (in combination with IV cytarabine [high-dose], intrathecal cytarabine, and idarubicin) (Ref).
Maintenance: Oral: 25 mg/m2/day in 2 divided doses on days 1 to 14 (in combination with oral methotrexate, mercaptopurine, and intrathecal cytarabine [first cycle only]) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: Note: Refer to specific protocol(s) for detailed information related to management for the following and other drug-related toxicities.
Children and Adolescents:
APL differentiation syndrome: Hold tretinoin and initiate dexamethasone 0.25 mg/kg/dose (maximum dose: 10 mg) IV or orally every 12 hours for 3 days; resume tretinoin after resolution of signs/symptoms; if symptoms persistent longer than 3 days or recur with therapy, hold tretinoin therapy and evaluate case on an individual basis (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
Baseline: There are no dosage adjustments provided in the manufacturer's labeling.
Hepatotoxicity during treatment: Based on experience in adult patients, liver enzymes may normalize with dosage reduction or with continued treatment; discontinue if normalization does not readily occur or if hepatitis is suspected.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Cardiac arrhythmia (23%), chest discomfort (32%), edema (29%), flushing (23%), hypertension (11%), hypotension (14%), peripheral edema (52%), phlebitis (11%)
Dermatologic: Alopecia (14%), diaphoresis (20%), pruritus (20%), skin changes (14%), skin rash (54%), xeroderma (≤77%)
Endocrine & metabolic: Hypercholesterolemia (≤60%), hypertriglyceridemia (≤60%), weight gain (23%), weight loss (17%)
Gastrointestinal: Abdominal distention (11%), abdominal pain (31%), anorexia (17%), constipation (17%), diarrhea (23%), dry mucous membranes (≤77%), dyspepsia (14%), gastrointestinal hemorrhage (34%), nausea (≤57%), stomatitis (26%), vomiting (≤57%)
Hematologic & oncologic: Differentiation syndrome (≤25%), disseminated intravascular coagulation (26%), hemorrhage (60%), leukocytosis (40%)
Hepatic: Increased liver enzymes (50% to 60%)
Infection: Infection (58%)
Nervous system: Anxiety (17%), confusion (11%), depression (14%), dizziness (20%), headache (86%), insomnia (14%), malaise (66%), pain (37%), paresthesia (17%), shivering (63%)
Neuromuscular & skeletal: Myalgia (14%), ostealgia (77%)
Ophthalmic: Eye disease (17%), visual disturbance (17%)
Otic: Otalgia (23%; including a feeling of ear fullness)
Renal: Renal insufficiency (11%)
Respiratory: Dyspnea (60%), pleural effusion (20%), pneumonia (14%), rales (14%), respiratory insufficiency (26%), upper respiratory system symptoms (63%), wheezing (expiratory: 14%)
Miscellaneous: Fever (83%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (3%), cardiomegaly (3%), cardiomyopathy (3%), heart failure (6%), heart murmur (3%), ischemia (3%), myocarditis (3%), pericarditis (3%)
Dermatologic: Cellulitis (8%), pallor (6%)
Endocrine & metabolic: Acidosis (3%), fluid volume disorder (6%)
Gastrointestinal: Gastrointestinal ulcer (3%)
Genitourinary: Benign prostatic hypertrophy (3%), dysuria (9%), urinary frequency (3%)
Hematologic & oncologic: Disorder of the lymphatic system (6%)
Hepatic: Ascites (3%), hepatitis (3%), hepatosplenomegaly (9%)
Hypersensitivity: Facial edema (6%)
Nervous system: Abnormal gait (3%), agitation (9%), agnosia (3%), aphasia (3%), asterixis (3%), ataxia (3%), brain edema (3%), central nervous system depression (3%), cerebellar disorder (3%), cerebral hemorrhage (9%), cerebrovascular accident (3%), coma (3%), dementia (3%), drowsiness (3%), dysarthria (3%), encephalopathy (3%), facial nerve paralysis (3%), forgetfulness (3%), hallucination (6%), hemiplegia (3%), hyporeflexia (3%), hypothermia (3%), intracranial hypertension (9%), loss of consciousness (3%), seizure (3%), speech disturbance (slowing: 3%), tremor (3%)
Neuromuscular & skeletal: Lower extremity weakness (3%), osteomyelitis (3%)
Ophthalmic: Decreased pupillary reflex (3%), decreased visual acuity (6%), visual field defect (3%)
Otic: Hearing loss (≤6%; may be irreversible)
Renal: Acute kidney injury (3%), flank pain (9%), renal tubular necrosis (3%)
Respiratory: Asthma (3%), laryngeal edema (3%), lower respiratory signs and symptoms (9%), pulmonary edema (3%), pulmonary hypertension (3%), pulmonary infiltrates (6%)
Frequency not defined: Nervous system: Asthenia, fatigue
Postmarketing:
Cardiovascular: Arterial thrombosis, atrioventricular block (Shih 2015), bradycardia (Karakatsanis 2014), venous thrombosis
Dermatologic: Dermal ulcer (genital) (Yanamandra 2016), erythema nodosum, Sweet syndrome (van Der Vliet 2000), vasculitis of the skin
Endocrine & metabolic: Hypercalcemia
Gastrointestinal: Pancreatitis
Hematologic & oncologic: Basophilia (Koike 1992), thrombocythemia (Aldapt 2018)
Hypersensitivity: Histamine release (hyperhistaminemia) (Koike 1992)
Neuromuscular & skeletal: Myositis (van Der Vliet 2000)
Renal: Renal infarction
Hypersensitivity to tretinoin, other retinoids, parabens, or any component of the formulation.
Canadian labeling: Additional contraindications (not in the US labeling): Pregnancy; breastfeeding; patients at risk of becoming pregnant who are unable to follow or comply with required contraceptive measures; concurrent use with vitamin A, tetracyclines, or other retinoids.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Cardiovascular effects: Venous thrombosis and myocardial infarction (MI) have been reported in patients without risk factors for thrombosis or MI. The risk for thrombosis (arterial and venous) is increased during the first month of treatment. Use with caution with antifibrinolytic agents; thrombotic complications have been reported (rarely) with concomitant use.
• CNS effects: May cause headache, malaise, and/or dizziness; caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).
• Differentiation syndrome: About 25% of patients with acute promyelocytic leukemia (APL) treated with tretinoin have experienced differentiation syndrome (formerly called retinoic-acid-APL [RA-APL] syndrome or APL differentiation syndrome), which is characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural or pericardial effusions, edema, and hepatic, renal, and/or multiorgan failure. Differentiation syndrome may be accompanied by impaired myocardial contractility and episodic hypotension. It has been observed with or without concomitant leukocytosis. Intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia; fatalities due to multiorgan failure have occurred. Differentiation syndrome generally occurs during the first month of treatment, with some cases reported following the first dose.
• Leukocytosis: During treatment, ~40% of patients will develop rapidly evolving leukocytosis. Patients who present with a high WBC at diagnosis (>5,000/mm3) are at increased risk of further rapid increase in WBC. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.
• Lipid effects: Up to 60% of patients experienced hypercholesterolemia or hypertriglyceridemia, which were reversible upon completion of treatment.
• Liver function test abnormalities: Elevated liver function test results occur in 50% to 60% of patients during treatment. Most liver function test abnormalities will resolve without interruption of treatment or after therapy completion.
• Pseudotumor cerebri: Retinoids have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children. Concurrent use of other drugs associated with this effect (eg, tetracyclines) may increase risk. Early signs and symptoms include papilledema, headache, nausea, vomiting, visual disturbances, intracranial noises, or pulsate tinnitus.
Concurrent drug therapy issues:
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Dosage form specific issues:
• Do not interchange: Tretinoin (which is also known as all-trans retinoic acid, or ATRA) and isotretinoin may be confused; while both products may be used in cancer treatment, they are not interchangeable. Verify product prior to dispensing and administration to prevent medication errors.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: 10 mg
Yes
Capsules (Tretinoin Oral)
10 mg (per each): $37.35
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Vesanoid: 10 mg [contains soybean oil]
Generic: 10 mg
Oral: Administer with food.
Tretinoin has also been administered sublingually by squeezing the capsule contents beneath the tongue (Ref).
Low plasma concentrations have been reported when tretinoin has been administered through a feeding tube, although patient-specific impaired absorption or a lack of excipient (eg, soybean oil) may have been a contributing factor (Ref).
Oral: Administer with a meal.
For patients unable to swallow capsules, the following options may be considered and contents consumed within 1 hour: Poke a small hole in the capsule and patients may chew the capsule; capsules may be softened in water and then softened capsule chewed, swallowed, or mixed with jam/fatty food and then consumed; or puncture the capsule and squeeze contents onto a fatty food, mix, and consume (for this method, it is ideal to have patient suck on empty capsule to assist with getting full dose) (Ref).
NG tube: In a patient with a nasogastric (NG) tube, tretinoin capsules were cut open, with partial aspiration of the contents into a glass syringe, the residual capsule contents were mixed with soy bean oil and aspirated into the same syringe and administered (Ref). Tretinoin capsules have also been mixed with sterile water (~20 mL) and heated in a water bath (37°C) to melt the capsules and create an oily suspension for NG tube administration (Ref). Tretinoin has also been administered sublingually by squeezing the capsule contents beneath the tongue (Ref). For pediatric patients, some centers have suggested contents of capsule may be mixed with milk and administered NG (Ref). Low plasma levels have been reported when contents of tretinoin capsules were administered directly through a feeding tube, although patient-specific impaired absorption may have been a contributing factor (Ref).
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Acute promyelocytic leukemia (remission induction): Induction of remission in patients with acute promyelocytic leukemia, French American British (FAB) classification M3 (including the M3 variant) characterized by t(15;17) translocation and/or PML/RARα gene presence
Acute promyelocytic leukemia (consolidation therapy); Acute promyelocytic leukemia (maintenance therapy in high-risk patients)
Tretinoin may be confused with alitretinoin, ISOtretinoin, trientine
Vesanoid may be confused with VESIcare
Tretinoin (which is also called all-trans retinoic acid, or ATRA) may be confused with isotretinoin; while both products may have uses in cancer treatment, they are not interchangeable.
Substrate of CYP2A6 (minor), CYP2B6 (minor), CYP2C8 (minor), CYP2C9 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP2E1 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Antifibrinolytic Agents: Tretinoin (Systemic) may enhance the thrombogenic effect of Antifibrinolytic Agents. Management: Concomitant use of antifibrinolytics and tretinoin is not recommended. If combined, monitor patients closely for any signs of thrombotic complications. Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tretinoin (Systemic). Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Fluconazole: May increase the serum concentration of Tretinoin (Systemic). Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methotrexate: Retinoic Acid Derivatives may enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Multivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Progestins (Contraceptive): Retinoic Acid Derivatives may diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Microdosed progesterone-only preparations (ie, minipills that do not contain estrogen) are considered an inadequate method of contraception. Risk D: Consider therapy modification
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Tetracyclines: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Risk X: Avoid combination
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin A: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Absorption of retinoids has been shown to be enhanced when taken with food. Management: Administer with food.
A serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL must be done within 1 week prior to the institution of tretinoin capsules. When possible, tretinoin capsules should be delayed until a negative result is obtained. If a delay is not possible, the patient should be placed on two reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of tretinoin capsules treatment.
Two reliable forms of contraception must be used simultaneously during therapy and for 1 month following discontinuation of tretinoin. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Microdosed progesterone products ("minipill") may provide inadequate pregnancy protection.
If tretinoin capsules are the best available treatment for a patient who can become pregnant, it must be assured that the patient has received full information and warnings of the risk to the fetus if pregnancy were to occur during tretinoin therapy and of the risk of possible contraception failure.
Tretinoin was detected in the serum of a neonate at birth following maternal use of standard doses during pregnancy (Takitani 2005).
There is a high risk that a severely deformed infant will result if tretinoin capsules are administered during pregnancy. Major fetal abnormalities and spontaneous abortions have been reported with other retinoids; some of these abnormalities were fatal. Birth defects associated with exposure to retinoids include facial dysmorphia, cleft palate, eye abnormalities and abnormalities of the central nervous system, cardiovascular system, musculoskeletal system, and parathyroid hormone deficiencies. All exposed fetuses have the potential to be affected.
Use in humans for the treatment of acute promyelocytic leukemia (APL) is limited and exposure occurred after the first trimester in most cases (Santolaria 2020). If the clinical condition of a patient presenting with APL during pregnancy warrants immediate treatment, tretinoin use should be avoided in the first trimester; treatment with tretinoin may be considered in the second and third trimester with careful fetal monitoring, including cardiac monitoring (ELN [Sanz 2019]). The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy; the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team that includes an obstetrician, a neonatologist, and the oncology team (ESMO [Peccatori 2013]).
A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).
It is not known if tretinoin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding should be discontinued prior to treatment initiation.
Capsule contains soybean oil.
Bone marrow cytology to confirm t(15;17) translocation or the presence of the PML/RARα fusion protein (do not withhold treatment initiation for results). Monitor CBC with differential, coagulation profile, liver function tests, and triglyceride and cholesterol levels frequently; monitor serum creatinine (at baseline). Monitor closely for signs of differentiation syndrome (eg, monitor volume status, pulmonary status, temperature, respiration). Monitor for signs/symptoms of cardiovascular or CNS adverse effects and pseudotumor cerebri.
Pregnancy testing (in patients who can become pregnant): A serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL should be conducted within 1 week prior to the institution of tretinoin treatment; repeat pregnancy testing monthly throughout tretinoin treatment.
The American Society of Clinical Oncology hepatitis B virus screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Tretinoin appears to bind one or more nuclear receptors and decreases proliferation and induces differentiation of APL cells; initially produces maturation of primitive promyelocytes and repopulates the marrow and peripheral blood with normal hematopoietic cells to achieve complete remission.
Note: Reported pediatric values similar to adult (Smith 1992; Takitani 2004)
Absorption: Well absorbed
Protein binding: >95%, predominantly to albumin
Metabolism: Hepatic via CYP; primary metabolite: 4-oxo-all-trans-retinoic acid; displays autometabolism
Half-life elimination: Terminal: Parent drug: 0.5 to 2 hours
Time to peak, serum: 1 to 2 hours
Excretion: Urine (63%); feces (30%)
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