MERCAPTOPURINE Drug Interactions: What You Need to Know

INTERACTIONS

• Allopurinol : Reduce the dose of mercaptopurine when coadministered with allopurinol. ( 2.4 , 7.1 )
• Warfarin : Mercaptopurine may decrease the anticoagulant effect. ( 7.2 )

7.1 Allopurinol Allopurinol can inhibit the first-pass oxidative metabolism of mercaptopurine by xanthine oxidase, which can lead to an increased risk of mercaptopurine adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 )]</span> . Reduce the dose of mercaptopurine when coadministered with allopurinol <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .

7.2 Warfarin The coadministration of mercaptopurine with warfarin may decrease the anticoagulant effectiveness of warfarin. Monitor the international normalized ratio (INR) in patients receiving warfarin and adjust the warfarin dosage as appropriate.

7.3 Myelosuppressive Products Mercaptopurine can cause myelosuppression. Myelosuppression may be increased when mercaptopurine is coadministered with other drugs that cause myelosuppression. Enhanced myelosuppression has been noted in some patients receiving trimethoprim-sulfamethoxazole. Monitor the CBC and adjust the dose of mercaptopurine for excessive myelosuppression <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 )]</span> .

7.4 Aminosalicylates Aminosalicylates (e.g., mesalamine, olsalazine or sulfasalazine) may inhibit the TPMT enzyme, which may increase the risk of myelosuppression when coadministered with mercaptopurine. When aminosalicylates and mercaptopurine are coadministered, use the lowest possible doses for each drug and monitor more frequently for myelosuppression <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

7.5 Hepatotoxic Products Mercaptopurine can cause hepatotoxicity. Hepatotoxicity may be increased when mercaptopurine is coadministered with other products that cause hepatotoxicity. Monitor liver tests more frequently in patients who are receiving mercaptopurine with other hepatotoxic products <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

7.6 Methotrexate Mercaptopurine dosage may need adjustment when administered concomitantly with high dose methotrexate <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . Mercaptopurine exposure increases with concomitant methotrexate use <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> which may increase the risk of mercaptopurine adverse reactions. The mechanism of this interaction has not been fully characterized <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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AND PRECAUTIONS

• Myelosuppression : Monitor complete blood count (CBC) and adjust the dose of mercaptopurine for excessive myelosuppression. Consider testing in patients with severe myelosuppression or repeated episodes of myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency. Patients with homozygous-TPMT or homozygous-NUDT15 deficiency may require a dose reduction. ( 2.2 , 5.1 )
• Hepatotoxicity : Monitor transaminases, alkaline phosphatase and bilirubin. Withhold mercaptopurine at onset of hepatotoxicity. ( 5.2 )
• Immunosuppression : Response to all vaccines may be diminished and there is a risk of infection with live virus vaccines. Consult immunization guidelines for immunocompromised pediatrics. ( 5.3 )
• Treatment Related Malignancies : Aggressive and fatal cases of hepatosplenic T-cell lymphoma have occurred. ( 5.4 )
• Macrophage Activation Syndrome : Monitor for and treat promptly; discontinue mercaptopurine. ( 5.5 )
• Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )
• Phenylketonuria : Patients should be informed that mercaptopurine oral suspension contains phenylalanine, a component of aspartame. Each mL of the 20 mg/mL oral suspension contains 0.015 mg of phenylalanine. ( 5.7 )

5.1 Myelosuppression The most consistent, dose-related adverse reaction of mercaptopurine is myelosuppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Monitor CBC and adjust the dosage of mercaptopurine for excessive myelosuppression <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . Consider testing for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency in patients with severe myelosuppression or repeated episodes of myelosuppression. 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 may require a dose reduction <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.5 )]</span> . Myelosuppression can be exacerbated by coadministration with allopurinol, aminosalicylates or other products that cause myelosuppression <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 , 7.3 , 7.4 )]</span> . Reduce the dosage of mercaptopurine when coadministered with allopurinol <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .

5.2 Hepatotoxicity Mercaptopurine is hepatotoxic. There are reports of deaths attributed to hepatic necrosis associated with the administration of mercaptopurine. Hepatic injury can occur with any dosage but seems to occur with greater frequency when the recommended dosage is exceeded. In some patients, jaundice has cleared following withdrawal of mercaptopurine and reappeared with rechallenge. Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months); however, jaundice has been reported as early as 1 week and as late as 8 years after starting mercaptopurine. The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice, ascites, and pruritus. Hepatic encephalopathy has occurred. Monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels at weekly intervals when first beginning therapy and at monthly intervals thereafter. Monitor liver tests more frequently in patients who are receiving mercaptopurine with other hepatotoxic drugs <span class="opacity-50 text-xs">[see Drug Interactions ( 7.5 )]</span> or with known pre-existing liver disease. Withhold mercaptopurine at onset of hepatotoxicity.

Intrahepatic

Cholestasis of Pregnancy Postmarketing cases of intrahepatic cholestasis of pregnancy (ICP) have been reported in patients with inflammatory bowel disease who received mercaptopurine during pregnancy. Mercaptopurine is not indicated for use in inflammatory bowel disease [see Indications and Usage ( 1.1 )] . Discontinue mercaptopurine if ICP develops in a pregnant woman .

5.3 Immunosuppression Mercaptopurine is immunosuppressive and may impair the immune response to infectious agents or vaccines. Due to the immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines. Consult immunization guidelines for immunocompromised patients.

5.4 Treatment Related Malignancies Hepatosplenic T-cell lymphoma has been reported in patients treated with mercaptopurine for inflammatory bowel disease (IBD), an unapproved use. Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the risk of secondary malignancies. Patients receiving immunosuppressive therapy, including mercaptopurine, are at an 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. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder. A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

5.5 Macrophage Activation Syndrome Macrophage activation syndrome (MAS) (hemophagocytic lymphohistiocytosis) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and 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 mercaptopurine. Monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

5.6 Embryo-Fetal Toxicity Mercaptopurine can cause fetal harm when administered to a pregnant woman. An increased incidence of miscarriage has been reported in women who received mercaptopurine in the first trimester of pregnancy. Adverse embryo-fetal findings, including miscarriage and stillbirth, have been reported in women who received mercaptopurine after the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine and for 3 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.7 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). Phenylketonuric patients should be informed that mercaptopurine oral suspension contains phenylalanine, a component of aspartame. Each mL of the mercaptopurine oral suspension, 20 mg/mL contains 0.015 mg of phenylalanine.