Mefloquine hydrochloride (also known as Lariam or Mefaquin) is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine. The brand name drug, Lariam, is manufactured by the Swiss company Hoffmann–La Roche. In August 2009, Roche stopped marketing Lariam in the United States. Generic mefloquine from other manufacturers, is still widely available. Rare but serious neuropsychiatric problems have been associated with its use.
Medical uses
Mefloquine is used to both prevent and treat certain forms of
malaria.
Malaria prevention
Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may have resistance to multiple drugs. It is typically taken for one to two weeks before entering an area with malaria.
Doxycycline and
atovaquone/proguanil provide protection within one to two days and may be better tolerated. If a person becomes ill with malaria despite prophylaxis with mefloquine the use of
halofantrine and
quinine for treatment may be ineffective.
Malaria treatment
Once a person has contracted malaria, mefloquine is recommended as a second line treatment for
chloroquine sensitive or resistant
falciparum malaria and is deemed a reasonable alternative for uncomplicated chloroquine resistant
vivax malaria.
It is not recommended for severe malaria infections, particularly infections from P.falciparum which should be treated with intravenous antimalarials. Mefloquine does not eliminate parasites in the liver phase of the disease, and people with P. vivax malaria should be treated with a second drug that is effective for the liver phase, such as primaquine.
In pregancy and breastfeeding
The
World Health Organization gives approval for the use of mefloquine in the 2nd and 3rd trimester of
pregnancy and use in the 1st trimester does not mandate termination of pregnancy. Women should however not become pregnant and should use effective birth control while taking mefloquine. It may be used during breastfeeding, though the drug appears in breast milk in low concentrations.
Adverse effects
Mefloquine is contraindicated in those with a previous history of
seizures or a recent history of
psychiatric disorders. Severe side effects requiring hospitalization are rare. Rates of side effects appear similar to other medications used for malaria prevention.
Neuropsychiatric
Neuropsychiatric effects are reported with mefloquine use. It is not known if this is a causal relationship. The FDA product guide states it can cause mental health problems including: anxiety, hallucinations, depression, unusual behavior, and suicidal ideations among others. Some have reported severe central nervous system events requiring hospitalization in about 1:10,000 people taking mefloquine for malaria prevention with milder events (e.g., dizziness, headache, insomnia, and vivid dreams) in up to 25%. When some measure of subjective severity is applied to the rating of adverse events, about 11-17% of travelers are incapacitated to some degree.
Pneumonitis
The FDA has reported an association with
pneumonitis and
eosinophilic pneumonia
Cardiac
Mefloquine may cause abnormalities with heart rhythms that are visible on
electrocardiogram. Combining mefloquine with other drugs that cause similar effects, such as quinine or
quinidine, can increase these effects. Combining mefloquine with halofantrine can cause significant increases in
QTc interval.
Mechanism of action
The exact mechanism as to how mefloquine works against malaria is unknown.
Elimination
Mefloquine is metabolized primarily through the liver. Elimination of mefloquine in anyone with impaired liver function may be prolonged, resulting in higher plasma levels and an increased risk of adverse reactions. The mean elimination plasma half-life of mefloquine is between 2 and 4 weeks. Total clearance is through the liver and the primary means of excretion is through the bile and feces as opposed to only 4% to 9% excreted through the urine. During long-term use, the plasma half-life remains unchanged.
Liver function tests should be performed during long-term administration of mefloquine. Alcohol use should be avoided during treatment with mefloquine.
Chirality
Mefloquine is a
chiral molecule with two
asymmetric carbon centres, which means it has four different
stereoisomers. The drug is currently manufactured and sold as a
racemate of the (
R,
S)- and (
S,
R)-enantiomers by
Hoffman-LaRoche, a Swiss
pharmaceutical company. Essentially it is two drugs in one. Plasma concentrations of the (-)-enantiomer are significantly higher than those for the (+)-enantiomer and the pharmokinetics between the two enantiomers are significanly different. The (+)-enantiomer has a shorter half-life than the (–)-enantiomer.
According to some research, the (+)-enantiomer is more effective in treating malaria, and the (–)-enantiomer specifically binds to adenosine receptors in the central nervous system, which may explain some of its psychotropic effects. It is not known whether mefloquine goes through stereoisomeric switching in vivo.
History
Mefloquine was invented at
Walter Reed Army Institute of Research (WRAIR) in the 1970s shortly after the end of the Vietnam war where 1% of US combat troops contracted malaria every day. Mefloquine was number 142,490 out of a total of 250,000 antimalarial compounds screened during the study.
Mefloquine was the first Public-Private Venture (PPV) between the US Department of Defense and a pharmaceutical company. WRAIR transferred all its phase I and phase II clinical trial data to Hoffman LaRouche and Smith Kline. FDA approval as a treatment for malaria was swift. Most notably, phase III safety and tolerability trials were skipped.
However, mefloquine was not approved by the FDA for prophylactic use until 1989. This approval was based primarily on compliance while safety and tolerability were overlooked. Because of the drug's very long half-life, the Centers for Disease Control originally recommended a mefloquine dosage of 250 mg every two weeks; however, this caused an unacceptably high malaria rate in the Peace Corps volunteers that participated in the approval study, so the drug regimen was switched to once a week.
The first randomized controlled trial on a mixed population was first performed in 2001. Roughly 67% reported greater than or equal to 1 adverse event with 6% of the users reporting severe events requiring medical attention.
With this kind of data, it is certain the FDA and other international licensing authorities would not have approved mefloquine for prophylactic use.
There have also been no studies on the effects of co-administration of mefloquine and other drugs. The fatal drug reactions that ensued might have been a result of this lack of knowledge of possible contraindications. Trials in the 1990s and early 2000s verified mefloquine's neurotoxicity and significant potential for neuropsychiatric side effects.
Post marketing data was easily discounted as anecdotal and "media hype" by the US Army researchers and travel medicine practitioners. Since the side effects that mefloquine can cause have not been fully defined, and there appears to be no incentive for the current manufacturers to further investigate mefloquine, the drug may be discarded. As evidence, the US military dropped mefloquine as its primary antimalarial in 2009.
Society and culture
United States military
On 2 February 2009, Lieutenant General Eric Schoomaker, Army Surgeon General, issued the following directive:
"In areas where doxycycline and mefloquine are equally efficacious in preventing malaria, doxycycline is the drug of choice. Mefloquine should only be used for personnel with contraindications to doxycycline and who do not have any contraindications to the use of mefloquine . . . . Mefloquine should not be given to soldiers with recent history of Traumatic Brain Injury (TBI) or who have symptoms from a previous TBI. Malarone would be the treatment of choice for these soldiers who cannot take doxycycline or mefloquine."
The following September, Hon. Ellen Embry, then Acting Assistant Secretary of Defense for Health, issued the same policy making doxycycline the antimalarial of choice across all the US armed services.
Research
A study to assess mefloquine as a treatment for
progressive multifocal leukoencephalopathy (PML) was initiated in 2008. To date, no results have been posted. WRAIR has published several papers outlining ongoing efforts at that institution to make mefloquine safer by producing a drug composed of only the (+)-
enantiomer.
References
External links
Manufacturer's information
Mefloquine (Lariam) Action, Clearinghouse for information on mefloquine news, research, toxicity
Controversies and Misconceptions in Malaria Chemoprophylaxis for Travelers
The position of mefloquine as a 21st century malaria chemoprophylaxis
Category:Antimalarial agents
Category:Quinolines
Category:Piperidines
Category:Organofluorides
Category:World Health Organization essential medicines
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