Mechanism of Antiviral Action

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC 50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC 50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC 50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC 50 of 1.35 mcg/mL.

Drug Resistance

Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

General

The recommended dosage, frequency of applications and length of treatment should not be exceeded (see DOSAGE AND ADMINISTRATION). There are no data to support the use of acyclovir ointment 5% to prevent transmission of infection to other persons or prevent recurrent infections when applied in the absence of signs and symptoms. Acyclovir ointment 5% should not be used for the prevention of recurrent HSV infections. Although clinically significant viral resistance associated with the use of acyclovir ointment 5% has not been observed, this possibility exists.

Drug Interactions

Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir ointment 5%.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis and fertility are not included in the full prescribing information for acyclovir ointment 5% due to the minimal exposures of acyclovir that result from dermal application. Information on these studies is available in the full prescribing information for acyclovir capsules, tablets and suspension and acyclovir for injection.

Pregnancy

Nursing Mothers

It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following topical administration is minimal. After oral administration of acyclovir, acyclovir concentrations have been documented in breast milk in 2 women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Nursing mothers who have active herpetic lesions near or on the breast should avoid nursing.

Geriatric Use

Clinical studies of acyclovir ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal (see CLINICAL PHARMACOLOGY).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Observed During Clinical Practice

Based on clinical practice experience in patients treated with acyclovir ointment in the U.S., spontaneously reported adverse events are uncommon. Data are insufficient to support an estimate of their incidence or to establish causation. These events may also occur as part of the underlying disease process. Voluntary reports of adverse events that have been received since market introduction include:

General: Edema and/or pain at the application site.

Skin: Pruritus, rash.