Usual Adult Dose for Acute Promyelocytic Leukemia

45 mg/m2/day administered as 2 evenly divided doses until complete remission

Duration of therapy: Discontinue therapy 30 days after complete remission or after 90 days of therapy, whichever comes first.

Comments:

• If after initiation of therapy the presence of the t(15;17) translocation is not confirmed by cytogenetics and/or polymerase chain reaction studies and the patient has not responded to therapy, alternative treatment should be considered.
• This drug is for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined. All patients should receive a standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy, unless contraindicated.

Use: For induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RAR alpha gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated.

Usual Pediatric Dose for Acute Promyelocytic Leukemia

1 year and older:
45 mg/m2/day administered as 2 evenly divided doses until complete remission

Duration of therapy: Discontinue therapy 30 days after complete remission or after 90 days of therapy, whichever comes first.

Comments:

• There are limited clinical data on the pediatric use of this drug.
• Out of 15 pediatric patients (1 to 16 years) treated with this drug the incidence of complete remission was 67%.
• Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable toxicity; however, the safety and efficacy of doses less than 45 mg/m2/day have not been evaluated in the pediatric population.

Use: For induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RAR alpha gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Data not available

Precautions

US BOXED WARNINGS:
EXPERIENCED PHYSICIAN AND INSTITUTION:

• Patients with acute promyelocytic leukemia (APL) can have severe adverse reactions to this drug; therefore, it should only be administered to these patients under the supervision of a physician experienced in the management of acute leukemia and in a facility equipped to monitor drug tolerance and protect/maintain a patient compromised by drug toxicity, including respiratory compromise.
• The benefit should outweigh the risk of using this drug.

RETINOIC ACID-APL SYNDROME:

• About 25% of patients with APL treated with this drug experience a syndrome called 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 multi-organ failure.
• This syndrome is occasionally accompanied by impaired myocardial contractility and episodic hypotension.
• It has been observed with or without concomitant leukocytosis.
• Endotracheal intubation and mechanical ventilation may be required due to hypoxemia and some patients have died from multi-organ failure.
• The syndrome generally occurs during the first month of therapy, with some cases reported following the first dose.
• High-dose steroids (dexamethasone 10 mg IV every 12 hours for 3 days or until resolution of symptoms) should be immediately initiated irrespective of the leukocyte count.
• Most patients do not require termination of therapy during treatment of the RA-APL syndrome; however, in cases of moderate and severe RA-APL syndrome, temporary interruption of therapy should be considered.

LEUKOCYTOSIS AT PRESENTATION AND RAPIDLY EVOLVING LEUKOCYTOSIS DURING THERAPY:

• About 40% of patients develop rapidly evolving leukocytosis.
• Patients who present with high WBC at diagnosis [greater than 5 x 10(9)/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 RA-APL syndrome is present with leukocytosis, treatment with high-dose steroids should be initiated immediately. Some experts routinely add chemotherapy to this drug in the case of patients presenting with a WBC count of greater than 5 x 10(9)/L or in the case of a rapid increase in WBC count for patients leukopenic at start of therapy and have reported a lower incidence of the RA-APL syndrome.
• Consideration should be given to adding full-dose chemotherapy (including an anthracycline if not contraindicated) to this drug on Day 1 or 2 for patients presenting with a WBC count of greater than 5 x 10(9)/L, or immediately, for patients presenting with a WBC count of less than 5 x 10(9), if the WBC count reaches 6 x 10(9)/L or greater by day 5, or 10 x 10(9)/L or greater by day 10, or 15 x 10(9)/L or greater by day 28.

TERATOGENIC EFFECTS:

• There is a high risk that a severely deformed infant will result if this drug is administered during pregnancy.
• If this drug is given to a pregnant woman or a woman of childbearing potential, the patient should be advised of the risk to the fetus.
• Women of childbearing potential should be instructed to use 2 reliable forms of contraception simultaneously during therapy and for 1 month after.
• Within 1 week prior to starting this drug, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL.
• When possible, therapy should be delayed until a negative result from a pregnancy 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.

CONTRAINDICATIONS:

• Hypersensitivity to the active component or any of the ingredients
• Hypersensitivity to other retinoids
• In patients who are sensitive to parabens which are used as preservatives in the gelatin capsule

Safety and efficacy have not been established in patients younger than 1 year.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Swallow capsules whole with water; do not chew.
• This drug should be administered with a meal or shortly thereafter.
• This drug is indicated for the induction of remission only. All patients should receive a standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy unless contraindicated.

Storage requirements:

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

Monitoring:

• Regular liver function tests.

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