Usual Adult Dose for Acute Promyelocytic Leukemia

INDUCTION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day until bone marrow remission or up to a maximum of 60 days
CONSOLIDATION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day for 25 doses over a period of up to 5 weeks; begin consolidation 3 to 6 weeks after completion of induction therapy

Use: Induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Usual Pediatric Dose for Acute Promyelocytic Leukemia

4 YEARS AND OLDER:
INDUCTION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day until bone marrow remission or up to a maximum of 60 days
CONSOLIDATION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day for 25 doses over a period of up to 5 weeks; begin consolidation 3 to 6 weeks after completion of induction therapy

Use: Induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Renal Dose Adjustments

CrCl less than 30 mL/min: Dose adjustment(s) may be required; however, no specific guidelines have been suggested. Caution recommended.

Liver Dose Adjustments

Mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment: Use with caution.
Severe (Child-Pugh C): hepatic impairment: Use with caution; monitor for toxicity.

HEPATOTOXICITY, DEFINED BY 1 OR MORE OF THE FOLLOWING (total bilirubin [TB] greater than 3 times the upper limit of normal [ULN]; aspartate aminotransferase [AST] greater than 5 x ULN; alkaline phosphatase [AP] greater than 5 x ULN):

• Withhold therapy.
• Resume therapy at a 50% reduced dose of the withheld drug(s) when TB is less than 1.5 x ULN and AP/AST are less than 3 x ULN.
• Increase the dose of the withheld drug(s) back to the recommended dose after 7 days on the reduced dose in the absence of worsening of hepatotoxicity.
• Discontinue the withheld drug(s) permanently if hepatotoxicity recurs.

Dose Adjustments

RECOMMENDED DOSE REDUCTION SCHEDULE:

• Starting dose: 0.15 mg/kg IV once daily
• First dose reduction: 0.11 mg/kg IV once daily
• Second dose reduction: 0.1 mg/kg IV once daily
• Third dose reduction: 0.075 mg/kg IV once daily

• Temporarily withhold this drug; treat with dexamethasone 10 mg IV every 12 hours until resolution for a minimum of 3 days.
• Resume this drug when condition improves and reduce the dose of the withheld drug(s) by 50%.
• Increase the dose of the withheld drug(s) to the recommended dosage after 7 days in the absence of recurrence of symptoms of differentiation syndrome.
• If symptoms reappear, decrease the dose of this drug to the previous dose.

• Withhold this drug and any medication known to prolong the QTc interval.
• Replete electrolytes.
• After the QTc normalizes, resume this drug at a 50% reduced dose (0.075 mg/kg once daily) for 7 days.
• If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase the dose of arsenic trioxide injection to 0.11 mg/kg once daily for 7 days.
• Increase the dose of this drug to 0.15 mg/kg in the absence of QTc prolongation during the 14-day dose-escalation period.

• Withhold therapy.
• Resume therapy at a 50% reduced dose of the withheld drug(s) when TB is less than 1.5 x ULN and AP/AST are less than 3 x ULN.
• Increase the dose of the withheld drug(s) back to the recommended dose after 7 days on the reduced dose in the absence of worsening of hepatotoxicity.
• Discontinue the withheld drug(s) permanently if hepatotoxicity recurs.

• Temporarily withhold this drug.
• When adverse reaction resolves to no more than mild (Grade 1), resume this drug reduced by 2 dose levels.

• Administer hydroxyurea.
• Hydroxyurea may be discontinued when the WBC declines below 10 Gi/L.

• If myelosuppression lasts 50 days or longer OR occurs on 2 consecutive cycles, assess a marrow aspirate for remission status.
• In the case of molecular remission, resume this drug at 1 dose level lower.

Precautions

US BOXED WARNINGS:
DIFFERENTIATION SYNDROME:

• Differentiation syndrome has been reported and can be fatal if not treated.
• Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain or peripheral edema, hypotension, and renal, hepatic, or multi-organ dysfunction, in the presence or absence of leukocytosis.

• If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution.
• Temporary discontinuation of this drug may be required

• This drug can cause QTc interval prolongation, complete atrioventricular block, and a torsade de pointes-type ventricular arrhythmia, which can be fatal.

• Before initiating therapy, assess the QTc interval, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval.
• Do not administer this drug to patients with ventricular arrhythmia or prolonged QTcF.

• Serious encephalopathy, including Wernicke's, has been reported.
• Wernicke's is a neurologic emergency.

• Consider testing thiamine levels in patients at risk for thiamine deficiency.
• Administer parenteral thiamine in patients with or at risk for thiamine deficiency.
• Monitor patients for neurological symptoms and nutritional status while receiving this drug.
• If encephalopathy is suspected, immediately interrupt therapy and initiate parenteral thiamine.
• Monitor until symptoms resolve or improve and thiamine levels normalize

• Hypersensitivity to the active component or any of the ingredients

Dialysis

Data not available

Other Comments

Administration Advice:

• May extend IV infusion duration up to 4 hours if vasomotor reactions are observed; a central venous catheter is not required.

• Store this drug at 25C (77F); excursions permitted to 15C to 30C (59F to 86F). Do not freeze.
• After dilution, this drug is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.

• Dilute this drug with 100 to 250 mL 5% dextrose injection or 0.9% sodium chloride injection using proper aseptic technique, immediately after withdrawal from the vial.
• Do not save any unused portions for later administration.
• Consult the manufacturer product information.

• Do not mix this drug with other medications.

• This drug is cytotoxic. Follow applicable special handling and disposal procedures.

• Cardiovascular: ECG, QT/QTc interval, heartbeat
• Laboratory: Electrolytes, creatinine, glucose; hepatic, renal, hematologic, and coagulation profiles
• Nervous System: Neuropathy signs/symptoms
• Oncologic: APL differentiation syndrome signs/symptoms; development of second primary malignancies.