Are there any interactions between mefloquine and diclofenac, misoprostol, prednisolone, tramadol,

Fråga: Are there any interactions between mefloquine and diclofenac, misoprostol, prednisolone, tramadol, methotrexate or gabapentin?

A woman with severe rheumatoid arthritis is going abroad for 6 months and needs malariaprophylaxis with mefloquine (Lariam). The patients rheumatoid arthritis is treated with diclofenac + misoprostol (Arthrotec), prednisolone, tramadol (Nobligan), methotrexate and gabapentin.

Sammanfattning: There is limited in vitro data indicating that the methotrexate concentration may increase during concomitant use of mefloquine. Careful observation for adverse effects and monitoring of the methotrexate concentration is recommended.

Svar: Mefloquine is used as malaria prophylaxis in areas with risk of chloroquine resistant malaria.

Less than 50% of administered mefloquine is metabolised, and interaction data indicates that mefloquine is mainly metabolised by CYP3A4. About 9 % of mefloquine is excreted unchanged in urine and the rest of the unmetabolised drug is excreted trough bile. The half-life of mefloquine is approximately 21 days (range 10-33) (1, 2, 3).

No documented interactions between mefloquine and any of the patients drugs have been found.

Mefloquine increases the effect of doxorubicin in multidrug-resistant cells in vitro, indicating that mefloquine may inhibit the transport protein P-glycoprotein (4). Some in vitro data indicate that methotrexate is a substrate of P-glycoprotein and some does not (5, 6). If methotrexate is a P-glycoprotein substrate the concentration of methotrexate may theoretically increase when given together with mefloquine. The evidence in the literature is weak and the clinical consequence is not known.

Misoprostol is metabolised by CYP3A4, tramadol and prednisolone are partly metabolised by CYP3A4 (7, 8). None of these drugs is a known strong inhibitor of CYP3A4 and no clinically relevant interaction is suspected (7, 8). On theoretical basis, no other interactions are suspected but cannot be excluded due to the limited amount of interaction data about mefloquine. It can be noted that both mefloquine and high doses of prednisolone in rare cases have been suspected to cause psychosis (9) and an increased risk when combining these two drugs cannot be excluded.

We have found no documentation about the use of mefloquine in patients with rheumatoid arthritis.

In this case we recommend careful observation for adverse effects of methotrexate. Monitoring of the plasma concentration of methotrexate may, if practially feasible, be considered. Since mefloquine has a long half-life (21 days) it is recommended to start mefloquine treatment as long as possible before travel to be able to measure the effect of mefloquine on the concentration of mehotrexate. Drugline no 22171 (year 2005) Baxter K (Ed), Stockley´s Drug interactions. London: Pharmaceutical Press. Electronic version (Edition date) Fass 2006. Fujita R, Ishikawa M, Takayanagi M, Takayanagi Y, Sasaki K. Enhancement of doxorubicin activity in multidrug-resistant cells by mefloquine. Methods Find Exp Clin Pharmacol 2000;22(5):281-4. Norris MD, DeGraaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J, Kwan E, Stewart BW, Mechetner EB, Gudkov AV, Roninson IB. Involvement of MDR1 P-glycoprotein in mutifactorial resistance to methotrexate. Int J Cancer 1996;65(5):613-9. Hider SL, Hoggard P, Khoo S, Back D, Bruce IN. Drug efflux transporters in rheumatoid arthritis: comment on the article by Kremer. Arthritis Rheum 2005;52(2):670 Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M. Metabolic drug interactions. Philadelphia: Williams & Wilkins; 2000 Heikinheimo O. Clinical pharmacokinetics of mifepristone. Clin Pharmacokinet 1997;33(1):7-17 Aronson JK, editor. Meyler´s Side effects of drugs. 15th ed. Amsterdam; Elsevier: (2006)