Mercaptopurine

Actions Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase and is converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP inhibit de novo purine ribonucleotide synthesis. Absorption of oral mercaptopurine is incomplete and variable, averaging 50%. Plasma protein binding averages 19%. Plasma half-life averages 21 and 47 min in children and adults, respectively. Metabolites appear in urine within 2 hr. After 24 hours, > 50% of a dose is recovered in urine as intact drug and metabolites.

 Indications

Adult

Acute lymphoblastic leukemias.

Pediatric

Acute lymphoblastic leukemias.

Acute myeloblastic leukemias (adults).

 Contraindications Prior resistance to this drug.

 Route/Dosage

Acute Lymphocytic Leukemia, Remission Induction

ADULTS: PO Initiate therapy with 2.5 mg/kg/day, rounded to the nearest 25 mg. If no response after 4 wk of therapy, may increase dose £ 5 mg/kg/day PO. An alternative regimen is to initiate therapy with 80 to 100 mg/m2/day, rounded to the nearest 25 mg.

PEDIATRIC: PO Initiate therapy with 2.5 mg/kg/day, rounded to the nearest 25 mg. If no response after 4 wk of therapy, may increase dose £ 5 mg/kg/day PO. An alternative regimen is to initiate therapy with 70 to 100 mg/m2/day, rounded to the nearest 25 mg.

Acute Lymphocytic Leukemia, Maintenance

ADULTS: PO Usual range is 1.5 to 2.5 mg/kg/day as a single dose.

PEDIATRIC: PO Usual range is 1.5 to 2.5 mg/kg/day as a single dose. An alternative regimen is 75 mg/m2/day, rounded to the nearest 25 mg.

Interactions

Allopurinol

Inhibition of mercaptopurine metabolism; coadministration may cause increased toxicity.

Co-trimoxazole

Potentiates bone marrow suppression associated with mercaptopurine.

Methotrexate

May increase oral bioavailability of mercaptopurine.

Warfarin

Mercaptopurine may decrease the hypoprothrombinemic effect of warfarin; monitor and adjust warfarin therapy as necessary.

Lab Test Interferences None well documented.

 Adverse Reactions

DERMATOLOGIC: Rash; hyperpigmentation. GI: Very low potential for nausea and vomiting; anorexia, diarrhea, mucositis, intestinal ulceration, ascites, hepatocellular necrosis, cholestatic jaundice. HEMATOLOGIC: Bone marrow suppression, nadir at 7 to 14 days.

 Precautions

Pregnancy: Category D. Lactation: Undetermined. Bone marrow toxicity: Most consistent dose-related toxicity is bone marrow suppression manifested by anemia, leukopenia, or thrombocytopenia. Hepatotoxicity: Hepatotoxicity occurs with greatest frequency when doses of 2.5 mg/kg/day are exceeded. Deaths have occurred from hepatic necrosis. Renal function impairment: Start with smaller doses because of the possibility of slower drug elimination and a greater cumulative effect.

 Administration/Storage

• Store tablets at room temperature.
• Extemporaneous oral suspension (50 mg/mL oral suspension): Crush thirty 50 mg oral tablets completely. Combine with 1:2 mixture of methylcellulose 1% and syrup to form a paste. Dilute with sufficient amount of methylcellulose/syrup mixture for a final total volume of 30 mL. Simple syrup or cherry syrup may be used. It is stable for 14 days at room temperature in amber glass bottles.
• Administer PO. Give on an empty stomach since food may reduce bioavailability.
• Shake suspension well before using.
• Follow procedures for proper handling and disposal of anticancer drugs. Wear gloves and avoid skin exposure and inhalation of fumes.

 Assessment/Interventions

• Monitor CBC at least once weekly during therapy. During induction therapy, these parameters may need to be assessed more frequently.
• Monitor LFTs at baseline and periodically. Monitor more frequently if patient is receiving other hepatotoxic drugs concurrently.
• Hyperuricemia may occur because of rapid cell lysis; monitor serum uric acid. Minimize effects of hyperuricemia with hydration, urinary alkalinization, and allopurinol.

 Patient/Family Education

• Contraceptive measures are recommended during therapy for men and women.
• Notify health care provider if fever, sore throat, chills, nausea, vomiting, unusual bleeding or bruising, yellow discoloration of the skin or eyes, abdominal pain, flank or joint pain, swelling of the feet or legs, or symptoms suggestive of anemia occurs.
• May cause diarrhea, fever, and weakness; notify health care provider if these become pronounced.
• Maintain adequate fluid intake.