Skip to Content

Tretinoin (Systemic)

Pronunciation

Pronunciation

(TRET i noyn)

Index Terms

  • All trans Retinoic Acid
  • All-trans Retinoic Acid
  • All-trans Vitamin A Acid
  • ATRA
  • Ro 5488
  • tRA
  • trans Vitamin A Acid
  • trans-Retinoic Acid
  • Tretinoinum
  • Vesanoid

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Generic: 10 mg

Pharmacologic Category

  • Antineoplastic Agent, Retinoic Acid Derivative
  • Retinoic Acid Derivative

Pharmacology

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

Absorption

Well absorbed

Metabolism

Hepatic via CYP; primary metabolite: 4-oxo-all-trans-retinoic acid; displays autometabolism

Excretion

Urine (63%); feces (30%)

Time to Peak

Serum: 1 to 2 hours

Half-Life Elimination

Terminal: Parent drug: 0.5 to 2 hours

Protein Binding

>95%, predominantly to albumin

Use: Labeled Indications

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

Use: Unlabeled

Post-consolidation and maintenance therapy in APL; combination therapy (with arsenic trioxide) for remission induction in APL

Contraindications

Hypersensitivity to tretinoin, other retinoids, parabens, or any component of the formulation

Dosing: Adult

Note: 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.

Acute promyelocytic leukemia (APL): Oral:

Remission induction (manufacturer’s labeling): 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

Remission induction (in combination with an anthracycline ± cytarabine): 45 mg/m2/day in 2 equally divided doses until complete remission or 90 days (Powell 2010) or until complete hematologic remission (Ades 2008; Sanz 2008; Sanz 2010)

Remission induction (in combination with arsenic trioxide; off-label combination): 45 mg/m2/day in 2 equally divided doses until <5% blasts in marrow and no abnormal promyelocytes or up to 85 days (Estey 2006; Ravandi 2009)

Consolidation therapy (off-label use): 45 mg/m2/day in 2 equally divided doses for 15 days each month for 3 months (in combination with chemotherapy) (Lo-Coco 2010; Sanz 2010) or 45 mg/m2/day for 14 days every 4 weeks for 7 cycles (in combination with arsenic trioxide) (Ravandi 2009)

Maintenance therapy, intermediate- and high-risk patients (off-label use): 45 mg/m2/day in 2 equally divided doses for 15 days every 3 months for 2 years (Ades 2008; Sanz 2004) or 45 mg/m2/day in 2 equally divided doses for 7 days every other week for 1 year (Powell 2010)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: 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.

Acute promyelocytic leukemia (APL): Oral:

Remission induction (manufacturer’s labeling): 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

Remission induction (in combination with an anthracycline; off-label dose): 25 mg/m2/day in 2 equally divided doses until complete remission or 90 days (Ortega 2005)

Consolidation therapy, intermediate- and high-risk patients (off-label use): 25 mg/m2/day in 2 equally divided doses for 15 days each month for 3 months (Ortega 2005)

Maintenance therapy, intermediate- and high-risk patients (off-label use): 25 mg/m2/day in 2 equally divided doses for 15 days every 3 months for 2 years (Ortega 2005)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

APL differentiation syndrome: Initiate dexamethasone 10 mg IV every 12 hours for 3 to 5 days; consider interrupting tretinoin until resolution of hypoxia

Liver function tests >5 times the upper limit of normal: Consider temporarily withholding treatment

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

Although the manufacturer does not recommend the use of the capsule contents to extemporaneously prepare a suspension of tretinoin (due to reports of low plasma levels) (Vesanoid data on file), there are limited case reports of use in patients who are unable to swallow the capsules whole. In a patient with a nasogastric (NG) tube, tretinoin capsules were cut open, with partial aspiration of the contents aspirated into a glass syringe. The residual capsule contents were mixed with soybean oil, aspirated into the syringe, and administered (Shaw 1995). Tretinoin capsules have also been mixed with sterile water (~20 mL) and heated in a water bath to melt the capsules and create an oily suspension for NG tube administration (Bargetzi 1996). Tretinoin has also been administered sublingually by squeezing the capsule contents beneath the tongue (Kueh 1999).

Bargetzi MJ, Tichelli A, Gratwohl A, et al, "Oral All-Transretinoic Acid Administration in Intubated Patients With Acute Promyelocytic Leukemia," Schweiz Med Wochenschr, 1996, 126(45):1944-5.8946598Kueh YK, Liew PP, Ho PC, et al, "Sublingual Administration of All-Trans-Retinoic Acid to a Comatose Patient With Acute Promyelocytic Leukemia," Ann Pharmacother, 1999, 33(4):503-5.10332546Shaw PJ, Atkins MC, Nath CE, et al, "ATRA Administration in the Critically Ill Patient," Leukemia, 1995, 9(7):1288.7630206Vesanoid data on file, Roche Pharmaceuticals

Administration

Administer orally with a meal; do not crush capsules.

Tretinoin has also been administered sublingually by squeezing the capsule contents beneath the tongue (Kueh 1999).

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 (Takitani 2004).

Hazardous agent - use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]). NIOSH recommends single gloving for administration of intact capsules. Although the manufacturer does not recommend the use of the capsule contents to extemporaneously prepare a tretinoin suspension, if necessary to manipulate the capsules (eg, to prepare an oral solution), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Dietary Considerations

The absorption of retinoids (as a class) is enhanced when taken with food. Capsule contains soybean oil.

Storage

Store capsule at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Antifibrinolytic Agents: Tretinoin (Systemic) may enhance the thrombogenic effect of Antifibrinolytic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Contraceptives (Estrogens): Retinoic Acid Derivatives may diminish the therapeutic effect of Contraceptives (Estrogens). Two forms of contraception are recommended in females of child-bearing potential during retinoic acid derivative therapy. Monitor therapy

Contraceptives (Progestins): Retinoic Acid Derivatives may diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Consider therapy modification

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May decrease the metabolism of CYP2C8 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lumacaftor: May increase the serum concentration of CYP2C8 Substrates. Lumacaftor may decrease the serum concentration of CYP2C8 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

Multivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

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. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tetracycline Derivatives: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin A: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

Adverse Reactions

Most patients will experience drug-related toxicity, especially headache, fever, weakness and fatigue. These are seldom permanent or irreversible and do not typically require therapy interruption.

>10%:

Cardiovascular: Peripheral edema (52%), chest discomfort (32%), edema (29%), arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%)

Central nervous system: Headache (86%), fever (83%), malaise (66%), pain (37%), dizziness (20%), anxiety (17%), depression (14%), insomnia (14%), confusion (11%)

Dermatologic: Skin/mucous membrane dryness (77%), rash (54%), pruritus (20%), alopecia (14%), skin changes (14%)

Endocrine & metabolic: Hypercholesterolemia and/or hypertriglyceridemia (≤60%)

Gastrointestinal: Nausea/vomiting (57%), GI hemorrhage (34%), abdominal pain (31%), mucositis (26%), diarrhea (23%), weight gain (23%), anorexia (17%), constipation (17%), weight loss (17%), dyspepsia (14%), abdominal distention (11%)

Hematologic: Hemorrhage (60%), leukocytosis (40%), disseminated intravascular coagulation (DIC) (26%)

Hepatic: Liver function tests increased (50% to 60%)

Local: Phlebitis (11%)

Neuromuscular & skeletal: Bone pain (77%), paresthesia (17%), myalgia (14%)

Ocular: Ocular disorder (17%), visual disturbances (17%)

Otic: Earache/ear fullness (23%)

Renal: Renal insufficiency (11%)

Respiratory: Upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), expiratory wheezing (14%), pneumonia (14%), rales (14%)

Miscellaneous: Shivering (63%), infections (58%), retinoic acid-acute promyelocytic leukemia syndrome differentiation syndrome (≤25%), diaphoresis (20%)

1% to 10%:

Cardiovascular: Cerebral hemorrhage (9%), cardiac failure (6%), facial edema (6%), pallor (6%), cardiac arrest (3%), cardiomyopathy (3%), heart enlarged (3%), heart murmur (3%), ischemia (3%), MI (3%), myocarditis (3%), pericarditis (3%), stroke (3%)

Central nervous system: Agitation (9%), intracranial hypertension (9%), hallucination (6%), aphasia (3%), cerebellar edema (3%), CNS depression (3%), coma (3%), dementia (3%), encephalopathy (3%), facial paralysis (3%), forgetfulness (3%), hypotaxia (3%), hypothermia (3%), light reflex absent (3%), seizure (3%), slow speech (3%), somnolence (3%), spinal cord disorder (3%), unconsciousness (3%)

Dermatologic: Cellulitis (8%)

Endocrine & metabolic: Fluid imbalance (6%), acidosis (3%)

Gastrointestinal: Hepatosplenomegaly (9%), ulcer (3%)

Genitourinary: Dysuria (9%), micturition frequency (3%), prostate enlarged (3%)

Hepatic: Ascites (3%), hepatitis (3%)

Neuromuscular & skeletal: Flank pain (9%), abnormal gait (3%), asterixis (3%), bone inflammation (3%), dysarthria (3%), hemiplegia (3%), hyporeflexia (3%), leg weakness (3%), tremor (3%)

Ocular: Visual acuity change (6%), agnosia (3%), visual field deficit (3%)

Otic: Hearing loss (6%)

Renal: Acute renal failure (3%), renal tubular necrosis (3%)

Respiratory: Lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), larynx edema (3%), pulmonary hypertension (3%)

Miscellaneous: Lymph disorder (6%)

<1% (Limited to important or life-threatening): Arterial thrombosis, basophilia, erythema nodosum, genital ulceration, hypercalcemia, hyperhistaminemia, irreversible hearing loss, myositis, organomegaly, pancreatitis, pseudotumor cerebri, renal infarct, Sweet's syndrome, thrombocytosis, vasculitis (skin), venous thrombosis

ALERT: U.S. Boxed Warning

Experienced physician:

Patients with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to tretinoin. Therefore, administer tretinoin only to patients with APL under the strict supervision of a health care provider 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 requires that the health care provider conclude the possible benefit to the patient outweighs the following known adverse reactions in therapy.

APL differentiation syndrome:

Approximately 25% of patients with APL treated with tretinoin have experienced 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.

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 (eg, unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings, radiographic abnormalities), initiate high-dose steroids (dexamethasone 10 mg intravenous [IV] administered every 12 hours for 3 days or until the resolution of symptoms) immediately, irrespective of the leukocyte count. The majority of patients do not require termination of tretinoin therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, consider temporary interruption of tretinoin therapy.

Leukocytosis:

During tretinoin treatment, approximately 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high white blood cell (WBC) at diagnosis (more than 5 × 109/L) have an increased risk of a further rapid increase in WBC counts. 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, immediately initiate treatment with high-dose steroids. Some investigators routinely add chemotherapy to tretinoin treatment in the case of patients presenting with a WBC count of more than 5 × 109/L or in the case of a rapid increase in WBC count for patients leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consider adding full-dose chemotherapy (including an anthracycline if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count of more than 5 × 109/L; immediately add for patients presenting with a WBC count of less than 5 x 109/L, if the WBC count reaches greater than or equal to 6 × 109/L by day 5, greater than or equal to 10 × 109/L by day 10, or greater than or equal to 15 × 109/L by day 28.

Pregnancy:

Pregnancy (Category D): There is a high risk that a severely deformed infant will result if tretinoin is administered during pregnancy. If, nonetheless, it is determined that tretinoin represents 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. Instruct the patient to use 2 reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and emphasize the need for using dual contraception, unless abstinence is the chosen method.

Within 1 week prior to the institution of tretinoin therapy, collect blood or urine from the patient for a serum or urine pregnancy test with a sensitivity of at least 50 milliunits/mL. When possible, delay tretinoin therapy until a negative result from this test is obtained. When a delay is not possible, place the patient on 2 reliable forms of contraception. Repeat pregnancy testing and contraception counseling monthly throughout the period of tretinoin treatment.

Warnings/Precautions

Concerns related to adverse effects:

• APL differentiation syndrome: [US Boxed Warning]: About 25% of patients with APL treated with tretinoin have experienced APL differentiation syndrome (formerly called retinoic-acid-APL [RA-APL] syndrome), which is characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusions, edema, and hepatic, renal, and/or multiorgan failure. The 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. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose. Management has not been defined, although high-dose steroids given at the first suspicion appear to reduce morbidity and mortality. 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 to 5 days (or until the symptoms resolve); taper off over 2 weeks. Most patients do not require termination of tretinoin therapy during treatment of the APL differentiation syndrome.

• Cardiovascular effects: Venous thrombosis and MI have been reported in patient 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).

• Leukocytosis: [US Boxed Warning]: 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 counts. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. Initiate treatment with high-dose corticosteroids immediately if signs and symptoms of APL differentiation syndrome are present with leukocytosis. Chemotherapy may be added to tretinoin treatment in patients presenting with a WBC count >5,000/mm3 or for a rapid WBC increase in patients leukopenic at start of treatment (may result in a lower incidence of APL differentiation syndrome). Consider adding full-dose chemotherapy (including an anthracycline if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count >5,000/mm3; immediately add for patients presenting with a WBC count <5,000/mm3 if the WBC count reaches ≥6,000/mm3 by day 5, ≥10,000/mm3 by day 10, or ≥15,000/mm3 by day 28.

• 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. Carefully monitor liver function test results during treatment and give consideration to a temporary withdrawal of tretinoin if test results reach >5 times the upper limit of normal. 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.

Disease-related concerns:

• APL: Tretinoin treatment for APL should be initiated early, discontinue if pending cytogenetic analysis does not confirm APL by t(15;17) translocation or the presence of the PML/RARα fusion protein (caused by translocation of the promyelocytic [PML] gene on chromosome 15 and retinoic acid receptor [RAR] alpha gene on chromosome 17).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations:

• Pregnancy: [US Boxed Warning]: High risk of teratogenicity; if treatment with tretinoin is required in women of childbearing potential, two reliable forms of contraception should be used during and for 1 month after discontinuation of treatment, unless abstinence is the chosen method. Within 1 week prior to starting therapy, serum or urine pregnancy test (sensitivity at least 50 milliunits/mL) should be collected. If possible, delay therapy until results are available. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment. Microdosed progesterone products (“minipill”) may provide inadequate pregnancy protection. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment. If possible, initiation of treatment with tretinoin should be delayed until negative pregnancy test result is confirmed.

Dosage form specific issues:

• Product 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Patients with APL are at high risk and can have severe adverse reactions to tretinoin. Administer tretinoin only to patients with APL under the close supervision of a provider who is experienced in the management of patients with acute leukemia, and in a facility with laboratory and supportive services for appropriate monitoring.

Monitoring Parameters

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 test results, and triglyceride and cholesterol levels frequently; monitor closely for signs of APL differentiation syndrome (eg, monitor volume status, pulmonary status, temperature, respiration)

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. [US Boxed Warning]: High risk of teratogenicity; if treatment with tretinoin is required in women of childbearing potential, two reliable forms of contraception should be used simultaneously during and for 1 month after discontinuation of treatment, unless abstinence is the chosen method. Within 1 week prior to starting therapy, serum or urine pregnancy test (sensitivity at least 50 milliunits/mL) should be collected. If possible, delay therapy until results are available. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Tretinoin was detected in the serum of a neonate at birth following maternal use of standard doses during pregnancy (Takitani 2005). Use in humans for the treatment of acute promyelocytic leukemia (APL) is limited and exposure occurred after the first trimester in most cases (Valappil 2007). However, major fetal abnormalities and spontaneous abortions have been reported with other retinoids; some of these abnormalities were fatal. 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 (Sanz 2009).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flushing, headache, constipation, diarrhea, nausea, vomiting, bone pain, skin irritation, loss of strength and energy, dry mouth, dry eyes, dry skin, dry lips, sweating a lot, hair loss, mouth sores, muscle pain, weight loss, lack of appetite, ear pain, mouth sores, anxiety, dizziness, or insomnia. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of infection, signs of retinoic-acid-APL syndrome (fever, shortness of breath, difficulty breathing, or weight gain); confusion; hallucinations; signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain); signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice); signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities); signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes); hearing impairment, hearing loss; abdominal edema; abnormal heartbeat; burning or numbness feeling; depression; angina; severe abdominal pain; shortness of breath; excessive weight gain; swelling of arms or legs; or signs of brain edema (severe headache, dizziness, nausea, vomiting, seizures) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Hide