Mefloquine Hydrochloride (mefloquine hydrochloride 250 mg) Dailymed

Precautions

Hypersensitivity Reactions
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted.

In patients with epilepsy, mefloquine may increase the risk of convulsions. The drug should therefore be prescribed only for curative treatment in such patients and only if there are compelling medical reasons for its use (see PRECAUTIONS: Drug Interactions ).
Central and Peripheral Nervous System Effects
Caution should be exercised with regard to activities requiring alertness and fine motor coordination such as driving, piloting aircraft, operating machinery, and deep-sea diving, as dizziness or vertigo, a loss of balance, or other disorders of the central or peripheral nervous system have been reported during and following the use of mefloquine. These effects may occur after therapy is discontinued due to the long half-life of the drug. In a small number of patients, dizziness or vertigo and loss of balance have been reported to continue for months after discontinuation of the drug (see ADVERSE REACTIONS: Postmarketing ).

Mefloquine should be used with caution in patients with psychiatric disturbances because mefloquine use has been associated with emotional disturbances (see ADVERSE REACTIONS ).
Use in Patients with Hepatic Impairment
In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels.
Long-Term Use
This drug has been administered for longer than one year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests should be performed.

Although retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) (see ANIMAL TOXICOLOGY ). Therefore, periodic ophthalmic examinations are recommended.
Cardiac Effects
Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the anti-fibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. However, transitory and clinically silent ECG alterations have been reported during the use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc interval and abnormal T waves (see also cardiovascular effects under PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS ). The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
Laboratory Tests
Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.
Information for Patients
Medication Guide: As required by law, a Mefloquine Medication Guide is supplied to patients when mefloquine is dispensed. An information wallet card is also supplied to patients when mefloquine is dispensed. Patients should be instructed to read the Medication Guide when mefloquine is received and to carry the information wallet card with them when they are taking mefloquine. The complete texts of the Medication Guide and information wallet card are reprinted at the end of this document.

Patients should be advised:

• that malaria can be a life-threatening infection in the traveler;
• that mefloquine hydrochloride tablets are being prescribed to help prevent or treat this serious infection;
• that in a small percentage of cases, patients are unable to take this medication because of side effects, including dizziness or vertigo and loss of balance, and it may be necessary to change medications. Although side effects of dizziness or vertigo and loss of balance are usually mild and do not cause people to stop taking the medication, in a small number of patients it has been reported that these symptoms may continue for months after discontinuation of the drug;
• that when used as prophylaxis, the first dose of mefloquine hydrochloride tablets should be taken one week prior to arrival in an endemic area;
• that if the patients experience psychiatric symptoms such as acute anxiety, depression, restlessness or confusion, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted;
• that no chemoprophylactic regimen is 100% effective, and protective clothing, insect repellents, and bednets are important components of malaria prophylaxis;
• to seek medical attention for any febrile illness that occurs after return from a malarious area and to inform their physician that they may have been exposed to malaria.

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 and Other Antimalarials
Halofantrine 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 ).

Concomitant administration of mefloquine and other related antimalarial compounds (eg, 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)
Co-administration 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 C_max 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
Co-administration of other drugs known to alter cardiac conduction (eg, 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 uled agents has an effect on cardiac function.
Anticonvulsants
In patients taking an anticonvulsant (eg, 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 antiseizure medication and mefloquine should have the blood level of their antiseizure 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)
Co-administration 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 C_max 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 and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction. However, co-administration of CYP 450 inhibitors or inducers may increase or decrease mefloquine plasma concentrations, respectively.
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 comedication, 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 C
Mefloquine has been demonstrated to be teratogenic in rats and mice at a dose of 100 mg/kg/day. In rabbits, a high dose of 160 mg/kg/day was embryotoxic and teratogenic, and a dose of 80 mg/kg/day was teratogenic but not embryotoxic. There are no adequate and well-controlled studies in pregnant women. However, clinical experience with mefloquine has not revealed an embryotoxic or teratogenic effect. Mefloquine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women of childbearing potential who are traveling to areas where malaria is endemic should be warned against becoming pregnant. Women of childbearing potential should also be advised to practice contraception during malaria prophylaxis with mefloquine and for up to 3 months thereafter. However, in the case of unplanned pregnancy, malaria chemoprophylaxis with mefloquine is not considered an indication for pregnancy termination.
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. Because of the potential for serious adverse reactions in nursing infants from mefloquine, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
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 DOSAGE AND ADMINISTRATION ).
Geriatric Use
Clinical studies of mefloquine did not include sufficient numbers of subjects aged 65 and over 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.