Formulation

Tablets of 100 mg of proguanil hydrochloride containing 87 mg of proguanil base.

Efficacy

Proguanil is a synthetic biguanide derivative of pyrimidine with a marked effect on the primary tissue stages of P. falciparum, P. vivax and P. ovale. Its effect on the primary exoerythrocytic forms of P. malariae is unknown. It has some causal prophylactic effect against sensitive strains in contrast to the suppressive prophylactic activity shown by pyrimethamine. Proguanil does not affect hypnozoites and therefore does not have antirelapse activity.

Proguanil also exhibits weak blood schizonticidal activity and, while it is not currently used for treatment, a 3-day regimen of a combination of proguanil with atovaquone, a hydroxynaphthoquinone, has been shown to be effective against multidrug-resistant P. falciparum in Thailand (146).

Proguanil is a dihydrofolate reductase inhibitor acting primarily through its major metabolite, cycloguanil. Recent evidence suggests, however, that other mechanisms of action may also be involved. For example: the action of proguanil but not cycloguanil with atovaquone is synergistic (147); and poor metabolizers of proguanil, i.e. persons with defective cytochrome P-450 activity, are at no greater risk of prophylactic breakthrough than normal subjects given proguanil (148). In addition, cross-resistance between cycloguanil and pyrimethamine is not absolute, resistance to the two drugs being controlled by different point mutations on the dihydrofolate reductase/thymidylate synthase (DHFR/TS) gene (149, 150). It is known that proguanil has a second, nonantifolate mechanism of action (129) and this may explain the effect of proguanil-atovaquone.

Use

Proguanil is currently used only for chemoprophylaxis (as a combination with chloroquine in areas with a low prevalence of chloroquine-resistant P. falciparum) and for treatment of malaria as a component of the combination proguanil- atovaquone. Some studies have shown that it is efficacious for the treatment of
P. falciparum malaria when given in combination with dapsone (151).

Treatment Proguanil is not currently used alone for the treatment of malaria.

Recommended chemoprophylaxis

Proguanil is used in combination with chloroquine (see Table 8 above), generally at a daily dose of 3 mg/kg, giving an adult dose of 200 mg per day. Pharmacokinetic profiles indicate, however, that a twice daily dose of 1.5 mg/kg provides plasma levels of proguanil and cycloguanil that should give better protection than single daily doses of 3 mg/kg (152). Compliance may be a problem with twice daily administration. Details of the dosage schedules for all age groups and according to weight are given in Table 11. In areas with moderate levels of P. falciparum resistance to chloroquine, the combination of proguanil plus chloroquine provides significantly less protection than mefloquine or doxycycline.

Drug disposition

Pharmacokinetic studies on proguanil are limited. Absorption is rapid, peak plasma concentrations of proguanil and its active metabolite, cycloguanil, being achieved within 4 h of administration. The elimination half-life is approximately 16 h (152).

Adverse effects

Proguanil is remarkably safe and few adverse reactions have been observed, although there are reports indicating that mouth ulcers and hair loss may occur following prophylactic use.

Contraindications

The use of proguanil is contraindicated in persons with liver or kidney dysfunction.

Overdosage

Gross overdosage gives rise to abdominal pain, vomiting, diarrhoea and haematuria. No specific antidote exists and symptoms should be treated as they arise.