Does malaria prophylaxis with chloroquine phosphate 500 mg per week and proguanil 200 mg daily cau

Fråga: "Does malaria prophylaxis with chloroquine phosphate 500 mg per week and proguanil 200 mg daily cause epileptic seizures?

A man aged 48, working as a general practitioner in Sweden, previously healthy with no heredity or history of epilepsia, developed epileptic seizures of a "grand mal" type on two occasions (931113 and 931127) about 15 hours after intake of chloroquine phosphate 500 mg. He was taking tablet chloroquine phosphate 500 mg per week (November 3, 7, 12, 19 and 26) and proguanil (tablet Paludrin) 100 mg 2x1 (November 3 to December 2) as malaria prophylaxis. A normal CT scan of his brain was recorded on 931208. As no other cause for the epileptic seizures have been found the chloroquine treatment is the most suspected as a causative agent. However, this is in contrast with a previous Drugline document (09837 from 1993). What is the current documentation?"

Sammanfattning: Epileptic seizures have been reported in a number of cases in association with chloroquine treatment. Although no formal studies of this association have been found, the overall assessment suggests that there may be a causal relationship between seizures and chloroquine use.

Svar: In the previous Drugline document (1), giving the background for chloroquine phosphate being contraindicated in patients with epilepsia, it is stated in the Swedish physicians catalogue of registered drugs (FASS 1993): "Chloroquine is a 4-aminoquinolone used for antimalarial treatment and prophylaxis. Despite the appearance of chloroquine-resistant P. falciparum parasites the drug remains the most widely used antimalarial drug in the world. Chloroquine has a narrow therapeutic range and concentration-dependent adverse reactions, such as accommodation disturbances and vertigo, have also been seen in individuals after administration of therapeutic doses (2).

In 1988, doctors Fish and Espir reported four patients who had tonic-clonic seizures while taking chloroquine for malaria prophylaxis (3). All patients were women. The chloroquine dose used was 300 mg base once weekly, but three patients also took dapsone/pyrimethamine or sulphadoxine/pyrimethamine. Three of the patients had never had seizures before, and none had seizures after discontinuing prophylaxis. The follow-up time was one to 14 months. The authors recommend that specific enquiries should be made concerning any history of epilepsy when considering malarial prophylaxis and that people with epilepsy should be advised about the risk of antimalarial drugs provoking seizures."

It was concluded that the lack of reports to the Swedish Medical Product Agency argues against an increased risk (1).

Three cases of tonic-clonic seizures following therapeutic doses of chloroquine monotherapy for malaria were reported from Africa, two women and one man, with no previous history of seizures and without risk factors for or a family history of seizures. Subsequent EEGs were all normal and all three were free from seizures during the follow-up period of four, six and 36 months, respectively (4).

Another three case reports with possible seizure-chloroquine associations have also been reported (5, 6, 7). In the authors´ (3) reply to Hellgren & Rombo (8) another two cases were also reported (9).

Furthermore, seizures are one of the effects reported in cases of chloroquine intoxication (FASS 1994).

The association between epileptic seizures and chloroquine treatment has been reported in a number of case reports from different sources, including reports concerning treatment of malaria as well as malaria prophylaxis, and some concerning concomitant treatment with other drugs. These reports are not conclusive and several may be confounded by the indication for the treatment (eg malaria with cerebral manifestations). No formal studies have been found, but considering the widespread use of chloroquine, a (population based) study estimating the frequency of this association seems now warranted. The overall assessment suggests that there may be a causal relationship between seizures and chloroquine use.

Concerning proguanil and seizures, no case reports have been found in the literature search. 1 Drugline nr 09837 (year 1993) 2 Gustafsson LL, Walker O, Alvan G, Beermann B, Estevez F; Gleisner L, Lindström B, Sjöqvist F: Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol 1983; 15: 471-479 3 Fish DR, Espir MLE: Convulsions associated with prophylactic antimalarial drugs: implications for people with epilepsy. Br Med J 1988; 297: 526-527 4 Adamolekun B: Seizures associated with chloroquine therapy. Centr Afr J Med 1992; 38: 350-352 5 Courtois X, Vincent F, Legoff F: Crises convulsives apres prophylaxie par chloroque. Presse Med 1993; 22: 315 6 Sopena B, Fernandez Rodriguez C, Ledo L, Rodriguez D: Convulsiones inducidas por la asociacion de metronidazol y chloroquina. Med Clin (Barc) 1990; 95: 675 7 Fröscher W, Hägele H: Verdacht auf anfallsfördernde Wirkung von Chloroquin (Resochin). Nervenarzt 1989; 60: 762-763 8 Hellgren U, Rombo L: Malaria prophylaxis and epilepsy. Br Med J 1988; 297: 1267 9 Fish DR, Espir MLE: Malaria prophylaxis and epilepsy. Br Med J 1988; 297: 1267