Formulations

• Tablets containing 200 mg of amodiaquine base as hydrochloride or 153.1 mg of base as chlorohydrate.
• Suspension containing 10 mg of amodiaquine base as hydrochloride or chloro-hydrate per ml.

Efficacy

Amodiaquine is a 4-aminoquinoline antimalarial drug similar in structure and activity to chloroquine. Like chloroquine, it also possesses antipyretic and anti-inflammatory properties.

A systematic review of relevant studies on the treatment of uncomplicated falciparum malaria conducted over the past ten years in Africa showed that amodiaquine proved significantly more effective than chloroquine in clearing parasites, with a tendency for faster clinical recovery. This difference was also observed in areas with considerable chloroquine resistance (30, 111, 112). Data from Cameroon demonstrate better activity of 35 mg/kg than of 25 mg/kg in chloroquine-resistant malaria. However, there is no conclusive evidence that doses of > 25 mg/kg are associated with either improved efficacy or increased toxicity. Amodiaquine also exhibited faster fever clearance times than sulfadoxine-pyrimethamine although the two drugs were equally effective at parasite clearance by day 7, and sulfadoxine-pyrimethamine was more effective on days 14 and 28. This may be related to the slower antimalarial action of the combination and the antipyretic effect of amodiaquine (113, 114).

The efficacy of amodiaquine in the treatment of chloroquine-resistant vivax malaria has not been adequately investigated although a report from Papua New Guinea showed that amodiaquine was more effective than chloroquine for this purpose (28).

Use

In the mid 1980s, fatal adverse drug reactions were reported in travellers using amodiaquine for malaria chemoprophylaxis, even after very few doses (115-118). As a consequence, it was recommended in 1990 that the drug should not be used for chemoprophylaxis or even as an alternative treatment for chloroquine failures (110). However, at its nineteenth meeting the WHO Expert Committee on Malaria did not totally accept this recommendation, stating that amodiaquine could be used for treatment if the risk of infection outweighs the potential for adverse drug reactions (119).

Although global use of amodiaquine has declined owing to the reports of adverse reactions (115, 116, 120-124), some countries have continued to use it as first-line treatment. During this period, there have been no reports of severe adverse effects following such treatment. Many of the data collected on amodiaquine toxicity that led to its withdrawal were from case reports (116, 120-122) in patients with an average age of over 40 years and more (122). Of the published reports in patients with agranulocytosis and toxic hepatitis (115, 116), mean doses of two to three times the recommended therapeutic doses were used over an average period of 9 weeks (125). Evidence has thus accumulated, particularly in Africa (using 35 mg/kg amodiaquine in West Africa) that supports the use of amodiaquine in the treatment of uncomplicated falciparum malaria (126, 113), with the provision that monitoring of efficacy and toxicity are continued (30, 125, 127). It has been suggested that amodiaquine is less toxic than sulfadoxine-pyrimethamine in HIV-positive patients (83).

Studies in East Africa, where there is widespread, intensive resistance to chloroquine and 20-25% of patients treated with amodiaquine have recrudescences of parasitaemia by day 14, have raised concerns that the useful therapeutic life of amodiaquine could be curtailed by partial cross-resistance with chloroquine (30).

Amodiaquine has the advantage over chloroquine of being more palatable and therefore easier to administer to children.

Recommended treatment

Amodiaquine is administered over 3 days at total doses ranging between 25 mg and 35 mg of amodiaquine base per kg in dosage regimens similar to those for chloroquine. At present there is no evidence that the higher doses are associated with either improved efficacy or increased toxicity. A regimen of 10 mg of amodiaquine base per day for 3 days (total dose 30 mg/kg) is recommended as it may offer the advantage of simplicity. Details of the schedules for all age groups are given in Table 9.

Chemoprophylaxis

Amodiaquine is no longer recommended for chemoprophylaxis because of the risk of severe adverse reactions (see below).

Use in pregnancy

There is no evidence to contraindicate the use of amodiaquine for treatment of malaria during pregnancy.

Drug disposition

After oral administration, amodiaquine is rapidly and extensively metabolized to a pharmacologically active metabolite, desethylamodiaquine, the parent compound being detectable for no longer than 8 h (124). Desethylamodiaquine is concentrated in erythrocytes and is slowly eliminated with a terminal elimination half-life of up to 18 days.

Adverse effects

Adverse reactions to the standard doses of amodiaquine used for malaria treatment are generally similar to those to chloroquine, the most common being nausea, vomiting, abdominal pain, diarrhoea and itching; a less common effect is bradycardia (B. Ngouesse et al., unpublished data, 2000). There is some evidence that itching may be less common with amodiaquine than with chloroquine.

In contrast to chloroquine, however, amodiaquine can induce toxic hepatitis and fatal agranulocytosis following its use for malaria chemoprophylaxis. Data suggest that, in United Kingdom travellers, the incidence of serious reactions for this use of the drug was 1 in 1 700. Blood disorders occurred in 1 in 2 200 travellers and serious hepatic disorders in 1 in 15 650. Fatal events occurred in 1 in 15 500 travellers (122). The toxicity of amodiaquine seems to be related to the immunogenic properties of the quinone imine produced by auto-oxidation of the parent drug (123, 128).

Contraindications

Amodiaquine is contraindicated:

• in persons with known hypersensitivity to amodiaquine,
• in persons with hepatic disorders,
• for chemoprophylaxis.

Overdosage

The acute toxicity of amodiaquine appears to differ from that of chloroquine.

Large doses of amodiaquine have been reported to produce syncope, spasticity, convulsions and involuntary movements (58). There are no reports of cardiovascular symptoms following overdose of amodiaquine but intoxication with amodiaquine is far less common than is the case with chloroquine.