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Lariam (Mefloquine Hydrochloride tablet)

Mefloquine : Drug Administration

Drug overdose

Mefloquine has a relatively wide therapeutic margin, but can cause predictable and sometimes long-lasting toxicity in overdose.

Accidental ingestion of 5.25 g of mefloquine over 6 days by a 36-year-old woman caused vertigo, difficulty in visual accommodation, myalgia, hypotension, and tachycardia; most of the anomalies disappeared in 2 weeks.

Two case reports have described how the antifungal drug terbinafine (Lamasil) was confused with Lariam, leading to accidental mefloquine overdosage and neuropsychiatric adverse effects, including ataxia, high-frequency hearing loss, depression, and paresthesia.

Drug-Drug Interactions

Alcohol

One case history has suggested that the use of alcohol with mefloquine can precipitate a neuropsychiatric reaction.

Other antimalarial drugs

Mefloquine has been given in combination with other antimalarial drugs, with the aim of delaying drug resistance. Empirical combinations have been made with pyrimethamine and sulfa drugs. However, no drug has been proven to be synergistic with mefloquine, which, with its very long half-life, is difficult to match.

The chemotherapeutic response of Plasmodium berghei to various combinations of mefloquine with other drugs (sulfadoxine + pyrimethamine, primaquine, floxacrine) have shown that the desired effects are purely additive, so the adverse effects too are probably only those of the individual compounds. Adverse reactions occurred in 46% of 400 patients treated with Fanimef (mefloquine + pyrimethamine + sulfadoxine). Of note were dizziness (29%), nausea (9.5%), vomiting (7.3%), weakness/lassitude (5.8%), abdominal discomfort or pain (5.5%), diarrhea (3.8%), pruritus (3.0%), insomnia (2.0%), and headache (2.0%).

The combination of mefloquine with artesunate improves tolerance to mefloquine and the therapeutic response is faster.

Rabies vaccine

Reports of a possible interaction between concurrent mefloquine administration and intradermal rabies immunization have not been substantiated. Four cases in which rabies vaccine and mefloquine were accidentally given concurrently all led to good antirabies antibody responses.

Valproate

Mefloquine has been reported to oppose the effect of valproate.

A 20-year-old woman with bilateral myoclonus and generalized tonic-clonic seizures which had been controlled with valproic acid was given 2 prophylactic doses of mefloquine and developed generalized tonic-clonic seizures.

The authors suggested a causal relation to the administration of mefloquine.

Mefloquine: Organs and Systems

Cardiovascular

Sinus bradycardia was seen in 18% of patients taking mefloquine, occurring some 4-7 days after administration; the bradycardia was asymptomatic and lasted about 3-4 days. Transient sinus arrhythmia was also reported, without a need for treatment. Asymptomatic dysrhythmias were also recorded in a dosage comparison trial.

Nervous system

Neurological and psychiatric reactions occur to such an extent, even during prophylactic use, that a general recommendation for the use of mefloquine as prophylaxis has been called into question, although disabling symptoms occur in under 1% of travellers. Headaches, dizziness, vertigo, and light-headedness are common,, the incidence varying between 20 and 90%. Dizziness is to some extent dose-related. Tinnitus and vertigo are less frequent.

A so-called postmalaria neurological syndrome (convulsions, tremor, confusion) has been described in about 4-5% of patients treated for severe malaria tropica with mefloquine.

All reports have suggested that the neuropsychiatric reactions to mefloquine are transient. They may be precipitated by alcohol.

Penetration into the brain of the (+) enantiomer of mefloquine is much higher than that of the (-) enantiomer whilst plasma concentrations are greater for the (-) enantiomer, potentially providing a way of minimizing neurological adverse effects, which are often significantly overstated, by using the less toxic enantiomer. However, chiral separation technology is not sufficiently well developed to be economically realistic for clinical practice in the foreseeable future.

Sensory systems

Three cases of previously healthy patients who developed persisting high-frequency sensorineural hearing loss and tinnitus whilst taking mefloquine have been reported.

Psychological, psychiatric

At first thought to occur only after therapeutic doses of mefloquine, it is now clear that neuropsychiatric reactions occur after prophylactic use as well. The incidence is estimated at about one in 13 000 with prophylactic use, but as high as one in 215 with therapeutic use. Combination with other drugs that affect thevnervous system can result in unpredictable reactions. The symptoms vary in type and severity: non-cooperation, disorientation, mental confusion, hallucinations, agitation, and impaired consciousness. An acute psychiatric syndrome with attempted suicide was reported in one case. A single dose can be all that is needed to evoke a mental reaction. Convulsions have been reported, with or without psychiatric symptoms; it seems that mefloquine can aggravate and perhaps even provoke latent epilepsy.

  • A severe psychiatric and neurological syndrome, with agitation, progressive delirium, and generalized rigors, was seen in a 47-year-old man after he had taken mefloquine 1500 mg over 24 hours.
  • A 7-year-old Indian boy was diagnosed as having “cerebral malaria” and received quinine followed by mefloquine (dose not given). He developed hallucinations and removed his clothes and danced. His symptoms resolved within 24 hours of stopping mefloquine. This case highlights the fact that mefloquine should not be given after quinine in cases of severe malaria.
  • A 42-year-old man with no previous psychiatric history suddenly developed visual symptoms after the third dose (total dose 750 mg) of prophylactic mefloquine. The symptoms consisted of an impression of focusing on two different planes and of perceiving his surroundings as very far from him. They were associated with slurred speech and altered comprehension. They occurred daily, lasting up to an hour, for 6 months. He had previously taken a course of mefloquine for 7 weeks without any adverse events.
  • A 52-year-old woman with no psychiatric history developed anxiety, paranoia, visual hallucinations, confusion, and depressive symptoms after 3 doses of prophylactic mefloquine (250 mg/week). She had previously taken mefloquine prophylaxis intermittently for 4 years with no adverse events.

These case reports illustrate important neuropsychiatric adverse effects of mefloquine in individuals who had previously taken mefloquine safely and had no psychiatric history.

A postal survey of 5446 returning Danish travellers examined the adverse effects of unstated doses of mefloquine, chloroquine, and chloroquine plus proguanil for malaria prophylaxis. There were 4158 responses (76%); 1223 travellers took chloroquine, 1827 took chloroquine plus proguanil, and 809 took mefloquine. Overall, although chloroquine and chloroquine plus proguanil were associated with a large number of mild (mainly gastrointestinal) adverse effects, 30-50% had diarrhea and about 20% had nausea or abdominal pain. There was a significantly larger number of reported “unacceptable symptoms” (not defined) with mefloquine: 2.7%, 1.0%, and 0.6% for mefloquine, chloroquine, and chloroquine plus proguanil respectively. Most of the more serious adverse events were in those who took mefloquine. Compared with chloroquine alone the relative risk (95% CI) of “depression,” experiencing “strange thoughts,” or having altered spatial perception were 5.1 (2.7), 6.4 (2.5, 16, and 3.0 (1.4) respectively. There was also a higher incidence of depression in wome than in men. The relative risk of hospital admission or early termination of travel possibly related to prophylaxis was higher with mefloquine than with either chloroquine or chloroquine plus proguanil; the relative risks (95% CI) were 162, 612, and 261 respectively.

A postal survey of the incidence of psychiatric disturbances in 2500 returning Israeli travellers showed that travellers with this class of adverse effects were more likely to have taken mefloquine than other antimalarial drugs. Of 117 travellers with psychiatric adverse effects, 115 had taken mefloquine compared with 948/ 1340 for the entire cohort. This was a retrospective postal study with a response rate of 54% (1340 out, and of those who responded 71% had taken mefloquine, 5% had taken chloroquine, and 24% had taken no prophylaxis. In this study 11% of the respondents reported psychiatric disturbances, mainly sleep disturbance, fatigue, vivid dreams, or “lack of mood.” Only 16 of the respondents had symptoms lasting 2 months or more. Those who had had a psychiatric disturbance were also more likely to have been female and to have taken recreational drug use.

Although the above studies were limited by retrospective design, their results are in broad agreement with the results of other studies over the past few years that indicate that women have a higher incidence of psychiatric adverse effects from mefloquine than men.

In a prospective, double-blind, randomized, placebo-controlled study in 119 healthy volunteers (mean age 35 years), who took either atovaquone 250 mg/day + chloro-guanide 100 mg/day or mefloquine 250 mg/week, depression, anger, and fatigue occurred during the use of mefloquine but not atovaquone + chloroguanide.

Airline pilots should not take routine prophylaxis with mefloquine because of the small risk of neuropsychiatric reactions.

Endocrine

A 30-year-old woman took mefloquine, 250 mg/week, and developed abdominal pain, palpitation, and tremor; thyroid function tests were abnormal; 1 month after withdrawal the tests had returned to normal.

Hematologic

Agranulocytosis occurred in a 31-year-old man with P. vivax parasitemia given an initial dose of mefloquine followed by 500 mg 8 hours later.

There have been no other reports of hematological toxicity.

Gastrointestinal

Gastrointestinal complaints, such as nausea, vomiting, abdominal discomfort, and (usually mild) diarrhea, have been mentioned in most reports, the incidence being 10-25%,. The frequency increases with higher doses, for example 25 instead of 15 mg/kg.

Liver

Acute fatty liver has recently been reported after malaria prophylaxis with mefloquine.

A 46-year-old woman took five, weekly, doses of mefloquine 250 mg before discontinuing treatment because of neuropsychiatric and gastrointestinal symptoms. Over the next month she had watery diarrhea, 11 kg weight loss, dependent edema, and abdominal fullness. On examination the liver was substantially enlarged; ultrasound imaging showed massive hepatomegaly with diffuse high-grade steatosis. Serological investigations for infective and autoimmune causes were negative. Her symptoms abated with fluid, electrolyte, and albumin replacement. A fine-needle liver biopsy showed features of diffuse macrovesicular hepatic steatosis. Clinical and radiological changes subsided without sequelae.

Acute fatty liver in this case may have been an idiosyncratic adverse effect of mefloquine.

Raised transaminases (up to 20 times normal activities) have been seen in a man taking mefloquine prophylaxis; they resolved after withdrawal of mefloquine.

Skin

Maculopapular rash, urticaria, and itching have been reported; itching may be more common with mefloquine than with chloroquine. However, there are isolated case reports concerning more serious skin conditions: exfolia-tive dermatitis; cutaneous vasculitis and a bilateral facial rash, comprising raised red lesions and flat bullae.

Mefloquine has been associated with erythema multiforme and its variants Stevens-Johnson syndrome, and toxic epidermal necrolysis.

It has tentatively been suggested that mefloquine can exacerbate psoriasis (as can other antimalarial drugs, such as quinidine, chloroquine, and proguanil).

Skin reactions to mefloquine have been reviewed, in relation to 74 case reports published between 1983 and 1997. Pruritus and maculopapular rash were the most common skin reactions: in some studies, their approximate frequency was 4-10% for pruritus and up to 30% for non-specific maculopapular rashes. Adverse effects less commonly associated with mefloquine included urticaria, facial lesions, and cutaneous vasculitis. There was one case of Stevens-Johnson syndrome and one fatal case of toxic epidermal necrolysis.

Mefloquine: Side Effects

Mefloquine, a fluorinated derivative of 4-quinoline methanol, is a product of the US Army’s antimalarial research program. It is active against chloroquine-resistant Plasmodium falciparum, and has an excellent schizonticidal effect in the blood in experimentally induced Plasmodium vivax infections in volunteers. It is not gametocidal. P. vivax infections can persist after successful treatment of the falciparum infection with other drugs; the fact that mefloquine is effective against both organisms is thus of practical importance.

Mefloquine is readily absorbed after oral administration; absorption is influenced by the formulation and is more rapid from an aqueous solution. Maximum serum concentrations occur after hours. Absorption is reduced by diarrhea. The half-life varies considerably and has been variously reported to be 7-23 days, 15-30 days, and 8-18 days,. Plasma protein binding is high. Sick patients have a prolonged fmax.

Mefloquine has a high cure rate after a single dose of 750-1000 mg. The use of combinations of mefloquine with other antimalarial drugs has been advocated in order to reduce the development of resistance. Mefloquine is effective as a prophylactic. Using a weekly dosage schedule, a dose of 250 mg is appropriate in adults. Because early reports also suggested that the drug was without serious adverse effects, mefloquine became widely advocated by various advisory bodies for prophylactic use, starting a week before travel to an endemic area where chloroquine resistance is common, and continuing for 4 weeks after departure from the area. Regrettably, but as might have been expected, it has also been used for prophylaxis in areas where its use is unnecessary.

Mefloquine remains useful in the treatment of uncomplicated malaria in areas of chloroquine resistance, but recommendations for mefloquine as prophylaxis in travellers are under constant review. In visitors to the Kruger National Park (South Africa), adverse effects were reported in 325 (25%) of 1300 subjects taking mefloquine; gastrointestinal and neuropsychia-tric effects were dominant. Four subjects required hospital attention for particularly severe neuropsychiatric reactions and 53 changed from mefloquine prophylaxis because of adverse effects. However in the same study chloroquine + proguanil prophylaxis led to reported adverse effects in 720 (29%) of 2488 subjects: one had a convulsion and 69 altered their prophylaxis because of adverse events or the dosing schedule. In this population mefloquine was as well tolerated as chloroquine + proguanil prophylaxis in general terms. This is in contrast to previous studies, in which the use of mefloquine led to higher rates of intolerance and severe adverse effects.

Observational studies

Malaria prevention measures taken by 5626 returning North American and European travellers departing from Kenyan airports have been examined in a cross-sectional questionnaire study. Mefloquine (74%) and chloroquine and proguanil (15%) were the most common drugs used. There were adverse events in 20% of the travellers who took mefloquine and 16% of those who took chloroquine and proguanil. Neuropsychological adverse events were reported by 7.8% of those taking mefloquine and 1.9% of those taking chloroquine. Despite adverse events, adherence was better in the mefloquine group (95 versus 81%; OR = 0, which may have been due to a lower dosing frequency.

Comparative studies

Atovaquone + proguanil (250/100 mg/day) and mefloquine (250 mg/week) have been compared in non-immune subjects attending travel clinics in North America, Europe, and South Africa in a randomized, double-blind study. Adverse events were reported by an equivalent proportion of subjects who had taken either drug (71 versus 67%; difference 4.1%, 95% CI = 1.7). Those who took atovaquone + proguanil had significantly fewer treatment-related neuropsychiatric adverse events (14 versus 29%), fewer adverse events of moderate or severe intensity (10 versus 19%), and fewer adverse events that caused prophylaxis to be withdrawn (1.2 versus 5%), compared with those who took mefloquine. Adherence was better in the atovaquone + proguanil group, which may have been due to the shorter duration of post-travel dosing (1 week versus 4 weeks for mefloquine). There were no confirmed cases of malaria.

Mefloquine (125 or 250 mg/week) has been compared with proguanil (100 or 200 mg/day) for short-term (6 months) malaria chemoprophylaxis in Nigerians with sickle cell anemia in a non-blinded, randomized study. Efficacy was similar (89% for mefloquine and 82% for proguanil). Adverse events were reported by 32% of those who took proguanil and 20% of those who took mefloquine. Surprisingly, only 3.6% of the mefloquine group reported neuropsychiatric adverse events.

Single-dose pyrimethamine + sulfadoxine (25 mg/kg) has been compared with mefloquine (15 mg/kg) in the treatment of uncomplicated P. falciparum malaria in an unblinded, randomized study in 102 Malawi children. Immediate vomiting was more common in those who took mefloquine (eight cases) than in those who took pyrimethamine + sulfadoxine (one case), with comparable parasite failure rates at 14 days (20 and 22% respectively).

General adverse effects

Although mefloquine is generally well tolerated, particularly when used prophylactically, the list of adverse effects has grown with accumulated experience. With therapeutic doses (for example 750-1500 mg in adults; 20 mg/kg in children) adverse effects are usually mild, but with occasional severe neuropsychiatric derangement. The overall incidence of adverse effects is about the same as with chloroquine, about 40-50%. Events most commonly reported include nausea, diarrhea, abdominal pain, dizziness, strange dreams, and insomnia. Adverse effects are dose-related, with an increase in dizziness and gastrointestinal complaints and fatigue at higher doses. Extensive acute, subacute, and chronic studies of mefloquine in animals have shown that it is not phototoxic, like some of the quinolone-methanols studied, nor was it mutagenic, teratogenic, or carcinogenic in these studies.

The adverse effects of mefloquine have been extensively reviewed both for prophylaxis (when rare neuropsychiatric adverse effects make its use controversial) and in treatment doses, when it has been linked to an increased incidence of the postmalaria neurological syndrome. A retrospective review of 5120 Italian soldiers showed an overall chemoprophylaxis curtailment rate of less than 1%, which was not significantly different from the combination of chloroquine and proguanil. A semi-systematic review also suggested no significant difference in tolerability compared with other antimalarial drugs.

The frequency and spectrum of adverse events associated with mefloquine (750 and 500 mg 6 hours apart) has been assessed in 22 healthy volunteers who were monitored for 21 days after drug administration. More women than men reported severe adverse reactions. The most commonly reported adverse effects were vertigo (96%), nausea (82%), and headache (73%). The vertigo was severe (grade in 73% and required bed rest and specific medication for 1-4 days. In most cases (17/1) the symptoms resolved within 3 weeks after drug administration. Biochemical and hematological measures stayed within the reference ranges, but there were significant rises in serum sodium, chloride, calcium, bilirubin, gammaglutamyl transpeptidase, and lactate dehydrogenase.

Mefloquine: Organs and Systems

Long-Term Effects

Drug tolerance

Instances of mefloquine resistance were reported in Tanzania in 1983, in Thailand in 1989, and in Africa (Malawi) in 1991. Resistance to combinations of mefloquine with sulfadoxine and pyrimethamine was reported in 1985 (40). The possibility of cross-resistance between mefloquine and halofantrine was raised in 1990. Currently there are extensive areas, including Thailand, Cambodia, Laos, Papua New Guinea, and Myanmar, where P. falciparum is resistant to mefloquine. High-dose mefloquine has been tried in areas with mefloquine-resistant P. falciparum; and a dose of 25 mg/kg is effective, even in a multidrug-resistant area.

Early laboratory studies suggested cross-resistance between mefloquine and halofantrine, but in a later rodent model cross-resistance was not absolute.

Mefloquine: Second-Generation Effects

Susceptibility Factors

Sex

A study of the pharmacokinetics of oral mefloquine in 12 healthy adults (6 men, 6 women) over 10 weeks has given insights into sex differences in mefloquine pharmacokinetics. Five weekly doses of mefloquine 250 mg were given to healthy volunteers. After this, half the subjects took 5 weekly doses of mefloquine 125 mg and half continued to have 250 mg per week.

By the second week, all the subjects had plasma mefloquine concentrations over 1.5 µmol/l (the effective prophylactic threshold), but it was only after the fourth dose that the trough concentrations reached this threshold. The women had significantly higher values of Coax and Cmin ss than the men. Although the dose of mefloquine was reduced to 125 mg, the plasma mefloquine concentration was maintained above 1.5 µmol/l in all subjects. In this small study, the most commonly reported adverse events were headache, insomnia, and vertigo, with most adverse events occurring between weeks 5 and 8, when plasma mefloquine concentrations were highest. Women had significantly more adverse events (number of days with adverse events/total number of days exposed 149/1) than men (43/1).

These results may explain why earlier studies in male military personnel failed to detect a higher proportion of neuropsychiatric problems with mefloquine compared with other prophylactic regimens.

Neuropsychiatric events have been extensively reviewed, but little is known about the sex-related incidence. Of 179 travellers (mean age 39 years) who took mefloquine for a 3-week prophylactic period before travelling, the women reported adverse events significantly more often than the men. There was an increase in fatigue exclusively in the women, especially in first-time users of mefloquine.

Mefloquine: Second-Generation Effects

Pregnancy

A review of the use of mefloquine in pregnancy did not suggest that mefloquine has a worse effect in pregnancy than other antimalarial drugs, such as chloroquine and pyrimethamine + sulfadoxine.

A 7-day quinine regimen (10 mg/kg salt, 8-hourly for 7 days) has been compared with oral mefloquine 25 mg/kg plus artesunate 4 mg/kg/day for 3 days in 108 women on the Thai-Burmese border. The mefloquine plus artesunate regimen was significantly more effective than quinine (day 63, cure rate 98 versus 67%). There were more episodes of dizziness (RR = 1.93; 95% CI = 1.14) and tinnitus (RR = 3.93; 95% CI = 1.98) with quinine, but no serious adverse events were attributable to either drug. There were also two mid-trimester abortions with mefloquine plus artesunate and none with quinine. There were no birth defects in either group. Although the numbers were very small, the authors concluded that despite a better parasitological cure rate, the increased risk of abortion associated with mefloquine in pregnancy precluded its routine use. Larger studies are needed to confirm this observation.

Teratogenicity

Mefloquine prophylaxis was studied in a group of 339 pregnant women on the Thai-Burmese border in a double-blind placebo-controlled trial. Infants in the mefloquine group had a lower mean birth weight; there was also a higher rate of stillbirths and congenital anomalies, though these differences were not statistically significant.

However, a further study of 208 pregnant women on the Thai-Burmese border showed a significantly increased incidence of still-births compared with 1565 women treated with other antimalarial drugs. Other adverse effects were no more common than with other antimalarial drugs. The study was performed during a period of emerging mefloquine-resistant malaria, and the findings may also reflect the effect of suboptimal malaria treatment.

In a postmarketing survey by Roche, spontaneous reports from 1267 women who had taken mefloquine during pregnancy showed that there was neither a specific pattern of malformations nor an overall increase in congenital malformations over the 4% prevalence observed among the general population. These data have been confirmed by a survey among 72 US Army soldiers who had taken mefloquine during pregnancy.

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