Mefloquine Hydrochloride Description

Mefloquine hydrochloride is an antimalarial agent available as 250 mg tablets of mefloquine hydrochloride (equivalent to 228 mg of the free base) for oral administration.

Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the specific chemical name of (R*,S*)-(±)-?-2- piperidinyI-2,8-bis(trifluoromethyl)-4-quinolinemethanoI hydrochloride. It is a 2-aryl substituted chemical structural analog of quinine. The drug is a white to almost white crystalline compound, slightly soluble in water.

Mefloquine hydrochloride has a calculated molecular weight of 414.78 and the following structural formula:

The inactive ingredients are calcium-ammonium alginate, colloidal silicon dioxide, crospovidone, lactose (regular), magnesium stearate, microcrystalline cellulose, poloxamer 331, povidone, and starch.

Mefloquine Hydrochloride Indications and Usage

Treatment Of Acute Malaria Infections

Mefloquine Hydrochloride Tablets are indicated for the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by Plasmodium vivax . There are insufficient clinical data to document the effect of mefloquine in malaria caused by P. ovale or P. malariae .

• Note: Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline derivative (eg, primaquine).

Prevention Of Malaria

Mefloquine Hydrochloride Tablets are indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum .

Mefloquine Hydrochloride Contraindications

Use of Mefloquine Hydrochloride Tablets is contraindicated in patients with a known hypersensitivity to mefloquine or related compounds (eg, quinine and quinidine) or to any of the excipients contained in the formulation. Mefloquine Hydrochloride Tablets should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders, or with a history of convulsions.

Mefloquine Hydrochloride Side Effects

In case of Iife-threatening, serious or overwhelming malaria infections due to P. falciparum , patients should be treated with an intravenous antimalarial drug. Following completion of intravenous treatment, mefloquine may be given to complete the course of therapy.

Data on the use of halofantrine subsequent to administration of mefloquine suggest a significant, potentially fatal prolongation of the QTc interval of the ECG. Therefore, halofantrine must not be given simultaneously with or subsequent to mefloquine. No data are available on the use of mefloquine after halofantrine (see PRECAUTIONS: Drug Interactions).

Mefloquine may cause psychiatric symptoms in a number of patients, ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior. On occasions, these symptoms have been reported to continue long after mefloquine has been stopped. Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed. To minimize the chances of these adverse events, mefloquine should not be taken for prophylaxis in patients with active depression or with a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. Mefloquine should be used with caution in patients with a previous history of depression.

During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness or confusion occur, 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.

Concomitant administration of mefloquine and quinine or quinidine may produce electrocardiographic abnormalities.

Concomitant administration of mefloquine and quinine or chloroquine may increase the risk of convulsions.

Mefloquine Hydrochloride Precautions

General

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).

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, 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. Mefloquine should be used with caution in patients with psychiatric disturbances because mefloquine use has been associated with emotional disturbances (see ADVERSE REACTIONS).

In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels.

This drug has been administered for longer than 1 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.

Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the antifibrillatory 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, proIongation 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. Patients should be instructed to read the MedGuide when mefloquine is received. The complete text of the MedGuide is reprinted at the end of this document.

Patients Should Be Advised

• that malaria can be a life-threatening infection in the traveler;
• that mefloquine is 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, and it may be necessary to change medications;
• that when used as prophylaxis, the first dose of mefloquine 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: General). 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.

Because of the danger of a potentially fatal prolongation of the QTc interval, halofantrine must not be given simultaneously with or subsequent to mefloquine (see WARNINGS).

Concomitant administration of mefloquine and other related 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. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Clinically significant QTc prolongation has not been found with mefloquine alone.

This appears to be the only clinically relevant interaction of this kind with mefloquine, although theoretically, coadministration 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 listed agents has an effect on cardiac function.

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: General).

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.

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.

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.

Mefloquine Hydrochloride Overdosage

In cases of overdosage with mefloquine, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced. The following procedure is recommended in case of overdosage: Induce vomiting or perform gastric lavage, as appropriate. Monitor cardiac function (if possible by ECG) and neuropsychiatric status for at least 24 hours. Provide symptomatic and intensive supportive treatment as required, particularly for cardiovascular disturbances.

Mefloquine Hydrochloride Information For Patients

Medication Guide: As required by law, a mefloquine Medication Guide is supplied to patients when mefloquine is dispensed. Patients should be instructed to read the MedGuide when mefloquine is received. The complete text of the MedGuide is reprinted at the end of this document.

Patients Should Be Advised

• that malaria can be a life-threatening infection in the traveler;
• that mefloquine is 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, and it may be necessary to change medications;
• that when used as prophylaxis, the first dose of mefloquine 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.