Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Glaxo Wellcome UK Ltd, trading as GlaxoSmithKline UK, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Pharmacotherapeutic group: Antimalarials
ATC code: P01BB51
The constituents of Malarone paediatric tablets, atovaquone and proguanil hydrochloride, interfere with two different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. The mechanism of action of atovaquone against P. falciparum is via inhibition of mitochondrial electron transport, at the level of the cytochrome bc1 complex, and collapse of mitochondrial membrane potential. One mechanism of action of proguanil, via its metabolite cycloguanil, is inhibition of dihydrofolate reductase, which disrupts deoxythymidylate synthesis. Proguanil also has antimalarial activity independent of its metabolism to cycloguanil. Proguanil, but not cycloguanil, is able to potentiate the ability of atovaquone to collapse mitochondrial membrane potential in malaria parasites. This latter mechanism may contribute to the antimalarial synergy seen when atovaquone and proguanil are used in combination.
Atovaquone has activity against Plasmodium spp (in vitro IC50 against P. falciparum 0.23-1.43 ng/mL).
Cross-resistance between atovaquone and antimalarial agents of other drug classes was not detected among more than 30 P. falciparum isolates that demonstrated resistance in vitro to one or more of chloroquine (41% of isolates), quinine (32% of isolates), mefloquine (29% of isolates), and halofantrine (48% of isolates).
The IC50 of the primary metabolite of proguanil-cycloguanil against various P. falciparum strains was 4-20 ng/mL; some activity of proguanil and another metabolite, 4-chlorophenylbiguanide, is seen in vitro at 600-3000 ng/mL).
The combination of atovaquone and proguanil was shown to be synergistic against P. falciparum in vitro. The combination was more effective than either drug alone in clinical studies of the treatment of malaria in both immune and non-immune patients.
The efficacy in non-immune paediatric travellers has not been directly established, but may be assumed through extrapolation by the results on safety and efficacy in studies of up to 12 weeks in paediatric residents (semi-immune) of endemic areas, and from results of safety and efficacy in both semi-immune and non-immune adults.
Data in the paediatric population are available from two trials that primarily evaluated the safety of Malarone paediatric tablets in (non-immune) travellers to endemic areas. In these trials, a total of 93 travellers weighing <40 kg were given Malarone and 93 received another prophylactic antimalarial regimen (81 chloroquine/proguanil and 12 mefloquine). The majority of travellers went to Africa and the mean duration of stay was between 2-3 weeks. There were no cases of malaria recorded in any subjects who took part in these studies.
An open-label, randomised, parallel-group trial was undertaken in Gabon in 200 children weighing ≥5 kg and <11 kg with confirmed, uncomplicated P. falciparum malaria. Treatment was with Malarone paediatric tablets or amodiaquine suspension. In the intent-to-treat population, the 28-day cure rate was 87% in the Malarone group (87/100 subjects). In the per-protocol population, the 28-day cure rate was 95% in the Malarone group (87/92 subjects). The parasitological cure rates for the Malarone group were 88% and 95% for the ITT and PP populations, respectively.
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended doses.
In prophylaxis clinical trials where children have received Malarone dosed by bodyweight, trough levels of atovaquone, proguanil and cycloguanil in children are generally within the range observed in adults (see following table).
Trough Plasma Concentrations [Mean ± SD, (range)] of Atovaquone, Proguanil and Cycloguanil during Prophylaxis with Malarone in Children* and Adults:
| Atovaquone:Proguanil HCl Daily Dose | 62.5 mg:25 mg | 125 mg:50 mg | 187.5 mg:75 mg | 250mg:100 mg |
|---|---|---|---|---|
| [Weight Category] | [11-20 kg] | [21-30 kg] | [31-40 kg] | Adult (>40 kg) |
| Atovaquone (μg/mL) No. Subjects | 2.2 ± 1.1 (0.2-5.8) n=87 | 3.2 ± 1.8 (0.2-10.9) n=88 | 4.1 ± 1.8 (0.7-8.8) n=76 | 2.1 + 1.2 (0.1-5.7) n=100 |
| Proguanil (ng/mL) No. Subjects | 12.3 ± 14.4 (<5.0-14.3) n=72 | 18.8 ± 11.2 (<5.0-87.0) n=83 | 26.8 ± 17.1 (5.1-55.9) n=75 | 26.8 + 14.0 (5.2-73.2) n=95 |
| Cycloguanil (ng/mL) No. Subjects | 7.7 ± 7.2 (<5.0-43.5) n=58 | 8.1 ± 6.3 (<5.0-44.1) n=69 | 8.7 ± 7.3 (6.4-17.0) n=66 | 10.9 + 5.6 (5.0-37.8) n=95 |
* Pooled data from two studies
Atovaquone is a highly lipophilic compound with low aqueous solubility. Although there are no atovaquone bioavailability data in healthy subjects, in HIV-infected patients the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 21% (90% CI: 17% - 27%).
Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3 times and Cmax 5 times over fasting. Patients are recommended to take Malarone paediatric tablets with food or a milky drink (see section 4.2).
Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.
Apparent volume of distribution of atovaquone and proguanil is a function of bodyweight.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.
Following oral administration, the volume of distribution of atovaquone and proguanil is approximately 8.8 L/kg.
Proguanil is 75% protein bound. Following oral administration, the volume of distribution of proguanil in adults and children (>5 kg) ranged from 20 to 79 L/kg.
In human plasma the binding of atovaquone and proguanil was unaffected by the presence of the other.
There is no evidence that atovaquone is metabolised, and there is negligible excretion of atovaquone in urine with the parent drug being predominantly (>90%) eliminated unchanged in faeces.
Proguanil hydrochloride is partially metabolised, primarily by the polymorphic cytochrome P450 isoenzyme 2C19, with less than 40% being excreted unchanged in the urine. Its metabolites, cycloguanil and 4-chlorophenylbiguanide, are also excreted in the urine.
During administration of Malarone at recommended doses proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.
The elimination half life of atovaquone is 1-2 days in children.
The elimination half lives of proguanil and cycloguanil are each about 12-15 hours in children.
Oral clearance for atovaquone and proguanil increases with increased body weight and is about 70% higher in a 40 kg subject relative to a 20 kg subject. The mean oral clearance in paediatric and adult patients weighing 5 to 40 kg ranged from 0.5 to 6.3 L/h for atovaquone and from 8.7 to 64 L/h for proguanil.
There are no studies in children with renal impairment.
In adult patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone, proguanil and cycloguanil are within the range of values observed in patients with normal renal function.
Atovaquone Cmax and AUC are reduced by 64% and 54%, respectively, in adult patients with severe renal impairment (<30 mL/min/1.73 m²).
In adult patients with severe renal impairment, the elimination half lives for proguanil (t½ 39 hours) and cycloguanil (t½ 37 hours) are prolonged, resulting in the potential for drug accumulation with repeated dosing (see sections 4.2 and 4.4).
There are no studies in children with hepatic impairment.
In adult patients with mild to moderate hepatic impairment, there is no clinically significant change in exposure to atovaquone when compared to healthy patients.
In adult patients with mild to moderate hepatic impairment there is an 85% increase in proguanil AUC, with no change in elimination half life, and there is a 65-68% decrease in Cmax and AUC for cycloguanil.
No data are available in adult patients with severe hepatic impairment (see section 4.2).
Findings in repeat dose toxicity studies with atovaquone-proguanil hydrochloride combination were entirely proguanilrelated and were observed at doses providing no significant margin of exposure in comparison with the expected clinical exposure. However, as proguanil has been used extensively and safely in the treatment and prophylaxis of malaria at doses similar to those used in the combination, these findings are considered of little relevance to the clinical situation.
In rats and rabbits there was no evidence of teratogenicity for the combination. No data are available regarding the effects of the combination on fertility or pre- and post-natal development, but studies on the individual components of Malarone paediatric tablets have shown no effects on these parameters. In a rabbit teratogenicity study using the combination, unexplained maternal toxicity was found at a systemic exposure similar to that observed in humans following clinical use.
A wide range of mutagenicity tests have shown no evidence that atovaquone or proguanil have mutagenic activity as single agents.
Mutagenicity studies have not been performed with atovaquone in combination with proguanil.
Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil (a dihydrofolate antagonist) were significantly reduced or abolished with folinic acid supplementation.
Oncogenicity studies of atovaquone alone in mice showed an increased incidence of hepatocellular adenomas and carcinomas. No such findings were observed in rats and mutagenicity tests were negative. These findings appear to be due to the inherent susceptibility of mice to atovaquone and are considered of no relevance in the clinical situation.
Oncogenicity studies on proguanil alone showed no evidence of carcinogenicity in rats and mice.
Oncogenicity studies on proguanil in combination with atovaquone have not been performed.
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