lariam

DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250-mgtablets of mefloquine hydrochloride (equivalent to 228.0 mg of the free base)for oral administration lariam.

Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the specificchemical name of (R*, S*)-(±)-(alpha)-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanolhydrochloride lariam. It is a 2-aryl substituted chemical structural analog of quinine lariam. The drug is a white to almost white crystalline compound, slightly soluble inwater lariam.

Mefloquine hydrochloride has a calculated molecular weight of 414.78 lariam.

The inactive ingredients are ammonium-calcium alginate, corn starch, crospovidone,lactose, magnesium stearate, microcrystalline cellulose, poloxamer #331, andtalc lariam.

CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The absolute oral bioavailability of mefloquine has not been determined sincean intravenous formulation is not available lariam. The bioavailability of the tabletformation compared with an oral solution was over 85% lariam. The presence of foodsignificantly enhances the rate and extent of absorption, leading to about a40% increase in bioavailability lariam. In healthy volunteers, plasma concentrationspeak 6 to 24 hours (median, about 17 hours) after a single dose of Lariam lariam. Ina similar group of volunteers, maximum plasma concentrations in [micro ]g/Lare roughly equivalent to the dose in milligrams (for example, a single 1000mg dose produces a maximum concentration of about 1000 [micro ]g/L) lariam. In healthyvolunteers, a dose of 250 mg once weekly produces maximum steady-state plasmaconcentrations of 1000 to 2000 [micro ]g/L, which are reached after 7 to 10weeks lariam.

Distribution
In healthy adults, the apparent volume of distribution is approximately 20 L/kg,indicating extensive tissue distribution lariam. Mefloquine may accumulate in parasitizederythrocytes lariam. Experiments conducted in vitro with human blood using concentrationsbetween 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasmaconcentration ratio of about 2 to 1 lariam. The equilibrium reached in less than 30minutes was found to be reversible lariam. Protein binding is about 98% lariam.

Mefloquine crosses the placenta lariam. Excretion into breast milk appears to be minimal(see PRECAUTIONS : Nursing Mothers ) lariam.

Metabolism
Two metabolites have been identified in humans lariam. The main metabolite, 2,8- bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparumlariam. In a study in healthy volunteers, the carboxylic acid metabolite appearedin plasma 2 to 4 hours after a single oral dose lariam. Maximum plasma concentrations,which were about 50% higher than those of mefloquine, were reached after 2 weeks lariam. Thereafter, plasma levels of the main metabolite and mefloquine declined ata similar rate lariam. The area under the plasma concentration-time curve (AUC) ofthe main metabolite was 3 to 5 times larger than that of the parent drug lariam. Theother metabolite, an alcohol, was present in minute quantities only lariam.

Elimination
In several studies in healthy adults, the mean elimination half-life of mefloquinevaried between 2 and 4 weeks, with an average of about 3 weeks lariam. Total clearance,which is essentially hepatic, is in the order of 30 mL/min lariam. There is evidencethat mefloquine is excreted mainly in the bile and feces lariam. In volunteers, urinaryexcretion of unchanged mefloquine and its main metabolite under steady-statecondition accounted for about 9% and 4% of the dose, respectively lariam. Concentrationsof other metabolites could not be measured in the urine lariam.

Pharmacokinetics in Special Clinical Situations
Children and the Elderly

No relevant age-related changes have been observed in the pharmacokineticsof mefloquine lariam. Therefore, the dosage for children has been extrapolated fromthe recommended adult dose lariam.

No pharmacokinetic studies have been performed in patients with renal insufficiencysince only a small proportion of the drug is eliminated renally lariam. Mefloquineand its main metabolite are not appreciably removed by hemodialysis lariam. No specialchemoprophylactic dosage adjustments are indicated for dialysis patients toachieve concentrations in plasma similar to those in healthy persons lariam.

Although clearance of mefloquine may increase in late pregnancy, in general,pregnancy has no clinically relevant effect on the pharmacokinetics of mefloquine lariam.

The pharmacokinetics of mefloquine may be altered in acute malaria lariam.

Pharmacokinetic differences have been observed between various ethnic populations lariam. In practice, however, these are of minor importance compared with host immunestatus and sensitivity of the parasite lariam.

During long-term prophylaxis (>2 years), the trough concentrations and theelimination half-life of mefloquine were similar to those obtained in the samepopulation after 6 months of drug use, which is when they reached steady state lariam.

In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphatedehydrogenase deficiency (see ANIMAL TOXICOLOGY ) lariam.

Microbiology
Mechanism of Action
Mefloquine is an antimalarial agent which acts as a blood schizonticide lariam. Itsexact mechanism of action is not known lariam.

Activity In Vitro and In Vivo
Mefloquine is active against the erythrocytic stages of Plasmodium species (seeINDICATIONS AND USAGE ) lariam. However, the drug has no effect against the exoerythrocytic(hepatic) stages of the parasite lariam. Mefloquine is effective against malaria parasitesresistant to chloroquine (see INDICATIONS AND USAGE ) lariam.

Drug Resistance
Strains of P lariam. falciparum with decreased susceptibility to mefloquine can beselected in vitro or in vivo lariam. Resistance of P lariam. falciparum to mefloquine hasbeen reported in areas of multi-drug resistance in South East Asia lariam. Increasedincidences of resistance have also been reported in other parts of the world lariam.

Cross-Resistance
Cross-resistance between mefloquine and halofantrine and cross-resistance betweenmefloquine and quinine have been observed in some regions lariam.

INDICATIONS AND USAGE
Treatment of Acute Malaria Infections
Lariam is indicated for the treatment of mild to moderate acute malaria causedby mefloquine-susceptible strains of P lariam. falciparum (both chloroquine-susceptibleand resistant strains) or by Plasmodium vivax lariam. There are insufficient clinicaldata to document the effect of mefloquine in malaria caused by P lariam. ovale or P lariam. malariae lariam.

Note: Patients with acute P lariam. vivax malaria, treated with Lariam, are at highrisk of relapse because Lariam does not eliminate exoerythrocytic (hepatic phase)parasites lariam. To avoid relapse, after initial treatment of the acute infectionwith Lariam, patients should subsequently be treated with an 8-aminoquinolinederivative (eg, primaquine) lariam.

Prevention of Malaria
Lariam is indicated for the prophylaxis of P lariam. falciparum and P lariam. vivax malariainfections, including prophylaxis of chloroquine-resistant strains of P lariam. falciparumlariam.

CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity tomefloquine or related compounds (eg, quinine and quinidine) or to any of theexcipients contained in the formulation lariam. Lariam should not be prescribed forprophylaxis in patients with active depression, a recent history of depression,generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatricdisorders, or with a history of convulsions lariam.

WARNINGS
In case of life-threatening, serious or overwhelming malaria infections dueto P lariam. falciparum , patients should be treated with an intravenous antimalarialdrug lariam. Following completion of intravenous treatment, Lariam may be given tocomplete the course of therapy lariam.

Data on the use of halofantrine subsequent to administration of Lariam suggesta significant, potentially fatal prolongation of the QTc interval of the ECG lariam. Therefore, halofantrine must not be given simultaneously with or subsequentto Lariam lariam. No data are available on the use of Lariam after halofantrine (seePRECAUTIONS : Drug Interactions ) lariam.

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

During prophylactic use, if psychiatric symptoms such as acute anxiety, depression,restlessness or confusion occur, these may be considered prodromal to a moreserious event lariam. In these cases, the drug must be discontinued and an alternativemedication should be substituted lariam.

Concomitant administration of Lariam and quinine or quinidine may produce electrocardiographicabnormalities lariam.

Concomitant administration of Lariam and quinine or chloroquine may increasethe risk of convulsions lariam.

PRECAUTIONS
General
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxiscannot be predicted lariam.

In patients with epilepsy, Lariam may increase the risk of convulsions lariam. Thedrug should therefore be prescribed only for curative treatment in such patientsand only if there are compelling medical reasons for its use (see PRECAUTIONS: Drug Interactions ) lariam.

Caution should be exercised with regard to activities requiring alertness andfine motor coordination such as driving, piloting aircraft, operating machinery,and deep-sea diving, as dizziness, a loss of balance, or other disorders ofthe central or peripheral nervous system have been reported during and followingthe use of Lariam lariam. These effects may occur after therapy is discontinued dueto the long half-life of the drug lariam. Lariam should be used with caution in patientswith psychiatric disturbances because mefloquine use has been associated withemotional disturbances (see ADVERSE REACTIONS ) lariam.

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

This drug has been administered for longer than 1 year lariam. If the drug is to beadministered for a prolonged period, periodic evaluations including liver functiontests should be performed lariam. Although retinal abnormalities seen in humans withlong-term chloroquine use have not been observed with mefloquine use, long-termfeeding of mefloquine to rats resulted in dose-related ocular lesions (retinaldegeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher)(see ANIMAL TOXICOLOGY ) lariam. Therefore, periodic ophthalmic examinations are recommended lariam.

Parenteral studies in animals show that mefloquine, a myocardial depressant,possesses 20% of the antifibrillatory action of quinidine and produces 50% ofthe increase in the PR interval reported with quinine lariam. The effect of mefloquineon the compromised cardiovascular system has not been evaluated lariam. However, transitoryand clinically silent ECG alterations have been reported during the use of mefloquine lariam. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block,prolongation of the QTc interval and abnormal T waves (see also cardiovasculareffects under PRECAUTIONS : Drug Interactions and ADVERSE REACTIONS ) lariam. The benefitsof Lariam therapy should be weighed against the possibility of adverse effectsin patients with cardiac disease lariam.

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