Mefloquine hydrochloride tablets, USP are an antimalarial agent available as 250 mg tablets of mefloquine hydrochloride (equivalent to 228 mg of the free base) for oral administration. Mefloquine hydrochloride, USP is a 4-quinolinemethanol derivative with the specific chemical name of (R*, S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol 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. The structural formula is as follows: C 17 H 16 F 6 N 2 O.HCl M.W.: 414.78 The inactive ingredients are colloidal silicon dioxide, corn starch, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, poloxamer and talc. FDA approved dissolution test specifications differ from USP. 1

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 (e.g., 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.

Malaria Treatment in Adults Treatment of mild to moderate malaria in adults caused by mefloquine-susceptible strains of P. falciparum or by P. vivax: Dosage: Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral dose. The drug should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water. If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine failed, mefloquine should not be used for curative treatment . 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 (e.g., primaquine). Malaria Prophylaxis in Adults Dosage: One 250 mg mefloquine hydrochloride tablet once weekly. Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent weekly doses should be taken regularly, always on the same day of each week, preferably after the main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the liver. Tablets should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water. In certain cases, e.g., when a traveler is taking other medication, it may be desirable to start prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is well tolerated . When prophylaxis with mefloquine fails, physicians should carefully evaluate which antimalarial to use for therapy. Malaria Treatment in Pediatric Patients Treatment of mild to moderate malaria in pediatric patients caused by mefloquine-susceptible strains of P. falciparum: Dosage: 20 to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of adverse effects. The pediatric dose should not exceed the adult dose. Experience with mefloquine in pediatric patients weighing less than 20 kg is limited. The drug should not be taken on an empty stomach and should be administered with ample water. The tablets may be crushed and suspended in a small amount of water, milk or other beverage for administration to small children and other persons unable to swallow them whole. If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, mefloquine should not be used for curative treatment. In pediatric patients, the administration of mefloquine for the treatment of malaria has been associated with early vomiting. In some cases, early vomiting has been cited as a possible cause of treatment failure . If a significant loss of drug product is observed or suspected because of vomiting, a second full dose of mefloquine should be administered to patients who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-dose should be given. If vomiting recurs, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time. The safety and effectiveness of mefloquine to treat malaria in pediatric patients below the age of 6 months have not been established. Malaria Prophylaxis in Pediatric Patients The recommended prophylactic dose of mefloquine is approximately 5 mg/kg body weight once weekly. One 250 mg mefloquine hydrochloride tablet should be taken once weekly in pediatric patients weighing over 45 kg. In pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body weight: 30 to 45 kg: 3/4 tablet 20 to 30 kg: 1/2 tablet Experience with mefloquine in pediatric patients weighing less than 20 kg is limited.

In case of life-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. QTc Interval Prolongation and Drug Interactions 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 . 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. Ketoconazole increases plasma concentrations and elimination half-life of mefloquine following coadministration . Concomitant administration of mefloquine and quinine or quinidine may produce electrocardiographic abnormalities. Psychiatric and Neurologic Adverse Reactions Mefloquine may cause neuropsychiatric adverse reactions in adults and children. Neuropsychiatric symptoms can be difficult to identify in children. Therefore, vigilance is required to monitor for the occurrence of these symptoms, especially in nonverbal children. Psychiatric Adverse Reactions Psychiatric symptoms ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior can occur with mefloquine use. Symptoms may occur early in the course of mefloquine use. In some cases, these symptoms have been reported to continue for months or years after mefloquine has been stopped. Cases of suicidal ideation and suicide have been reported. Mefloquine should not be prescribed for prophylaxis in patients with active 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, the occurrence of psychiatric symptoms such as acute anxiety, depression, restlessness or confusion suggest a risk for more serious psychiatric disturbances or neurologic adverse reactions. In these cases, the drug should be discontinued and an alternative medication should be substituted. Neurologic Adverse Reactions Neurologic symptoms such as dizziness or vertigo, tinnitus, and loss of balance have been reported. These adverse reactions may occur early in the course of mefloquine use and in some cases have been reported to continue for months or years after mefloquine has been stopped. Dizziness or vertigo, tinnitus, and loss of balance have been reported to be permanent in some cases. During prophylactic use, if neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted. 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, while symptoms persist. Mefloquine may increase the risk of convulsions in patients with epilepsy. The drug should therefore be prescribed only for curative treatment in such patients and only if there are compelling medical reasons for its use . Concomitant administration of mefloquine and quinine or chloroquine may increase the risk of convulsions. Ocular Effects Eye disorders, including but not limited to optic neuropathy and retinal disorders, have been reported during treatment with mefloquine. Any patient presenting with visual symptoms should be referred to the treating physician and an ophthalmologist as certain conditions (such as retinal disorders or optic neuropathy) may require stopping treatment with mefloquine .

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) . 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 potentially fatal prolongation of the QTc interval . 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 . 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 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 . 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 H 1 -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 . 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 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 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.