No

Antineoplastic Agent, Antimetabolite

Treatment of acute leukemias (ALL or AML) maintenance therapy

D

Hypersensitivity to mercaptopurine or any component; patients whose disease showed prior resistance to mercaptopurine or thioguanine; severe liver disease, severe bone marrow suppression

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Mercaptopurine may cause birth defects; potentially carcinogenic; adjust dosage in patients with renal impairment or hepatic failure; use with caution in patients with prior bone marrow suppression; patients may be at risk for pancreatitis. Toxicity to immunosuppressives is increased in elderly. Start with lowest recommended adult doses. Signs of infection, such as fever and WBC rise, may not occur. Lethargy and confusion may be more prominent signs of infection.

>10%: Hepatic: 6-MP can cause an intrahepatic cholestasis and focal centrilobular necrosis manifested as hyperbilirubinemia, increased alkaline phosphatase, and increased AST. This may be dose related, occurring more frequently at doses >2.5 mg/kg/day; jaundice is noted 1-2 months into therapy, but has ranged from 1 week to 8 years.

1% to 10%:

Dermatologic: Hyperpigmentation, rash

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Nausea, vomiting, diarrhea, stomatitis, anorexia, stomach pain, and mucositis may require parenteral nutrition and dose reduction; 6-TG is less GI toxic than 6-MP

Hematologic: Leukopenia, thrombocytopenia, anemia may occur at high doses

Myelosuppressive:

WBC: Moderate

Platelets: Moderate

Onset (days): 7-10

Nadir (days): 14

Recovery (days): 21

Renal: Renal toxicity

<1%: Drug fever, dry and scaling rash, glossitis, tarry stools, eosinophilia

Symptoms of overdose include:

Delayed: Bone marrow suppression, hepatic necrosis, gastroenteritis

Decreased effect: Warfarin: 6-MP inhibits the anticoagulation effect of warfarin by an unknown mechanism

Increased toxicity:

Allopurinol: Can cause increased levels of 6-MP by inhibition of xanthine oxidase; decrease dose of 6-MP by 75% when both drugs are used concomitantly; seen only with oral 6-MP usage, not with I.V.; may potentiate effect of bone marrow suppression (reduce 6-MP to 25% of dose)

Doxorubicin: Synergistic liver toxicity with 6-MP in >50% of patients, which resolved with discontinuation of the 6-MP

Hepatotoxic drugs: Any agent which could potentially alter the metabolic function of the liver could produce higher drug levels and greater toxicities from either 6-MP or 6-TG

Store at room temperature

Purine antagonist which inhibits DNA and RNA synthesis; acts as false metabolite and is incorporated into DNA and RNA, eventually inhibiting their synthesis. 6-MP is substituted for hypoxanthine; must be metabolized to active nucleotides once inside the cell.

Absorption: Variable and incomplete (16% to 50%)

Distribution: V_d = total body water; CNS penetration is poor

Protein binding: 30%

Metabolism: Undergoes first-pass metabolism in the GI mucosa and liver; metabolized in the liver by xanthine oxidase and methylation to sulfate conjugates, 6-thiouric acid and other inactive compounds

Half-life: Age dependent: Children: 21 minutes; Adults: 47 minutes

Time to peak serum concentration: Within 2 hours

Elimination: Prompt excretion in the urine; with high doses of I.V. 6-MP, the renal excretion of unchanged drug is 20% to 40% and can produce hematuria and crystalluria; at conventional doses renal elimination is minor

Oral (refer to individual protocols):

Adults:

Induction: 2.5-5 mg/kg/day (100-200 mg)

Maintenance: 1.5-2.5 mg/kg/day OR 80-100 mg/m²/day given once daily

Elderly: Due to renal decline with age, start with lower recommended doses for adults

Dosing adjustment in renal or hepatic impairment: Dose should be reduced to avoid accumulation, but specific guidelines are not available

Hemodialysis: Removed; supplemental dosing is usually required

Should not be administered with meals

Further dilute the 10 mg/mL reconstituted solution in normal saline or D₅W to a final concentration for administration of 1-2 mg/mL; administer by slow I.V. continuous infusion

CBC with differential and platelet count, liver function tests, uric acid, urinalysis

None reported

May cause leukopenia; use caution with clozapine or carbamazepine

No information available to require special precautions

No effects or complications reported

Take daily dose at the same time each day. Preferable to take an on empty stomach (1 hour before or 2 hours after meals). Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). You may experience nausea and vomiting, diarrhea, or loss of appetite (frequent small meals may help/request medication) or weakness or lethargy (use caution when driving or engaging in tasks that require alertness until response to drug is known). Use good oral care to reduce incidence of mouth sores. You may be more susceptible to infection (avoid crowds or exposure to infection). May cause headache (request medication). Report signs of opportunistic infection (eg, fever, chills, sore throat, burning urination, fatigue); bleeding (eg, tarry stools, easy bruising); unresolved mouth sores, nausea, or vomiting; swelling of extremities, difficulty breathing, or unusual weight gain. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Do not breast-feed.

Adjust dosage in patients with renal insufficiency to lowest recommended dose; monitor dose response with WBC and platelet counts; observe for signs of infection and bleeding or bruising; further dilute the 10 mg/mL reconstituted solution in normal saline or D₅W to a final concentration for administration of 1-2 mg/mL; administer by slow I.V. continuous infusion

Tablet, scored: 50 mg

A 50 mg/mL oral suspension was made by crushing the tablets, mixing with a volume of Cologel® suspending agent equal to 1/3 the final volume, and adding a 2:1 mixture of simple syrup and cherry syrup to make the final volume; stable for 14 days when stored in an amber glass bottle at room temperature

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Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Kaplan HG, "Use of Cancer Chemotherapy in the Elderly," Drug Treatment in the Elderly, Vestal RE, ed, Boston, MA: ADIS Health Science Press, 1984, 338-49.

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Pinkel D, "Intravenous Mercaptopurine: Life Begins at 40," J Clin Oncol, 1993, 11(9):1826-31.

Van Scoik KG, Johnson CA, and Porter WR, "The Pharmacology and Metabolism of the Thiopurine Drugs 6-Mercaptopurine and Azathioprine," Drug Metab Rev, 1985, 16(1-2):157-74.

Zimm S, Ettinger LJ, Holcenberg JS, et al, "Phase I and Clinical Pharmacological Study of Mercaptopurine Administered as a Prolonged Intravenous Infusion," Cancer Res, 1988, 45(4):1869-73.