Mefloquine, adverse effects

The broad picture is that mefloquine appears not to worsen the psychomotor effects of moderate amounts of alcohol. Just why an unusual toxic reaction developed in one individual is not known, although mefloquine alone can increase the risk of psychiatric events. It has been postulated that many of the adverse effects of mefloquine are associated with liver damage, and concurrent insults to the liver, such as from alcohol and dehydration, may be related to the development of severe or prolonged adverse reactions to mefloquine. In a review of 516 published case reports of mefloquine adverse effects, 11 cited alcohol as a possible contributing fac-tor. It was suggested that travellers taking mefloquine should avoid alcohol particularly within 24 hours of their weekly mefloquine dose. However, the manufacturers have not issued such a warning. More study is needed. 

Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. Neuropsychiatric toxicities have received a good deal of publicity, but despite frequent anecdotal reports of seizures and psychosis, a number of controlled studies have found the frequency of serious adverse effects from mefloquine to be no higher than that with other common antimalarial chemoprophylactic regimens. Leukocytosis, thrombocytopenia, and aminotransferase elevations have been reported. 

The latter adverse effects are more common with the higher dosages required for treatment. These effects may be lessened by administering the drug in two doses separated by 6-8 hours. The incidence of neuropsychiatric symptoms appears to be about ten times more common than with chemoprophylactic dosing, with widely varying frequencies of up to about 50% being reported. Serious neuropsychiatric toxicities (depression, confusion, acute psychosis, or seizures) have been reported in less than one in 1000 treatments, but some authorities believe that these toxicities are actually more common. Mefloquine can also alter cardiac conduction, and arrhythmias and bradycardia have been reported. 

There was a high frequency of amphetamine abuse and withdrawal among patients from the Thai-Myanmar border area admitted to hospital with Plasmodium falciparum malaria (90). This co-morbidity can cause diagnostic confusion, alter malaria pathophysiology, and lead to drug interactions. Considering the potential neuropsychiatric adverse effects of mefloquine, an important component of current antimalarial treatment in Southeast Asia, it should be avoided in patients who abuse amphetamines. 

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 the incidence of psychiatric disturbances in 2500 returning Israeli travellers (505) 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 of 2500), and of those who responded 71% had taken mefloquine, 5% had taken chloroquine, and 24% had taken no prophylaxis. In this study 11% (117) 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 (506-509). 

In a review of 10 trials (n = 2750 non-immune adult travelers) (512) the effects of mefloquine in adult travellers were compared with the effects of other regimens in relation to episodes of malaria, withdrawal from prophylaxis, and adverse effects. Five trials were field studies of male soldiers. One comparison of mefloquine with placebo showed that mefloquine was effective in an area of drug resistance (OR = 0.04 95% Cl = 0.02, 0.08) and withdrawals in the mefloquine group were consistently higher in four placebo-controlled trials (OR = 3.56 95% Cl = 1.67, 7.60). 

In five comparisons of mefloquine with other chemoprophylaxis regimens, there was no difference in tolerability. The only consistent adverse effects consistently specific to mefloquine in the controlled trials were insomnia and fatigue, but there were also 516 reports of adverse effects of mefloquine, 63% of which were in tourists and travellers. Four deaths were attributed to mefloquine. 

MEFLOQUINE H2 RECEPTOR BLOCKERS-CIMETIDINE t efficacy and adverse effects of antimalarials Inhibition of metabolism, some definitely via CYP3A4 Avoid co-administration... 

Adverse effects include nausea, dizziness, disturbance of balance, vomiting, abdominal pain, diarrhoea and loss of appetite. More rarely, hallucinations, seizures and psychoses occur. Mefloquine should be avoided in patients taking (i-adrenoceptor and calcium channel antagonists for it causes sinus bradycardia quinine can potentiate these and other... 

The artemisinin derivatives are limited by an unacceptable incidence of recrudescence with monotherapy, and they therefore need to be used in combination. A summary of prospective trials that looked specifically for adverse effects showed that artemisinins alone are very well tolerated (10). The same study showed no evidence of adverse interactions of artesunate with mefloquine, with an incidence of adverse effects similar to that expected from malaria and mefloquine (25 mg/kg) together. Reducing doses of mefloquine increases recrudescence rates to unacceptable levels (11). Combinations of artemisinins with quinine, co-trimoxazole, and doxycycUne are well tolerated. 

A large trial of the first fixed-dose combination of an artemisinin derivative likely to be licensed (artemether + benflumetol) had disappointing relapse rates compared with mefloquine monotherapy (6). In the 126 patients who took artemether + benflumetol there were no adverse effects attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations (12) but toxicity studies are lacking. 

In a second Thai study, 652 adults and children were treated with artesunate plus mefloquine (15). A single dose of artesunate 4 mg/kg plus mefloquine 25 mg/kg gave a rapid response but did not improve cure rate. Artesunate given for 3 days in a total dose of 10 mg/kg plus mefloquine was 98% effective. The incidence of vomiting was significantly reduced by giving the mefloquine on day 2 of the treatment. There were no adverse effects attributed to artesunate. 

Table 1 Adverse effects of artesunate with or without mefloquine in acute uncomplicated malaria tropica...

An inpatient study of 79 patients given proguanil + atovaquone compared with 79 patients given mefloquine showed no malaria-independent adverse effects (10). Although there was a significant transient increase in liver enzymes, this was probably of limited clinical importance. 

Lumefantrine is a synthetic aminoalcohol fluorene derivative, related to halofantrine and mefloquine (1). It was highly effective in uncomplicated chloroquine-resistant malaria tropica in an open, non-comparative trial in 102 patients in China when given in four oral doses over 48 hours (2). No significant adverse effects have been reported. It has also been marketed in a combination of artemether (20 mg) plus lumefantrine (120 mg). 

Lumefantrine was inferior to artesunate + mefloquine in an open, randomized comparison in 617 patients in Thailand with uncomplicated multidrug-resistant malaria tropica, but produced two to four times fewer adverse effects, such as nausea, vomiting, dizziness, sleep disorders, or other neurological symptoms (4). 

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 Itahan soldiers showed an overall chemoprophylaxis curtailment rate of less than 1%, which was not significantly different from the combination of chloroquine and proguanil (11). A semi-systematic review also suggested no significant difference in tolerabihty compared with other antimalarial drugs (12). 

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 (13). More women than men reported severe adverse reactions. The most commonly reported adverse effects were vertigo (96%), nausea (82%), and headache (73%). The... 

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

Skin reactions to mefloquine have been reviewed, in relation to 74 case reports published between 1983 and 1997 (39). 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. 

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 (51). 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. 

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 (SEDA-13, 809), 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) (SEDA-12, 693). 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%). 

Pyrimethamine (25 mg), sulfadoxine (500 mg), and mefloquine (250 mg) are available in the combination formulation known as Fansimef. The adverse effects characteristic of aU three components can be expected. 

WR-243251 is a floxacrine analogue, a dihydroacridine-dione. It is active in vitro against chloroquine-resistant, mefloquine-resistant, and pyrimethamine-resistant strains of malaria (1). By analogy to quinacrine and floxacrine, there is concern about possible dermatological, cardiac, and neuropsychiatric toxicity and vascular adverse effects. 

Toxicity Mefloquine is less toxic than quinine its adverse effects include gastrointestinal distress, skin rash, headache, and dizziness. At high doses, mefloquine may cause neurologic symptoms and seizures. 

---