Formulations

Tablets containing 274 mg of mefloquine hydrochloride, equivalent to 250 mg of mefloquine base. The formulation available in the USA contains 250 mg of mefloquine hydrochloride equivalent to 228 mg of mefloquine base. The three commercial preparations currently available show differences in bioequivalence of both mefloquine and its carboxylic acid metabolite as indicated by differences in maximum plasma concentration (Cmax) and area under the curve (AUC, time-concentration) (153, 154).

Efficacy

Mefloquine is a 4-quinoline methanol chemically related to quinine. It is a potent long-acting blood schizonticide active against P. falciparum resistant to 4-aminoquinolines and sulfa drug-pyrimethamine combinations. It is also highly active against P. vivax and, P. malariae and most probably P. ovale. It is not gametocytocidal and is not active against the hepatic stages of malaria parasites. Owing to its long elimination half-life and consequent long-lived subtherapeutic concentrations in the blood, the development of resistance is to be expected especially in areas of high transmission. Since the late 1980s, resistance of P. falciparum to mefloquine has developed in areas near the borders between Cambodia and Thailand and between Myanmar and Thailand, and > 50% of patients have recrudescences of parasitaemia within 28 days after a dose of 15 mg/kg (155). The sensitivity of P. falciparum populations recrudescing after treatment with mefloquine is substantially reduced compared with the original population (156). P. falciparum resistance to mefloquine is accompanied by cross-resistance to halofantrine and reduced sensitivity to quinine. In contrast, laboratory studies have shown some increase in the sensitivity of mefloquine-resistant isolates to chloroquine in Thailand (28). High levels of resistance have not been documented outside South-East Asia, although sporadic reports of drug failure and in vitro evidence of reduced sensitivity have been reported from Brazil and several countries in Asia, Africa and the Middle East.

Use

Mefloquine can be used both for therapy and chemoprophylaxis. It should only be used for therapy following either microscopical or careful clinical diagnosis of
P. falciparum infections known or suspected to be resistant to chloroquine or sulfa drug-pyrimethamine combinations. It should not be used for treatment where chloroquine or sulfa drug-pyrimethamine combinations are effective because of its potential toxicity, cost and long elimination half-life. In Thailand, introduction of combination therapy with mefloquine and artesunate was temporally associated with a halt in the steady increase in mefloquine resistance that had been observed when mefloquine was used alone (10).

Mefloquine is recommended as a prophylactic drug for travellers to areas with significant risk of chloroquine-resistant falciparum malaria.

Recommended treatment

15 mg or 25 mg of mefloquine base per kg.

For many years, the standard adult dose of mefloquine for treatment of uncomplicated malaria in areas not affected by significant resistance to mefloquine has been 15 mg/kg. When resistance to mefloquine becomes a problem, however, its efficacy can be increased and its practical usefulness extended by a few years by increasing the standard dose to 25 mg of base per kg (157). In addition, recent pharmacokinetic modelling indicates that a dose of 25 mg/kg provides better protection against the selection of resistant strains (158). Optimum solubility and increased bioavailability can be obtained by drinking water before drug administration (159). The bioavailability of mefloquine is also improved if it is taken after food (160).

The 25 mg/kg dosage of mefloquine is associated with greater drug intolerance, especially vomiting in young children. If vomiting occurs within 1 h of drug intake, a full dose needs to be repeated. Later vomiting does not require repeat therapy. Administration of the drug as a split dose at an interval of 6-24 h substantially improves tolerability (161). Oesophagitis following mefloquine ingestion has been reported and highlights the importance of taking mefloquine with ample amounts of water and preferably not just prior to sleeping. The suggestion that drug-related vomiting can be decreased by treatment of febrile children with an antipyretic has not been borne out by additional studies (162).

Recommended chemoprophylaxis

5 mg of mefloquine base per kg weekly, giving an adult dose of 250 mg of base per week.

It is recommended that, whenever possible, mefloquine chemoprophylaxis should be started 2-3 weeks before departure to achieve higher pre-travel blood levels (163, 164), to detect adverse reactions before travel and to allow consideration of alternatives, e.g. doxycycline or chloroquine plus proguanil. Although steady-state blood levels with this regimen are not achieved until week 6 or 7 and many travellers do not begin chemoprophylaxis until 2-3 weeks before departure, the efficacy of this regimen for chemoprophylaxis does not appear to be compromised; commencing chemoprophylaxis one week before departure did compromise efficacy (P. Schlagenhauf, personal communication, 2000).

A 3-day loading dose of 250 mg/day followed by 250 mg weekly in adults achieves steady-state blood levels very rapidly and may be considered in special circumstances for travellers who will be at high risk of malaria immediately upon arrival in a malarious area (e.g. military groups) but do not have sufficient time for 2-3 pre-travel doses (165). This regimen is associated with a higher incidence of adverse reactions (see below).

Use in pregnancy

Concern has been expressed about the safety of mefloquine use during pregnancy. Cumulative evidence from 1 627 women inadvertently given mefloquine before conception and during pregnancy as well as from clinical trials involving pregnant women has not confirmed initial fears of embryotoxic or teratogenic effects (166). A retrospective analysis of pregnancy outcomes among women living on the Thai-Myanmar border showed that mefloquine treatment during pregnancy may be associated with an increased risk of stillbirths, but no definite conclusions could be drawn. Thus, while mefloquine may be given with confidence for both chemoprophylaxis and treatment during the second and third trimesters of pregnancy, until further information becomes available, it should be used with caution during the first trimester (161, 167). In non-pregnant women of childbearing potential, mefloquine can be prescribed for chemoprophylaxis, but pregnancy should preferably be avoided during and for 3 months after completing chemoprophylaxis. In the case of inadvertent pregnancy, chemoprophylaxis with mefloquine is not considered an indication for pregnancy termination.

Mefloquine is excreted in breast milk in small amounts, the activity of which is unknown (168). Circumstantial evidence suggests that adverse effects do not occur in breastfed infants whose mothers are taking the drug (169).

Drug disposition

Mefloquine is highly protein bound (98% in plasma) and has a long elimination half-life, varying between 10 and 40 days in adults but tending to be shorter in children and pregnant women. The elimination half-life was found to be longer in Caucasians than Africans or Thais, the variations being attributed to differences in lipid stores. The pharmacokinetic parameters of mefloquine are changed in acute falciparum malaria; the drug reaches a higher Cmax, probably due to a contraction of the apparent volume of distribution (169).

The drug shows stereo-specific elimination with a significantly longer half-life of 531 h for (-)-mefloquine compared to 206 h for (+)-mefloquine (170). Mefloquine is extensively metabolized in the liver and mainly eliminated in the faeces.

The main metabolite, carboxymefloquine, appears 2-4 h after drug intake with concentrations surpassing that of the parent drug by the end of the first week. It is eliminated more slowly than the parent drug. The metabolite lacks anti-malarial activity but has a similar toxicity profile to the parent compound. Urinary excretion of mefloquine and its metabolites accounts for 13% of the total dose.

Adverse effects

Between 1984, when it was first registered, and the end of 1995, nearly 11 million people were exposed to mefloquine and another 5 million received it in combination with sulfadoxine and pyrimethamine. The use of mefloquine is, however, subject to diverse opinions, particularly related to its safety. The main problem relates to the drug’s potential for inducing neuropsychiatric adverse reactions. There have also been concerns that other adverse effects, such as dizziness, may impair the ability of patients performing activities that require a high level of precision; that vomiting may affect treatment efficacy; and that use of the drug during pregnancy and in persons taking cardioactive drugs for other indications may lead to an increased risk of adverse events (see below).

Frequent adverse effects

These include dizziness, mild to moderate nausea, vomiting, diarrhoea and abdominal pain (self-limiting but may be severe in some users).

Vomiting was nearly three times higher in young children receiving treatment with single doses of 25 mg/kg mefloquine than in those given 15 mg/kg. Splitting the higher dose over 2 days (15 mg/kg followed 24 h later with 10 mg/kg) halved the incidence of vomiting (157). Transient post-treatment dizziness was significantly more frequent in patients given 25 mg/kg and took twice as long to resolve (157). Adverse events have been observed in 18.7% of travellers using mefloquine prophylaxis, a similar incidence to those reported following the use of chloroquine or chloroquine plus proguanil (62).

Neuropsychiatric adverse reactions

Between 1985 and mid-1995, Hoffmann-La Roche received reports of a total of 1 574 neuropsychiatric adverse events associated with mefloquine use, irrespective of causal relationship. These included affective disorders, anxiety disorders, hallucinations, sleep disturbances including nightmares and, in a few people, overt psychosis, toxic encephalopathy, convulsions and acute brain syndrome (171-173). The border between the very unpleasant and "serious events" is difficult to delineate. Risks appear to vary with ethnic groups, rates reported in Caucasians and Africans being higher than those in Asians for unknown reasons (157, 174-176). Risk is highest in people with a neurological or psychiatric history, a third of patients reporting to the manufacturer with convulsions having had a personal or family history of such events (177). More adverse events were reported in females than in males following prophylactic use, which may reflect higher mg/kg dosing (157, 176-178). On the basis of anecdotal reports, alcohol is postulated to exacerbate the risk, but no adverse events occurred in 20 volunteers in a mefloquine-ethanol interaction study (178, 179).

The frequency of neuropsychiatric adverse reactions is reported to be more common following mefloquine treatment than prophylactic use, occurring in 1 in 200 to 1 in 1 200 patients, depending on their ethnic origins (173, 174;
F.O. ter Kuile, C. Luxemburger and F. Nosten, unpublished data). The severe events also appear to be dose-related and were found to be seven-fold higher in those persons retreated with mefloquine within one month (165). Symptoms occurred within 3 days in 73% of patients, with only 9% reporting onset 10 days or more after treatment. The majority (78%) reported resolution of symptoms within 3 weeks. Concomitant administration of quinine may increase the risk of serious neuropsychiatric reactions and convulsions (165).

Following prophylactic use, the prevalence of "serious" neuropsychiatric reactions defined according to the definitions of the Council for International Organizations of Medical Sciences (CIOMS) (180-182), has been reported to be relatively low, being in the order of 1 in 10 000 and usually occurring early in the use of the drug (176, 177). Retrospective assessment of these events reported to the manufacturer indicates that 41% of cases experienced symptoms in the first week of chemoprophylaxis, 59% by week two and 78% by the third week. Over 90% of effects occurred during the first five weeks of chemoprophylaxis (176). In one study of Peace Corps Volunteers, in which long-term weekly chemoprophylaxis was continued despite adverse events in several participants, the rate of adverse reactions decreased with time (61).

The use of a loading dose during chemoprophylaxis may increase the risk of adverse reactions. Strange dreams occurred more frequently after three daily loading doses of 250 mg of mefloquine followed by 250 mg weekly, than after weekly chemoprophylaxis when steady state was achieved in 7 weeks. Depressive feelings, which were more frequent with mefloquine than with chloroquine, resolved as chemoprophylaxis continued (165).

A more recent study of British travellers taking mefloquine for chemoprophylaxis suggests that the relative frequencies of adverse reactions vary with the criteria used. The frequency of "serious" adverse events as defined by the CIOMS criteria was two cases for mefloquine and one for chloroquine plus proguanil, each in a population of around 2 300. However, more pronounced differences were observed between the two regimens in self-reported adverse reactions. Neuropsychiatric adverse events categorized by the traveller as "bad enough to interfere with daily activities" (9.2% of users) or "bad enough to seek medical advice" (2.2%) were each about twice as common with mefloquine than with chloroquine plus proguanil, whereas the percentage of patients reporting any adverse reactions was similar in the two groups (approximately 41%) (183).

Cardiovascular effects

Bradycardia and sinus arrhythmia have been consistently reported in up to 68% of patients treated with mefloquine in hospital-based studies (184), but comparative studies show the incidence to be similar to that observed following treatment with chloroquine, halofantrine or artesunate (184-186). No ECG or blood pressure changes were observed in 45 healthy Australian volunteers who received 250 mg of mefloquine weekly for 4 weeks compared to 50 controls (187). Concomitant administration of mefloquine with other related compounds such as quinine, quinidine and chloroquine may, however, produce ECG abnormalities and increase the risk of convulsions. The use of halofantrine after mefloquine causes significant lengthening of the QTc interval (185) and has been linked with three cardiac arrests in patients treated with both drugs. Halofantrine should, therefore, not be used in persons who have recently received mefloquine.

Since the first use of mefloquine, there have been concerns that its coadministration with drugs used to treat cardiovascular disease such as anti-arrhythmic drugs, beta-adrenergic blocking agents and calcium channel blockers as well as antihistamines, tricyclic antidepressants and phenothiazines might lead to severe adverse reactions. Theoretically, concomitant use of mefloquine and such drugs might also contribute to the prolongation of the QTc interval. However, no evidence of such drug interaction has been reported to date and co-medication with such drugs is no longer contraindicated (54, 188).

Rare events

Haematological events have been reported with mefloquine therapy, < 3% of adverse events reported to the manufacturers being blood dyscrasias. Mefloquine causes transient elevation of transaminases but is rarely associated with hepatitis. Three cases of blackwater fever during mefloquine therapy have been reported (189). Rare dermatological events, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis, have been temporally related to mefloquine exposure in a few individuals with no prior history of a similar event (190-194).

Effects on performance

Dizziness is recognized as a frequent but transient adverse effect of mefloquine use. Four of seven healthy Caucasian volunteers were severely incapacitated for 3-4 days following administration of 25 mg/kg and all experienced light-headedness (195). This led to the concern that chemoprophylaxis with the drug may impair precision movements. There are, however, indications that, if tolerated, mefloquine does not impede performance. No functional compromise was identified in 203 United States Marines exposed to mefloquine prophylaxis (165) or in 23 trainee pilots who received mefloquine at 250 mg/day for 3 days, then weekly for a total 6 weeks (196). However, sleep disturbances and loss of concentration were reported in volunteers given mefloquine, although the incidence of the latter symptom was not statistically significant. Balance and hearing were unaffected by weekly chemoprophylaxis for 16 weeks in 10 healthy Swedish volunteers (197) and no effect was seen on subtle cerebral function, audiometry and supine/erect blood pressure measurement in a placebocontrolled study of 45 healthy volunteers taking weekly mefloquine (187). Driving, i.e. road-tracking and car-following tests, has also been reported to be unaffected by mefloquine prophylaxis (179). However, in view of the limited data WHO does not recommend the use of mefloquine in persons, such as air pilots and machine operators, involved in tasks requiring fine coordination and spatial discrimination. Any such persons who experience adverse reactions after mefloquine intake should abstain from work (for at least 3 weeks after treatment) until symptoms have fully resolved.

Drug interactions

Concurrent use of quinine can potentiate dose-related adverse reactions to mefloquine (174). This may be related to the fact that higher quinine and mefloquine blood concentrations than expected are observed when both drugs are given concurrently. In general, mefloquine should not be administered within 12 h of the last dose of quinine. Co-administration of mefloquine with tetracyclines or ampicillin also produces higher mefloquine blood concentrations (198, 199).

Contraindications

The use of mefloquine is contraindicated in persons:

• with a history of allergy to mefloquine,
• with a history of severe neuropsychiatric disease,
• receiving halofantrine treatment,
• who have received treatment with mefloquine in the previous 4 weeks,
• performing activities requiring fine coordination and spatial discrimination
  e.g. air pilots and machine operators.

Overdosage

Induction of emesis and gastric lavage are of value if undertaken within a few hours of ingestion. Cardiac function and neuropsychiatric status should be monitored for at least 1-3 days and symptomatic and intensive supportive treatment provided as required, particularly for cardiovascular disturbances.