Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489, Greifswald, Germany
Pharmaco-therapeutic group: Antiprotozoal agent
ATC code: P01BC02
Lariam acts on and destroys the asexual intraerythocytic forms of the human malaria parasites: Plasmodium falciparum, P. vivax. P. malariae and P. ovale. It is effective in the treatment and prophylaxis of malaria.
Lariam is also effective against malarial parasites resistant to other antimalarials such as chloroquine and other 4-aminoquinoline derivatives, proguanil, pyrimethamine and pyrimethamine-sulphonamide combinations.
In a randomized, double-blind study, non-immune travellers who visited a malaria-endemic area received either mefloquine (483 subjects) or atovaquoine-proguanil (493 subjects). The primary endpoint was the overall frequency of adverse events, assessed 7 days after leaving the malaria endemic area. Efficacy of chemoprophylaxis was evaluated as a secondary end point. The average duration of travel was ~2.5 weeks, and 79% of subjects travelled to Africa. 10 subjects (5 in each study arm) were identified with circumsporozoite antibodies, none of them developed malaria (minimum efficacy for both mefloquine and atovaquone-proguanil was 100%). Results indicated that mefloquine and atovaquone-proguanil are similarly effective for malaria prophylaxis in non-immune travelers (see Table 3).
However, patients in the mefloquine group exhibited a predominance of neuropsychiatric adverse reactions compared to those treated with atovaquone-proguanil (see also sections 4.4 and 4.8).
Table 3. Estimates of adverse events and minimum and maximum efficacy for malaria prophylaxis:
| Subjects who received | ||
|---|---|---|
| Variable | Atovaquone-proguanil | Mefloquine |
| Number of subjects who received study drug | 493 | 483 |
| Subjects with 60-day efficacy data available, no. | 486 | 477 |
| Subjects who developed circumsporozoite antibodies, no. | 5 | 5 |
| Subjects with confirmed malaria, no. | 0 | 0 |
| Minimum efficacy, % (95% CI)a | 100 (48-100) | 100 (48-100) |
| Maximum efficacy, % (95% CI)b | 100 (99-100) | 100 (99-100) |
| Occurrence of any adverse event | 149 | 204 |
| Neuropsychiatric events | 69 | 139 |
a Minimum efficacy = 100 x [1 – (no. of subjects with confirmed malaria/no. with circumsporozoite antibodies)]
b Maximum efficacy = 100 x [1 – (no. of subjects with confirmed malaria/no. with 60-day efficacy data)]
In vitro and in vivo studies with mefloquine showed no haemolysis associated with glucose-6-phosphate dehydrogenase deficiency.
The maximum plasma concentration is reached within 6 to 24 hours after a single oral dose of Lariam. The level in micrograms per litre is roughly equivalent to the dose in milligrams (for example approximately 1000 μg/l after a single dose of 1000 mg). The presence of food significantly enhances the rate and extent of absorption.
At a dose of 250 mg once weekly, maximum steady state plasma concentrations of 1000–2000 μg/l are reached after 7-10 weeks. The RBC concentration is almost twice as high as the plasma level. Plasma protein binding is about 98%. Clinical experience suggests a minimal suppressive plasma concentration of mefloquine in the order of 600 μg/l.
Mefloquine is extensively metabolised in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggest that CYP3A4 is the major isoform involved.
The average half-life of mefloquine in Europeans is 21 days. There is evidence that mefloquine is excreted mainly in the bile and faeces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite accounted for about 9% and 4% of the dose, respectively.
The pharmacokinetics of mefloquine may be altered in acute malaria. Pharmacokinetic differences have been observed between various ethnic populations. In practice however, these are of minor importance compared with the host immune status and sensitivity of the parasite.
Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal.
Mefloquine crosses the placenta and is teratogenic when administered to rats and mice in early gestation (see section 4.6).
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