MEFLOQUINE HYDROCHLORIDE- mefloquine hydrochloride tablet
A-S Medication Solutions
Mefloquine may cause neuropsychiatric adverse reactions that can persist after mefloquine has been discontinued.
Mefloquine should not be prescribed for prophylaxis in patients with major psychiatric disorders. During prophylactic use, if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted (see WARNINGS).
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:
C17 H16 F6 N2 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.
Absorption: The absolute oral bioavailability of mefloquine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of mefloquine. In a similar group of volunteers, maximum plasma concentrations in mcg/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 mcg/L). In healthy volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of 1000 to 2000 mcg/L, which are reached after 7 to 10 weeks.
Distribution: In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes was found to be reversible. Protein binding is about 98%.
Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see PRECAUTIONS, Nursing Mothers).
Metabolism: Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved.
Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis -trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.
Elimination: In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other metabolites could not be measured in the urine.
Pharmacokinetics in Special Clinical Situations: Children and the Elderly: No relevant age-related changes have been observed in the pharmacokinetics of mefloquine. Therefore, the dosage for children has been extrapolated from the recommended adult dose.
No pharmacokinetic studies have been performed in patients with renal insufficiency since only a small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy persons.
Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy has no clinically relevant effect on the pharmacokinetics of mefloquine.
The pharmacokinetics of mefloquine may be altered in acute malaria.
Pharmacokinetic differences have been observed between various ethnic populations. In practice, however, these are of minor importance compared with host immune status and sensitivity of the parasite.
During long-term prophylaxis (>2 years), the trough concentrations and the elimination half-life of mefloquine were similar to those obtained in the same population after 6 months of drug use, which is when they reached steady-state.
In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase deficiency (see ANIMAL TOXICOLOGY).
Mechanism of Action: Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action is not known.
Activity In Vitro and In Vivo: Mefloquine is active against the erythrocytic stages of Plasmodium species (see INDICATIONS AND USAGE). However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective against malaria parasites resistant to chloroquine (see INDICATIONS AND USAGE).
Drug Resistance: Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in vitro or in vivo. Resistance of P. falciparum to mefloquine has been reported in areas of multi-drug resistance in South East Asia. Increased incidences of resistance have also been reported in other parts of the world.
Cross-Resistance: Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions.
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).
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.
Use of mefloquine hydrochloride tablets is contraindicated in patients with a known hypersensitivity to mefloquine or related compounds (e.g., 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, schizophrenia or other major psychiatric disorders, or with a history of convulsions.
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