intravenous aciclovir has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with overdosage.
Treatment
Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.
5. Pharmacological properties
5.1 Pharmacodynamic properties
The antiviral activity of aciclovir is due to intracellular conversion to an active form that inhibits viral DNA synthesis and replication by inhibiting the herpes virus DNA polymerase enzyme as well as being incorporated into viral DNA. Herpes simplex virus type 1 appears to be the most susceptible, then type 2, followed by varicella-zoster virus.
The Epstein-Barr virus and cytomegalovirus are also susceptible to aciclovir to a lesser extent.
Aciclovir has no activity against latent viruses, but there is some evidence that it inhibits latent herpes simplex virus at an early stage of reactivation.
5.2 Pharmacokinetic properties
Aciclovir is slowly and poorly absorbed from the gastrointestinal tract and the time taken to reach peak concentrations is 1.5 to 2 hours. With multidose administration, steady-state plasma concentrations are achieved by the next day. Bioavailability is 13 to 21% and appears to decrease with increasing dosage. In adult patients with normal renal function the plasma half-life is 3.3 hours.
Aciclovir is widely distributed in tissues and body fluids including brain, kidney, lung, liver, muscle, spleen, uterus, vaginal mucosa, vaginal secretions, cerebrospinal fluid and herpetic vesicular fluid. Concentrations in kidney and lung were 10 to 13 times those of plasma concentrations after multiple dose therapy and 25 to 70% of the plasma level was found in the brain, spinal cord and cerebrospinal fluid. Limited human data show that aciclovir passes into breast milk and levels can be three to four times higher than in serum.
Aciclovir persists in the plasma of patients with renal insufficiency and the mean terminal plasma half-life recorded in patients with end stage renal disease is 19.5 hours. Aciclovir is readily removed by haemodialysis.
In infants of less than three months of age, the plasma half-life is slightly prolonged to about 3.8 hours and clearance is about one third of that found in older children and adults. In neonates (0 to 3 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 8 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 pharmacokinetics of aciclovir in children over one year old seem to be similar to those of adults.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber that are additional to those included in other sections.
6. Pharmaceutical particulars
6.1 List of excipients
Gelatin PhEur
Lactose PhEur
Maize Starch PhEur
Microcrystalline Cellulose PhEur
Sodium Starch Glycollate PhEur
Magnesium Stearate
