lariam dosing

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 dosing.

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

Mefloquine hydrochloride has a calculated molecular weight of 414.78 lariam dosing.

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

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

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

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

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

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

Pharmacokinetics in Special Clinical Situations
Children and the Elderly

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

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

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

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

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

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 dosing.

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

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

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

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

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

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

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

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

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 dosing. 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 dosing.

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

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

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

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

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

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

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

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

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

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

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

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

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