side affects of 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 side affects of lariam.

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

Mefloquine hydrochloride has a calculated molecular weight of 414.78 side affects of lariam.

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

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

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

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

Metabolism
Two metabolites have been identified in humans side affects of lariam. The main metabolite, 2,8- bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparumside affects of lariam. In a study in healthy volunteers, the carboxylic acid metabolite appearedin plasma 2 to 4 hours after a single oral dose side affects of lariam. Maximum plasma concentrations,which were about 50% higher than those of mefloquine, were reached after 2 weeks side affects of lariam. Thereafter, plasma levels of the main metabolite and mefloquine declined ata similar rate side affects of 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 side affects of lariam. Theother metabolite, an alcohol, was present in minute quantities only side affects of 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 side affects of lariam. Total clearance,which is essentially hepatic, is in the order of 30 mL/min side affects of lariam. There is evidencethat mefloquine is excreted mainly in the bile and feces side affects of lariam. In volunteers, urinaryexcretion of unchanged mefloquine and its main metabolite under steady-statecondition accounted for about 9% and 4% of the dose, respectively side affects of lariam. Concentrationsof other metabolites could not be measured in the urine side affects of lariam.

Pharmacokinetics in Special Clinical Situations
Children and the Elderly

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

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

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

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

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

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

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

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

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

Cross-Resistance
Cross-resistance between mefloquine and halofantrine and cross-resistance betweenmefloquine and quinine have been observed in some regions side affects of 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 side affects of lariam. falciparum (both chloroquine-susceptibleand resistant strains) or by Plasmodium vivax side affects of lariam. There are insufficient clinicaldata to document the effect of mefloquine in malaria caused by P side affects of lariam. ovale or P side affects of lariam. malariae side affects of lariam.

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

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

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 side affects of 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 side affects of lariam.

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

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

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

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

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

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

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

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

This drug has been administered for longer than 1 year side affects of lariam. If the drug is to beadministered for a prolonged period, periodic evaluations including liver functiontests should be performed side affects of 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 ) side affects of lariam. Therefore, periodic ophthalmic examinations are recommended side affects of 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 side affects of lariam. The effect of mefloquineon the compromised cardiovascular system has not been evaluated side affects of lariam. However, transitoryand clinically silent ECG alterations have been reported during the use of mefloquine side affects of 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 ) side affects of lariam. The benefitsof Lariam therapy should be weighed against the possibility of adverse effectsin patients with cardiac disease side affects of lariam.

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