In adults, mean steady state peak plasma concentrations (Cssmax) following a one-hour infusion of 2.5 mg/kg, 5 mg/kg, and 10 mg/kg were 22.7 micromolar (5.1 microgram/ml), 43.6 micromolar (9.8 microgram/ml), and 92 micromolar (20.7 microgram/ml) respectively. The corresponding trough levels (Cssmin) 7 hours later were 2.2 micromolar (0.5 microgram/ml), 3.1 micromolar (0.7 microgram/ml) and 10.2 micromolar (2.3 microgram/ml) respectively. In children over one year of age similar mean peak (Cssmax) and trough (Cssmin) levels were observed when a dose of 250 mg/m2 was substituted for 5 mg/kg and a dose of 500 mg/m2 was substituted for 10 mg/kg. In neonates (0 to three months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the Cssmax was found to be 61.2 micromolar (13.8 microgram/ml) and the Cssmin.to be 10.1 micromolar (2.3 microgram/ml). A separate group of neonates treated with 15 mg/kg every eight hours showed approximate dose proportional increases, with a Cmax of 83.5 micromolar (18.8 microgram/ml) and Cmin of 14.1 micromolar (3.2 microgram/ml).

The terminal plasma half-life in these patients was 3.8 hours. In the elderly, total body clearance falls with increasing age and is associated with decreases in creatinine clearance although there is little change in the terminal plasma half-life.

In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis.

In a clinical study in which morbidly obese female patients (n=7) were dosed with intravenous aciclovir based on their actual body weight, plasma concentrations were found to be approximately twice that of normal weight patients (n=5), consistent with the difference in body weight between the two groups.

Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels.

Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.

5.3 Preclinical safety data
The results of a wide range of mutagenicity test in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.

Aciclovir was not found to be carcinogenic in long-term studies in the rat and the mouse.

Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice

In a non-standard test in rats, foetal abnormalities were observed but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of (orally administered) aciclovir on fertility.

There is no experience of the effect of aciclovir for infusion on human fertility. Aciclovir tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.

6. Pharmaceutical particulars
6.1 List of excipients
Sodium hydroxide
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.