mercaptopurine (Rx)

>10%

Elevated LFT's (15%)

1-10%

Nausea (10%)

Vomiting (10%)

Stomatitis (3-10%)

Thrombocytopenia (3-10%)

Rash (1-3%)

Diarrhea (1-3%)

Dizziness (1-3%)

Alopecia (1-3%)

Leukopenia (1-3%)

Frequency Not Defined

Fatigue

Anorexia

Headache

Chills and fever

Chest pain

Mucositis

Upper respiratory infection

Cough

Ulceration of intestine

Ulcerative stomatitis

Myelosuppression

Decreased hematocrit

Hepatotoxicity

Decreased resistance to infections

Hyperuricemia

Nephrotoxicity

Increased risk of pancreatitis in pts with IBD

Hyperpigmentation of skin

Arthralgias

Eye discomfort

Tinnitus

Postmarketing Reports

Photosensitivity

Hypoglycemia

Portal hypertension

Macrophage activation syndrome

Urticaria

Hyperbilirubinemia

Bone marrow toxicity

Hyperuricemia and/or hyperuricosuria

Skin rashes and hyperpigmentation

Alopecia

Fever (rare)

Contraindications

Hypersensitivity; prior resistance to 6-MP or thioguanine

Not effective for CLL, lymphomas, CNS leukemia

Cautions

Renal impairment

Reduce dose by 75% (ie, give quarter dose) when used concurrently with allopurinol

Recommended that evaluation of hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while patient is on therapy

Bone marrow examination may be useful for evaluation of marrow status; decision to increase, decrease, continue, or discontinue a given dosage must be based upon degree of severity and rapidity with which changes are occurring; in many instances, particularly during induction phase of acute leukemia, complete blood counts will need to be done more frequently than once weekly in order to evaluate effect of therapy

Increased risk of bone marrow toxicity; evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency; TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes; patients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions of the drug

Increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ; increased risk appears to be related to degree and duration of immunosuppression; discontinuation of immunosuppression reported to provide partial regression of lymphoproliferative disorder; a treatment regimen containing multiple immunosuppressants (including thiopurines) should be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities; a combination of multiple immunosuppressants, given concomitantly increases risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders

Macrophage activation syndrome (MAS) (hemophagocytic lymphohistiocytosis) a life-threatening disorder, may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD); there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine (an unapproved use); if MAS occurs, or is suspected, discontinue therapy; monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS

Drug fever very rarely reported; before attributing fever to drug, make every attempt to exclude more common causes of pyrexia, such as sepsis, in patients with acute leukemia

Avoid pregnancy

Hepatosplenic T-cell lymphomas

• Rare postmarketing cases reported primarily in adolescent and young adult patients with Crohn disease and ulcerative colitis treated with TNF blockers
• Reports have also included a patient being treated for psoriasis and 2 patients being treated for rheumatoid arthritis
• HSTCL is an aggressive, rare type of T-cell lymphoma (usually fatal)
• Most reported cases with TNF blockers have occurred with concomitant treatment with azathioprine or 6-mercaptopurine, although there have been cases reported receiving azathioprine or mercaptopurine alone
• The following HSTCL cases have been identified in the FDA Adverse Event Reporting System (AERS) database, the literature, and the HSTCL Cancer Survivors' Network: infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0), azathioprine (12), and mercaptopurine (3)

Pregnancy Category: D

Lactation: not known if excreted in breast milk, do not nurse

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Analog of naturally occurring purines hypoxanthine and guanine

Purine antagonist, antineoplastic

Absorption

Bioavailability: 5-37%

Peak Plasma Time: 2 hr

Onset: 2 hr

Duration: variable

Distribution

Protein Bound: 19%

Vd: 0.56-0.9 L/kg

Metabolism

GI mucosa, liver

Metabolites: 6-thiouric acid

Elimination

Half-Life: 21 minutes (children), 47 min (adult)

Clearance: 11 mL/min/kg

Excretion: urine

Dialyzable: no

Pharmacogenomics

6-mercaptopurine is activated by guanine phosphoribosyltransferase (HGPRT) to form thioinosine monophosphate (TIMP) and by kinase enzymatic pathways to form active 6-thioguanine nucleotides

Thiopurine S-methyltransferase (TPMT) inactivates 6-mercaptopurine

Although complete TPMT deficiency is rare in the general population (0.3%), TPMT screening should be performed prior to administration in all patients prescribed azathioprine or 6-mercaptopurine

With TPMT deficiency, a larger proportion of 6-mercaptopurine is converted to the cytotoxic 6-thioguanine nucleotide analogues, which can lead to bone marrow toxicity and myelosuppression

Alleles associated with decreased TPMT enzymatic activity are TPMT*2, TPMT*3A, and TPMT*3C

Genetic testing laboratories

• The following companies currently offer testing for TPMT variants
• Prometheus Labs (http://www.prometheuslabs.com/)
• Arup Laboratories (http://www.aruplab.com/)