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mercaptopurine

( mer-kap-toe-PURE-een )
Funding:
ODB - General Benefit (with Therapeutic Notes)
  • mercaptopurine
Other Name(s): Purinethol® (multiple brands available)
Appearance: tablet
A - Drug Name

mercaptopurine

SYNONYM(S):   6-mercaptopurine; 6-MP; NSC 755

COMMON TRADE NAME(S):   Purinethol® (multiple brands available)

 
B - Mechanism of Action and Pharmacokinetics

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).



Absorption
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)

Distribution

 Widely distributed to body tissues.

Cross blood brain barrier? Negligible with conventional doses.
PPB 19% (IV)
Metabolism

Rapid intracellular enzymatic activation. Inactivated by TMPT and xanthine oxidase.

Active metabolites thioguanine nucleotides, methylated nucleotides
Inactive metabolites

yes

Elimination

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
 
C - Indications and Status
Health Canada Approvals:

  • Maintenance therapy of acute lymphocytic or lymphoblastic leukemia as part of a combination regimen


Other Uses:

  • Acute promyelocytic leukemia (APL) as part of a combination regimen
 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   Not applicable

ORGAN SITE SIDE EFFECT* (%) ONSET**
Dermatological Alopecia (rare) E
Radiation recall reaction (facial edema; rare) I  E
Rash (2%)
Skin discolouration E
Gastrointestinal Anorexia E
Diarrhea E
Dyspepsia E
Mucositis (2%) E
Nausea, vomiting (23%) I
Hematological Immunosuppression /atypical infection E
Myelosuppression ± infection, bleeding (may be severe) E
Hepatobiliary ↑ LFTs (40%) (may be severe) E
Pancreatitis (rare) 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.
Dose-limiting side effects are underlined.

** 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.

 

 

 

 

 

 

 

 

 
E - Dosing

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.



Adults:

Mercaptopurine should be given as a single dose on an empty stomach; doses should be rounded to the nearest 25mg. Dose must be reduced to 33% or 25% when used with allopurinol.
Induction (adult):
Oral: 50 - 75 mg/m² daily then titrate to toxicity/response

Dosage with Toxicity:

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.



Dosage with Hepatic Impairment:

Adjustment required, no details found.

Dosage with Renal Impairment:

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
     < 50      24-48



Dosage in the elderly:

Use with caution, start at the low end of the dosing range. Consider dose reduction with renal or hepatic dysfunction.

Children:

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.



 
F - Administration Guidelines

  • 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.


 
G - Special Precautions
Contraindications:

  • 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

     

Other Warnings/Precautions:

  • Patients with hereditary thiopurine methyltrasferase (TPMT) deficiency, those receiving concomitant allopurinol or drugs that inhibit TPMT are at increased risk of myelosuppression

Pregnancy and Lactation:
  • Embryotoxicity: Yes
  • Teratogenicity: Yes
  • Mutagenicity: Yes
  • Fertility effects: Yes
    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: Yes

    Breastfeeding is not recommended.

     

 
H - Interactions

Mercaptopurine is not a substrate, inhibitor or inducer of CYP enzymes.

AGENT EFFECT MECHANISM MANAGEMENT
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
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

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



Suggested Clinical Monitoring

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
 
J - Supplementary Public Funding

ODB - General Benefit (with Therapeutic Notes) (

)
  • mercaptopurine ()

 
K - References

Cancer Drug Manual (the Manual), 1994, revised March 2007. British Columbia Cancer Agency (BCCA).

McEvoy GK, ed in chief, Snow ED, ed. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2011:1148-1151.
 
Product Monograph:  Purinethol® (mercaptopurine).  Novopharm Limited, July 16, 2014.


October 2017 added other indication

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.