Does methotrexate interact pharmacologically with rifampicin, pyrazinamide or ethambutol?/nA 21-yea

Fråga: Does methotrexate interact pharmacologically with rifampicin, pyrazinamide or ethambutol?

A 21-year-old woman is treated with rifampicin, pyrazinamide and ethambutol for tuberculosis. She is now due to start treatment with methotrexate (four intramuscular 50 mg injections per week every second week) for mola hydatinosa.

Sammanfattning: Methotrexate is likely to increase the risk of pyrazinamide-associated liver injury and could theoretically stimulate progression of the tuberculosis infection. Rifampicin may reduce the plasma levels of methotrexate through enzyme induction.

Svar: We found no reports of pharmacologic interactions between methotrexate and any of the three anti-tuberculosis drugs in Drugline, Medline or standard pharmacologic literature.

Hepatitis is a common side-effect of methotrexate, and although this has not been thoroughly studied, co-treatment with other potentially hepatotoxic drugs may aggravate the risk of liver injury (1). Since increased liver enzyme levels is a very common adverse pyrazinamide effect and liver damage is considered the most important of this drug´s side-effects (2), co-medication with methotrexate and pyrazinamide should only be undertaken with great caution. The risk may be further increased by exposure to ethambutol and rifampicin, since abnormal liver enzyme levels is a common side-effect of both these anti-tuberculosis drugs (3,4).

Methotrexate is primarily excreted unchanged in the urine, but a minor part undergoes oxidative metabolism (5). Rifampicin is a potent inducer of several drug metabolising enzymes and although there are no reports of altered methotrexate elimination in individuals exposed to rifampicin, enzyme-inducing antiepileptic drugs have been known to increase methotrexate clearance (6). Hence, it is theoretically possible that co-medication with rifampicine could reduce the plasma levels of methotrexate to some extent.

Methotrexate therapy has been known to reactivate dormant tuberculosis infections in exposed patients (7). Although the effect on symptomatic tuberculosis is unknown, methotrexate-associated immunosupression could theoretically counteract the anti-tuberculosis therapy in this patient.

Finally, increased awareness of interstitial pneumonitis (a less common methotrexate side-effect) may be warranted in this patient, since pulmonary tuberculosis may worsen the outcome of such an adverse effect should it occur (1). Methotrexate. SPC (2009-02-12)

Pyrazinamaide. SPC (December 2007)
Myambutol. SPC (2006-05-05)
Rimactan. SPC (2008-02-19)

Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M. Metabolic drug interactions. Philadelphia: Williams & Wilkins; 2000 Relling MV, Pui CH, Sandlund JT, Rivera GK, Hancock ML, Boyett JM et al. Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 2000;356(9226):285-290 Lamb SR. Methotrexate and reactivation tuberculosis. J Am Acad Dermatol 2004;51(3):481-482