arznei-telegramm 2002; 33: 89


Psychoses, Suicides Et Cetara: Should Mefloquin (LARIAM) Still be Allowed?

The malaria drug mefloquin (LARIAM) has increasingly been associated with toxic CNS side effects (a-t 1996; No. 3: 31, 1997;  No. 11: 117) such as psychoses, aggressions and suicides (a-t 2000; 31: 23). If psychiatric symptoms, e.g. acute anxiety, depression, restlessness or confusion, occur while taking mefloquin, the drug should be stopped immediately, and the malaria prophylaxis should be continued with alternative medications in order to prevent the development of severe adverse reactions. These are the recommendations, Roche has made on the US product information leaflets. (1) However, due to the drug's half life of three to four weeks, the adverse side effects could last for months following its discontinuation. Patients with a past medical history of depression, general anxiety disorders, psychosis, schizophrenia, or other relevant psychiatric disorders as well as epilepsy, must not take mefloquin for prophylaxis. (1) It is also recommended to use caution in people with a current history of alcohol abuse. (2)

Increasing intensity of the warnings on product information in the USA coincides with local media reports regarding the increased potential for suizidal tendencies associated with mefloquin. Currently, the US Army is investigating whether a number of killings and suicides by soldiers are connected with the mefloquin prophylaxis that was provided during the war in Afghanistan. Conflicts of interest may become predominant: Mefloquin which was developed by the US Army has been licensed to Roche for marketing. Nevertheless, Roche AG supposedly did not inform the Army about a legal dispute regarding one case of suicide attributed to mefloquin in May of this year which was settled out of court - as is common in such cases (a-t 1997; No. 9: 93-4) - confidentially and without the acknowledgment of fault. (3)

The German product information leaflet for LARIAM (4) does not contain sufficient instructions ("Warnings: none"). "Rare cases of suicide" and a general contraindication to "psychiatric disorders in the past medical history" are mentioned; however, relevant information, pertaining to the potential risks for these patients when taking the drug, is missing. Since not even interactions with other drugs are specifically listed, travellers unknowingly take serious risks, which have all been described in detail some time ago, such as bleeding if taken in combination with Warfarin (5), or hypoglycemia if taken with antidiabetics. (6) Alcohol should be avoided the day before and after intake of mefloquin. (7) This instruction is also missing in the product information leaflet, although already in 1999, a Roche manager had been quoted voicing this warning. (8)

While Roche, USA, wants to mail Warning Letters to physicians (9), Roche, Germany, does not even intend to reevaluate its product information (10), and thus violates the obligation to responsibly adjust the product information according to the current state of knowledge. Also, the appropriate dose remains to be determined for this drug, which was tested primarily on soldiers: Following the usual weekly dosage of 250 mg given for prophylaxis, some women experienced peak blood levels that exceeded the values after a dosage of 1,250 mg given for therapy. This might explain why especially women don't tolerate prophylaxis with mefloquin well. (11) A gradual reduction in the dosage after achieving the steady state could improve the drug's tolerability by women.

Currently, mefloquin is being recommended for high risk areas of malaria, such as tropical Africa. Depending on the exposure and individual resistance situation, alternatives include chloroquin (e.g. RESOCHIN) in combination with proguanil (PALUDRINE; the combination is less reliable than mefloquin), doxycyclin (DOXYCYCLIN AL and others; not approved for malaria prophylaxis in Germany, beware of phototoxicity: if necessary, light protection), or atovaquon plus proguanil (MALARONE, extremely expensive, only few studies available) (a-t 2001; 32: 65-8, 70-1).

The dilemma: Neuropsychiatric effects occur even "locally" (e.g in Kenya) in "increasing numbers". (5) Since only few alternatives are available, CNS-toxic mefloquin cannot always be replaced. Yet, if there are any indications of present or previous psychiatric disorders in the patient's medical history, mefloquin should strictly be avoided. Before prescribing the drug, a thorough past medical history has to be taken. Neuropsychiatric disorders can, however, occur even without any identifiable risk factors. (6) Since more than 75% of all neuropsychiatric disorders occur prior to the third dosage, it is recommended to start taking the drug two-and-a-half weeks prior to travelling, in order to allow for sufficient time for changing the prophylaxis treatment before travelling, should CNS side effects develop. (12)

Anyone taking mefloquin prophylactically has to be informed in great detail about its potential risks. He will have to make sure that sufficient information regarding the use of mefloquin is provided to medical personnel abroad (best done by a note written in English and added to one's passport or identity card) so that depression, psychosis or suicidal tendencies that occur on travels may be recognized as drug related.



Roche (USA): LARIAM, Complete Product Information, Revised: July 2002 (28.08.2002)



KRÜGER, E. et al.: Psychiat. Prax. 1999; 26: 252-4



Boston Globe, 31.08.2002



Roche (Germany): Fachinformation (German product information) LARIAM, May 2000



WARSHOW, M.: Nairobi Hospital Proceedings 2001; 5: 223-6



KIOKO, E., LOEFLER, I.: Nairobi Hospital Proceedings 2001; 5: 227-31



CROFT, A.M., HERXHEIMER, A.: BMC Public Health 2002; 2: 6



RODGERS, M. (Roche/Ireland), cited according to Evening Herald, 05.04.1999



Wall Street Journal, 04.09.2002



Roche (Germany): letter dated 28.08.2002



KOLLARITSCH, H. et al.: Wien. Klin. Wochenschr. 2000; 112: 441-7



BRADLEY, D.J., BANNISTER, B.: Commun. Dis. Public Health 2001; 4: 84-101

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