No

Antineoplastic Agent, Miscellaneous

Acute promyelocytic leukemia (APL): Induction of remission in patients with APL, French American British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation or the presence of the PML/RARa gene who are refractory to or who have relapsed from anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated. Tretinoin is for the induction of remission only. All patients should receive an accepted form of remission consolidation or maintenance therapy for APL after completion of induction therapy with tretinoin.

D

Sensitivity to parabens, vitamin A, or other retinoids

Patients with acute promyelocytic leukemia (APL) are at high risk and can have severe adverse reactions to tretinoin. Administer under the 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 to protect and maintain a patient compromised by drug toxicity, including respiratory compromise.

Management of the syndrome has not been defined, but high-dose steroids given at the first suspicion of RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome, immediately initiate high-dose steroids (dexamethasone 10 mg I.V.) every 12 hours for 3 days or until resolution of symptoms, regardless of the leukocyte count. The majority of patients do not require termination of tretinoin therapy during treatment of the RA-APL syndrome.

During treatment, ~40% of patients will develop rapidly evolving leukocytosis. 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, initiate treatment with high-dose steroids immediately. Consider adding full-dose chemotherapy (including an anthracycline, if not contraindicated) to the tretinoin therapy on day 1 or 2 for patients presenting with a WBC count of >5 x 10⁹/L or immediately, for patients presenting with a WBC count of <5 x 10⁹/L, if the WBC count reaches greater than or equal to 6 x 10⁹/L by day 5, or greater than or equal to 10 x 10⁹/L by day 10 or greater than or equal to 15 x 10⁹/L by day 28.

Not to be used in women of childbearing potential unless the woman is capable of complying with effective contraceptive measures; therapy is normally begun on the second or third day of next normal menstrual period; two reliable methods of effective contraception must be used during therapy and for 1 month after discontinuation of therapy, unless abstinence is the chosen method. Within one week prior to the institution of tretinoin therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/L. When possible, delay tretinoin therapy until a negative result from this test is obtained. When a delay is not possible, place the patient on two reliable forms of contraception. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment.

Initiation of therapy with tretinoin may be based on the morphological diagnosis of APL. Confirm the diagnosis of APL by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RARa fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to tretinoin has not been demonstrated.

Retinoids have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children. Early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances.

Up to 60% of patients experienced hypercholesterolemia or hypertriglyceridemia, which were reversible upon completion of treatment.

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.

Virtually all patients experience some drug-related toxicity, especially headache, fever, weakness and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require therapy interruption

Cardiovascular: Arrhythmias, flushing, hypotension, hypertension, peripheral edema, chest discomfort, edema

Central nervous system: Dizziness, anxiety, insomnia, depression, confusion, malaise, pain

Dermatologic: Burning, redness, cheilitis, inflammation of lips, dry skin, pruritus, photosensitivity

Endocrine & metabolic: Increased serum concentration of triglycerides

Gastrointestinal: GI hemorrhage, abdominal pain, other GI disorders, diarrhea, constipation, dyspepsia, abdominal distention, weight gain or loss, xerostomia

Hematologic: Hemorrhage, disseminated intravascular coagulation

Local: Phlebitis, injection site reactions

Neuromuscular & skeletal: Bone pain, arthralgia, myalgia, paresthesia

Ocular: Itching of eye

Renal: Renal insufficiency

Respiratory: Upper respiratory tract disorders, dyspnea, respiratory insufficiency, pleural effusion, pneumonia, rales, expiratory wheezing, dry nose

Miscellaneous: Infections, shivering

1% to 10%:

Cardiovascular: Cardiac failure, cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy, cerebral hemorrhage, pallor

Central nervous system: Intracranial hypertension, agitation, hallucination, agnosia, aphasia, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, encephalopathy, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, unconsciousness, dementia, forgetfulness, somnolence, slow speech, hypothermia

Dermatologic: Skin peeling on hands or soles of feet, rash, cellulitis

Endocrine & metabolic: Fluid imbalance, acidosis

Gastrointestinal: Hepatosplenomegaly, ulcer

Genitourinary: Dysuria, polyuria, enlarged prostate

Hepatic: Ascites, hepatitis

Neuromuscular & skeletal: Tremor, leg weakness, hyporeflexia, dysarthria, facial paralysis, hemiplegia, flank pain, asterixis, abnormal gait

Ocular: Dry eyes, photophobia

Renal: Acute renal failure, renal tubular necrosis

Respiratory: Lower respiratory tract disorders, pulmonary infiltration, bronchial asthma, pulmonary/larynx edema, unspecified pulmonary disease

Miscellaneous: Face edema, lymph disorders

<1%: Mood changes, pseudomotor cerebri, alopecia, hyperuricemia, anorexia, nausea, vomiting, inflammatory bowel syndrome, bleeding of gums, increase in erythrocyte sedimentation rate, decrease in hemoglobin and hematocrit, conjunctivitis, corneal opacities, optic neuritis, cataracts

The maximum tolerated dose in adult patients with myelodysplastic syndrome in solid tumors was 195 mg/m²/day; the maximum tolerated dose in pediatric patients was lower at 60 mg/m²/day. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness, and ataxia. These symptoms resolved quickly without residual effects.

CYP3A3/4 enzyme substrate

Increased toxicity: Ketoconazole increases the mean plasma AUC of tretinoin

Retinoid that induces maturation of acute promyelocytic leukemia (APL) cells in cultures; induces cytodifferentiation and decreased proliferation of APL cells

Protein binding: >95%

Metabolism: In the liver via cytochrome P-450 enzymes

Half-life, terminal: Parent drug: 0.5-2 hours

Time to peak serum concentration: Within 1-2 hours

Elimination: Equally in urine and feces

Oral:

Adults: 45 mg/m²/day administered as two evenly divided doses until complete remission is documented. Discontinue therapy 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. If after initiation of treatment the presence of the t(15;17) translocation is not confirmed by cytogenetics or by polymerase chain reaction studies and the patient has not responded to tretinoin, consider alternative therapy.

Note: Tretinoin is for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined. All patients should therefore receive a standard consolidation or maintenance chemotherapy regimen for APL after induction therapy with tretinoin unless otherwise contraindicated.

Absorption of retinoids has been shown to be enhanced when taken with food

Monitor the patient's hematologic profile, coagulation profile, liver function test results and triglyceride and cholesterol levels frequently

Dizziness, anxiety, insomnia, depression, and confusion are common; may cause agitation, hallucinations, or cognitive impairment; may rarely cause mood changes

None reported

No information available to require special precautions

<1% of patients may have bleeding gums, dry mouth

Take with food. Do not crush, chew, or dissolve capsules. You will need frequent blood tests while taking this medication. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake), avoid alcohol and foods containing vitamin A, and foods with high fat content. You may experience lethargy, dizziness, visual changes, confusion, anxiety (avoid driving or engaging in tasks requiring alertness until response to drug is known). For nausea and vomiting, loss of appetite, or dry mouth small, frequent meals, chewing gum, or sucking lozenges may help. You may experience photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). You may experience dry, itchy, skin, and dry or irritated eyes (avoid contact lenses). Report persistent vomiting or diarrhea, difficulty breathing, unusual bleeding or bruising, acute GI pain, bone pain, or vision changes immediately. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication - both male and female should use appropriate barrier contraceptive measures. Do not give blood during this therapy or for 1 month following discontinuation of therapy. Breast-feeding is not recommended.

Capsule: 10 mg

Chen GQ, Shen ZX, Wu F, et al, "Pharmacokinetics and Efficacy of Low-Dose All- trans Retinoic Acid in the Treatment of Acute Promyelocytic Leukemia," Leukemia, 1996, 10(5):825-8.

Kurzrock R, Estey E, and Talpaz M, "All- trans Retinoic Acid: Tolerance and Biologic Effects in Myelodysplastic Syndrome," J Clin Oncol, 1993, 11(8):1489-95.

Lazzarino M, Regazzi MB, and Corso A, "Clinical Relevance of All- trans Retinoic Acid Pharmacokinetics and Its Modulation in Acute Promyelocytic Leukemia," Leuk Lymphoma, 1996, 23(5-6):539-43.

Muindi JR, Frankel SR, Huselton C, et al, "Clinical Pharmacology of Oral All- trans Retinoic Acid in Patients With Acute Promyelocytic Leukemia," Cancer Res, 1992, 52(8):2138-42.

Smith MA, Adamson PC, Balis FM, et al, "Phase I and Pharmacokinetic Evaluation of All- trans-Retinoic Acid in Pediatric Patients With Cancer," J Clin Oncol, 1992, 10(11):1666-73.