Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
The administration of mercaptopurine with food may decrease systemic exposure slightly. Mercaptopurine may be taken with food or on an empty stomach, but patients should standardise the method of administration to avoid large variability in exposure. The dose should not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme which metabolises mercaptopurine and might therefore lead to reduced plasma concentrations of mercaptopurine.

Effects of mercaptopurine on other medicinal products
Concomitant administration of yellow fever vaccine is contraindicated, due to the risk of fatal disease in immunocompromised patients (see section 4.3)

Vaccinations with other live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4).

Anticoagulants

Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine has been reported. Monitoring of the INR (International Normalised Ratio) value is recommended during concomitant administration with oral anticoagulants.


Antiepileptics
Cytotoxic agents may decrease the intestinal absorption of phenytoin. Careful monitoring of the phenytoin serum levels is recommended. It is possible that the levels of other anti-epileptic medicinal products may also be altered. Serum antiepileptic levels should be closely monitored during treatment with mercaptopurine, making dose adjustments as necessary.

Effects of other medicinal products on mercaptopurine

Allopurinol/oxipurinol/thiopurinol and other xanthine oxidase inhibitors 
Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol, which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid.

When allopurinol and mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of mercaptopurine is given since allopurinol decreases the rate of metabolism of mercaptopurine via xanthine oxidase.
Also other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of mercaptopurine and concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction.

Aminosalicylates

There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme. Therefore, lower doses of mercaptopurine may need to be considered when administered concomitantly with aminosalicylate derivatives (see Section 4.4 Special warnings and precautions for use).

Methotrexate

Methotrexate (20 mg/m2 orally) increased mercaptopurine AUC by approximately 31% and methotrexate (2 or 5 g/m2 intravenously) increased mercaptopurine AUC by 69 and 93%, respectively. Therefore, when mercaptopurine is administered concomitantly with high dose methotrexate, the dose should be adjusted and white blood cell counts should be very closely monitored.

Infliximab

Interactions have been observed between azathioprine, a pro-drug of mercaptopurine, and infliximab. Patients receiving ongoing azathioprine experienced transient increases in 6-TGN (6-thioguanine nucleotide, an active metabolite of azathioprine) levels and decreases in the mean leukocyte count in the initial weeks following infliximab infusion, which returned to previous levels after 3 months. Therefore, close monitoring of haematological parameters is necessary if mercaptopurine is administered with concomitant Infliximab therapy.

Ribavirin
Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of a pro-drug of mercaptopurine and ribavirin; therefore concomitant administration of ribavirin and mercaptopurine is not advised (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties: metabolism).

Myelosuppressive agents
When mercaptopurine is combined with other myelosuppressive agents caution should be used; dose reductions may be needed based on haematological monitoring (see section 4.4 Special warnings and precautions for use).