lariam and the military

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 and the military.

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

Mefloquine hydrochloride has a calculated molecular weight of 414.78 lariam and the military.

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

CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The absolute oral bioavailability of mefloquine has not been determined sincean intravenous formulation is not available lariam and the military. The bioavailability of the tabletformation compared with an oral solution was over 85% lariam and the military. The presence of foodsignificantly enhances the rate and extent of absorption, leading to about a40% increase in bioavailability lariam and the military. In healthy volunteers, plasma concentrationspeak 6 to 24 hours (median, about 17 hours) after a single dose of Lariam lariam and the military. 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 and the military. 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 and the military.

Distribution
In healthy adults, the apparent volume of distribution is approximately 20 L/kg,indicating extensive tissue distribution lariam and the military. Mefloquine may accumulate in parasitizederythrocytes lariam and the military. 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 and the military. The equilibrium reached in less than 30minutes was found to be reversible lariam and the military. Protein binding is about 98% lariam and the military.

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

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

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 and the military. Total clearance,which is essentially hepatic, is in the order of 30 mL/min lariam and the military. There is evidencethat mefloquine is excreted mainly in the bile and feces lariam and the military. In volunteers, urinaryexcretion of unchanged mefloquine and its main metabolite under steady-statecondition accounted for about 9% and 4% of the dose, respectively lariam and the military. Concentrationsof other metabolites could not be measured in the urine lariam and the military.

Pharmacokinetics in Special Clinical Situations
Children and the Elderly

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

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

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

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

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

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 and the military.

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

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

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

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

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

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 and the military. falciparum (both chloroquine-susceptibleand resistant strains) or by Plasmodium vivax lariam and the military. There are insufficient clinicaldata to document the effect of mefloquine in malaria caused by P lariam and the military. ovale or P lariam and the military. malariae lariam and the military.

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

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

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 and the military. 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 and the military.

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

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

Mefloquine may cause psychiatric symptoms in a number of patients, rangingfrom anxiety, paranoia, and depression to hallucinations and psychotic behavior lariam and the military. On occasions, these symptoms have been reported to continue long after mefloquinehas been stopped lariam and the military. Rare cases of suicidal ideation and suicide have been reportedthough no relationship to drug administration has been confirmed lariam and the military. 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 and the military. Lariam should be used with caution in patients with a previous history of depression lariam and the military.

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 and the military. In these cases, the drug must be discontinued and an alternativemedication should be substituted lariam and the military.

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

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

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

In patients with epilepsy, Lariam may increase the risk of convulsions lariam and the military. 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 and the military.

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 and the military. These effects may occur after therapy is discontinued dueto the long half-life of the drug lariam and the military. Lariam should be used with caution in patientswith psychiatric disturbances because mefloquine use has been associated withemotional disturbances (see ADVERSE REACTIONS ) lariam and the military.

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

This drug has been administered for longer than 1 year lariam and the military. If the drug is to beadministered for a prolonged period, periodic evaluations including liver functiontests should be performed lariam and the military. 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 and the military. Therefore, periodic ophthalmic examinations are recommended lariam and the military.

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 and the military. The effect of mefloquineon the compromised cardiovascular system has not been evaluated lariam and the military. However, transitoryand clinically silent ECG alterations have been reported during the use of mefloquine lariam and the military. 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 and the military. The benefitsof Lariam therapy should be weighed against the possibility of adverse effectsin patients with cardiac disease lariam and the military.

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