Mefloquine drug interactions

# Drug Interactions
Drug-drug interactions with mefloquine have not been explored in detail. There is one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol) (see Precautions, Cardiac Effects). The effects of mefloquine on the compromised cardiovascular system have not been evaluated. The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.

## Halofantrine
Halofantrine should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potential fatal prolongation of the QTc interval (see Warnings).

## Other Antimalarial Drugs
Concomitant administration of mefloquine and other related antimalarial compounds (e.g., quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions (see Warnings). If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 hours after the last dose. Clinically significant QTc prolongation has not been found with mefloquine alone.

## Ketoconazole (Potent Inhibitor of CYP3A4)
Coadministration of a single 500 mg oral dose of mefloquine with 400 mg of ketoconazole once daily for 10 days in 8 healthy volunteers resulted in an increase in the mean Cmax and AUC of mefloquine by 64% and 79%, respectively, and an increase in the mean elimination half-life of mefloquine from 322 hours to 448 hours. Ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval (see Warnings).

## Other Drugs that Prolong the QTc Interval
Coadministration of other drugs known to alter cardiac conduction (e.g., anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval. There are no data that conclusively establish whether the concomitant administration of mefloquine and the above listed agents has an effect on cardiac function.

## Anticonvulsants
In patients taking an anticonvulsant (e.g., valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking anti-seizure medication and mefloquine should have the blood level of their anti-seizure medication monitored and the dosage adjusted appropriately (see Precautions).

## Vaccines
When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunization cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine hydrochloride tablets.

## Rifampin (Potent Inducer of CYP3A4)
Coadministration of a single 500 mg oral dose of mefloquine and 600 mg of rifampin once daily for 7 days in 7 healthy Thai volunteers resulted in a decrease in the mean Cmax and AUC of mefloquine by 19% and 68%, respectively, and a decrease in the mean elimination half-life of mefloquine from 305 hours to 113 hours. Rifampin should be used cautiously in patients taking mefloquine.

## Inhibitors and Inducers of CYP3A4
Mefloquine does not inhibit or induce the CYP 450 enzyme system. Thus, concomitant administration of mefloquine hydrochloride tablets and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction. However, mefloquine is metabolized by CYP3A4 and inhibitors of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase in mefloquine plasma concentrations and potential risk of adverse reactions. Therefore, mefloquine hydrochloride tablets should be used with caution when administered concomitantly with CYP3A4 inhibitors. Similarly, inducers of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to a decrease in mefloquine plasma concentrations and potential reduction in efficacy of mefloquine hydrochloride tablets. Therefore, mefloquine hydrochloride tablets should also be used with caution when administered concomitantly with CYP3A4 inducers.

## Substrates and Inhibitors of P-glycoprotein
It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore, drug-drug interactions could also occur with drugs that are substrates or are known to modify the expression of this transporter. The clinical relevance of these interactions is not known to date.

## Other Potential Interactions
No other drug interactions are known. Nevertheless, the effects of mefloquine on travelers receiving concomitant medications, particularly diabetics or patients using anticoagulants, should be checked before departure.
In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the adverse reaction profile of mefloquine.

## Carcinogenesis, Mutagenesis, Impairment of Fertility

### Carcinogenesis
The carcinogenic potential of mefloquine was studied in rats and mice in 2-year feeding studies at doses of up to 30 mg/kg/day. No treatment-related increases in tumors of any type were noted.

### Mutagenesis
The mutagenic potential of mefloquine was studied in a variety of assay systems including: Ames test, a host-mediated assay in mice, fluctuation tests and a mouse micronucleus assay. Several of these assays were performed with and without prior metabolic activation. In no instance was evidence obtained for the mutagenicity of mefloquine.

### Impairment of Fertility
Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have demonstrated adverse effects on fertility in the male at the high dose of 50 mg/kg/day, and in the female at doses of 20 and 50 mg/kg/day. Histopathological lesions were noted in the epididymides from male rats at doses of 20 and 50 mg/kg/day. Administration of 250 mg/week of mefloquine (base) in adult males for 22 weeks failed to reveal any deleterious effects on human spermatozoa.

## Pregnancy
Teratogenic Effects
Pregnancy Category B
Data from published studies in pregnant women have shown no increase in the risk of teratogenic effects or adverse pregnancy outcomes following mefloquine treatment or prophylaxis during pregnancy. Reproduction studies in mice, rats and rabbits have shown teratogenic effects at doses similar to the clinical acute treatment dose in humans. Because the studies in humans cannot rule out the possibility of harm, mefloquine should be used during pregnancy only if clearly needed.
Published data on mefloquine use during pregnancy include randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series. These data showed that pregnant women who took mefloquine at various doses for both prevention and treatment of malaria did not have an increased risk of teratogenic effects or adverse pregnancy outcomes compared to the background rate in the general population. These data include more than 700 exposures to mefloquine in the first trimester of pregnancy and over 2,000 exposures in the second and third trimester.
Mefloquine administered to pregnant mice, rats, and rabbits was teratogenic at doses similar to the clinical acute treatment dose of 21 to 25 mg/kg, based on body surface area comparisons. In all three animal species, CNS effects (e.g., exencephaly, hydrocephaly or partially missing medulla oblongata) and craniofacial malformations were observed. At the same doses, mefloquine was also embryotoxic in mice and rabbits. All of these findings were observed at doses that were maternally toxic.

## Nursing Mothers
Mefloquine is excreted in human milk in small amounts, the activity of which is unknown. Based on a study in a few subjects, low concentrations (3% to 4%) of mefloquine were excreted in human milk following a dose equivalent to 250 mg of the free base. Caution should be exercised when administered to a nursing woman.

## Pediatric Use
Use of mefloquine to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by evidence from adequate and well-controlled studies of mefloquine in adults with additional data from published open-label and comparative trials using mefloquine to treat malaria caused by P. falciparum in patients younger than 16 years of age. The safety and effectiveness of mefloquine for the treatment of malaria in pediatric patients below the age of 6 months have not been established.
In several studies, the administration of mefloquine for the treatment of malaria was associated with early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of treatment failure. If a second dose is not tolerated, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time (see Warnings And Dosage And Administration).

## Geriatric Use
Clinical studies of mefloquine did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Since electrocardiographic abnormalities have been observed in individuals treated with mefloquine (see Precautions) and underlying cardiac disease is more prevalent in elderly than in younger patients, the benefits of mefloquine therapy should be weighed against the possibility of adverse cardiac effects in elderly patients.