Naman Shah over at the topnaman Malaria blog and I didn’t really agree with Jason’s last post on the risks of mefloqine (brand name Lariam), so in the grand tradition of MethodLogical (almost 6 months old!), we took to the comments section and responded. The following are excerpts from and additions to those comments. Most of the credit here goes to Naman (seriously check out his blog).
So why is mefloquine on the market despite possibly severe side effects?
1) Because it works. The current FDA approved dosing regimen for prophylaxis may be suboptimal but mefloquine is a very effective antimalarial without reported drug resistance in most parts of the world.
2) As with all drugs there are contraindications and side-effects but mefloquine is part of the first-line treatment for P. falciparum (the most deadly of the malarial parasites) in several countries (Bolivia, Peru, Venezuela, Thailand, Cambodia) and is used safely, at much higher doses, to cure thousands of patients every year.
The FDA has to be risk averse and highlight even tenuous links. Notice their statement is careful to say “associated,” not “caused,” and only specifies suicides which occurred in traumatized war veterans. That said, yes, our clinical experience indicates there are certainly neuropsychiatric side effects, a term that sounds misleadingly severe which is why grading the adverse event matters – common “vivid” dreams are one thing, amnesia or seizures are another.
On the matter of frequency, the 25% rate of central nervous system side effects mentioned were self-reported in a small non-representative convenience sample. Note, most of those were headaches, vivid dreams, and insomnia- a far cry from schizophrenia. We really don’t know how frequent side effects for mefloquine are, especially by severity. One review found “despite a negative media perception, large pharmaco-epidemiological studies have shown that serious adverse events are rare.” Another review found that mefloquine does have more adverse events, but the absolute rate is still low (<5%) and they are mostly mild. In the real world, absolute rate is much more significant than relative rate.
3) The other drugs are far from perfect.
Chloroquines are useless in much of the world, especially where P. falciparum is endemic.
Doxycycline dramatically increases photosensitivity which can be problematic for pale people in already hot places. It can cause some unpleasant GI symptoms. Now, these symptoms are probably preferable to schizophrenia, but are more common AND a huge reason people stop taking doxy. If patients stop taking it, they are not protected and they can get malaria. Further, doxy may interfere with oral contraceptives (aka, the pill). Getting malaria is worse than getting pregnant, but if alternatives exist, they are worth considering in a woman of child bearing age. Also, doxy is teratogenic (harmful to fetuses), so if you get pregnant while on it you may have problems.
While it is harder for some people to remember the weekly dosing regimen of mefloquine, the problem with the daily dosing of doxy is that if you aren’t consistent with taking it at the same time, you run the risk of having low levels of the drug in your system, increasing susceptibility to malaria. It may be easy to remember to take a drug every day, but taking it at the same time every day (with food to avoid those nasty GI side effects!) is another thing. Is there one time every day where you are always 100% sure you will have access to food, water and your pills? Further, taking doxy for a month after leaving a malaria-endemic area is tough. People are not good at taking medication when they are sick, and they are even worse at taking it when they are healthy. It’s hard enough to convince a healthy person in a malarial area to take prophylaxis, convincing them to take it for 4 weeks afterward is even harder.
Doxy is also the weakest antimalarial of the three leading prophylactic regimens, leading to many breakthrough infections (we believe).
Atovaquone-proguanil (brand name Malarone) has the shortest pre- and post-travel regimen and great activity but is crazy expensive. $6 to $8 a pill. That may be fine if your insurance covers it (but that really just masks the cost to the health care system- a different issue entirely) or if you are going somewhere for a week, but after a while you start to wonder if a little malarial fever may be worth $45 a week. Also, all the points about daily dosing from doxy apply here. However, if this one becomes generic before resistance becomes widespread, mefloquine’s days are numbered.
Artemisins are not used for prophylaxis due to short half-lives and the need for multiple daily doses to ensure therapeutic levels.
Primaquine is not commonly used for prophylaxis, as there is concern about possible failure in prevention P. falciparum. Definitely worth studying more.
There isn’t much comparative effectiveness research looking at atovaquone-proguanil v. mefloquine v. doxy. Some sources assert malarone’s potential superiority, but there’s nothing rock solid. In the end, such studies are hard to execute, because you need to account for both efficacy (how a drug works when taken perfectly) and effectiveness (how a drug works when taken under real-world conditions- i.e., missed doses).
Lastly, Jason made an excellent point about assessing the true risk of mefloquine in patients predisposed to psychiatric illness. Such patients are (rightfully) protected by institutional review boards (ethics boards that approve all academic research) because of their reduced capacity, increased vulnerability, and potential inability to consent for themselves. However, if we overprotect this population, we do them a disservice, as we never identify the best ways to manage their care.