Mercaptopurine has been in clinical use for over 30 years. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guaninehn and acts as a cytotoxic antimetabolite. Mercaptopurine requires intracellular anabolism by hypoxantine guanine phosphoribosyl transferase (HGPTPT) to be cytotoxic. Intracellular activation results in de novo inhibition of purine synthesis and incorporation into DNA. Mercaptopurine is cross-resistant with 6-thioguanine. Cytotoxicity is cell cycle phase-specific (S-phase).
|Bioavailability||oral: Incomplete and variable absorption ± 50%. Bioavailability is 5-37% largely due to first pass metabolism in the liver (less when given with food)|
Widely distributed to body tissues.
|Cross blood brain barrier?||Negligible with conventional doses.|
Rapid intracellular enzymatic activation. Inactivated by TMPT and xanthine oxidase.
|Active metabolites||thioguanine nucleotides, methylated nucleotides|
At conventional doses clearance is primarily hepatic and by xanthine oxidase, which is the main catabolic enzyme. Renal clearance may become important at high doses.
|Urine||7% of oral dose excreted unchanged in 12 hours.|
|Half-life||90 minutes; active metabolites longer|
- Maintenance therapy of acute lymphocytic or lymphoblastic leukemia as part of a combination regimen
- Acute promyelocytic leukemia (APL) as part of a combination regimen
Extravasation Potential: Not applicable
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Radiation recall reaction (facial edema; rare)||I E|
|Nausea, vomiting (23%)||I|
|Hematological||Immunosuppression /atypical infection||E|
|Myelosuppression ± infection, bleeding (may be severe)||E|
|Hepatobiliary||↑ LFTs (40%) (may be severe)||E|
|Hypersensitivity||Hypersensitivity (fever, arthralgia)||I E|
|Metabolic / Endocrine||Tumor lysis syndrome||I E|
|Neoplastic||Secondary malignancy (leukemia/lymphoma; rare)||L|
|Urinary||Crystalluria (high IV doses)||E|
|Hemorrhage (high IV doses)||E|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The major dose limiting effect of mercaptopurine is myelosuppression. Patients with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) are prone to develop rapid bone marrow suppression. Phenotypic or genetic screening tests for TPMT deficiency are available, but are not routine practice in Canada. Myelosuppression may be exacerbated by coadministration with drugs that inhibit TPMT, such as allopurinol, olsalazine, mesalazine or sulfasalazine.
Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g., some leukemias and lymphomas), can be minimized with allopurinol and hydration. However, the dose of mercaptopurine should be reduced to 25%-33% of the usual dose if allopurinol is given.
Hepatic toxicity ranges from asymptomatic elevation of liver enzymes with no clinical significance to jaundice (intrahepatic cholestasis 10-40%) and liver failure; liver failure is more common when mercaptopurine is used in combination with doxorubicin. Serious toxicity is manifested by rapid onset of jaundice, ascites, hepatic encephalopathy and/or elevated liver enzymes, usually associated with hepatic necrosis, failure and severe fibrosis. Clinical signs of jaundice are usually evident at 1-2 months but have been reported as early as 1 week and as late as 8 years after initiation of mercaptopurine therapy. Deaths have occurred from hepatic necrosis. The incidence of hepatotoxicity increases when dosage exceeds 2.5mg/kg daily, and in combination with doxorubicin.
Refer to protocol by which patient is being treated, Numerous dosing schedules exist depending on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.
Patients with severe TPMT deficiency are at increased risk of myelosuppression and require substantial dose reduction, especially if homozygous.
Oral: 50 - 75 mg/m² daily then titrate to toxicity/response
Dosage in myelosuppression:
Modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Hematologic and Non-Hematologic Toxicities."
Dosage with other toxicity:
Mercaptopurine should be discontinued immediately in the presence of hepatotoxicity.
The starting dose or frequency of administration should be modified in the presence of renal dysfunction. Suggested modification:
|Creatinine clearance (mL/min)||Dosing interval (h)|
|50 - 75||24-36|
Children (> 3 months):
- Induction: Daily: 2.5mg/kg; may increase dose to 5mg/kg after 4 weeks if tolerated and efficacy suboptimal
- Maintenance: 1.5-2.5mg/kg
Decrease dose by 50% in children less than 3 months of age.
- Oral self-administration; drug available by outpatient prescription
- If a dose is missed , the next dose should be taken as scheduled. An extra dose should not be taken to make up for the missed dose.
- Hypersensitivity to this drug or any ingredient in the formulation
- Patients whose disease has demonstrated prior resistance to this drug. Mercaptopurine is completely cross-resistant to thioguanine.
- Avoid the use of live vaccines
- Patients with hereditary thiopurine methyltrasferase (TPMT) deficiency, those receiving concomitant allopurinol or drugs that inhibit TPMT are at increased risk of myelosuppression
Mercaptopurine is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
Excretion into breast milk:
Breastfeeding is not recommended.
Mercaptopurine is not a substrate, inhibitor or inducer of CYP enzymes.
|Allopurinol||↑ myelosuppression by mercaptopurine||Inhibits inactivation of mercaptopurine||Decrease dose of mercaptopurine to 25%-33% of usual dose|
|Anticoagulants||May ↓ anticoagulant effect of warfarin||Unknown||Monitor INR/PT|
|Doxorubicin and other hepatotoxins||Enhances hepatotoxicity||Unknown||Avoid/caution|
|Trimethoprim-sulfamethoxazole||Enhanced myelosuppression||Additive||May need to ↓ dose of mercaptopurine|
|Sequential multiple analyzer 12/60||Falsely elevated serum glucose and uric acid values||Unknown||Caution|
|Aminosalicylates, sulfasalazine||↑ myelosuppression||Inhibition of TPMT||Caution|
|Azathioprine||↑ myelosuppression by mercaptopurine||active metabolite of azathioprine is mercaptopurine||Avoid|
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
|Liver function tests||Baseline and periodic (weekly then monthly); more frequently in patients with pre-existing liver disease or receiving hepatotoxic drugs|
|CBC||Baseline and regular (daily during induction)|
Clinical monitoring for hepatic, hematologic and immunosuppression effects
|At each visit|
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
|Monitor Type||Monitor Frequency|
|Renal function tests (if failure suspected)||Baseline|
|Screening test for TPMT deficiency (if available) especially with severe toxicity|
|INR||Baseline and as clinically required|
ODB - General Benefit (ODB Formulary )
- mercaptopurine ()
Cancer Drug Manual (the Manual), 1994, revised March 2007. British Columbia Cancer Agency (BCCA).
June 2019 Updated emetic risk category.
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