In patients with severe renal impairment, the elimination half lives for proguanil (t½ 39 h) and cycloguanil (t½ 37 h) are prolonged, resulting in the potential for drug accumulation with repeated dosing (see sections 4.2 and 4.4).

Pharmacokinetics in hepatic impairment

In patients with mild to moderate hepatic impairment there is no clinically significant change in exposure to atovaquone when compared to healthy patients.

In 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 patients with severe hepatic impairment (see section 4.2).

5.3 Preclinical safety data
Repeat dose toxicity:

Findings in repeat dose toxicity studies with atovaquone-proguanil hydrochloride combination were entirely proguanil related and were observed at doses providing no significant margin of exposure in comparison with the expected clinical exposure. 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.

Reproductive toxicity studies:

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 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.

Mutagenicity:

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.

Carcinogencity:

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.

6. Pharmaceutical particulars
6.1 List of excipients
Core

Poloxamer 188

Microcrystalline Cellulose

Low-substituted Hydroxypropyl Cellulose

Povidone K30

Sodium Starch Glycollate (Type A)

Magnesium Stearate

Coating

Hypromellose

Titanium Dioxide E171

Iron Oxide Red E172

Macrogol 400

Polyethylene Glycol 8000

6.2 Incompatibilities
Not applicable.

6.3 Shelf life
5 years.

6.4 Special precautions for storage
This medici