Pharmacology
Acyclovir, a synthetic acyclic purine nucleoside analog, is a substrate with a high degree of specificity for herpes simplex and varicella-zoster specified thymidine kinase. Acyclovir is a poor substrate for host cell-specified thymidine kinase. Herpes simplex and varicella-zoster specified thymidine kinase transform acyclovir to its monophosphate, which is then transformed by a number of cellular enzymes to acyclovir diphosphate and acyclovir triphosphate. Acyclovir triphosphate is both an inhibitor of, and a substrate for, herpesvirus-specified DNA polymerase. Although the cellular α-DNA polymerase in infected cells may also be inhibited by acyclovir triphosphate, this occurs only at concentrations of acyclovir triphosphate which are higher than those which inhibit the herpesvirus-specified DNA polymerase. Acyclovir is selectively converted to its active form in herpesvirus-infected cells and is thus preferentially taken up by these cells. Acyclovir has demonstrated a very much lower toxic potential in vitro for normal uninfected cells because: 1) less is taken up; 2) less is converted to the active form; 3) cellular α-DNA polymerase has a lower sensitivity to the action of the active form of the drug. A combination of the thymidine kinase specificity, inhibition of DNA polymerase and premature termination of DNA synthesis results in inhibition of herpesvirus replication. No effect on latent non-replicating virus has been demonstrated. Inhibition of the virus reduces the period of viral shedding, limits the degree of spread and level of pathology, and thereby facilitates healing. During suppression, there is no evidence that acyclovir prevents neural migration of the virus. It aborts episodes of recurrent herpes due to inhibition of viral replication following reactivation.
Indications
For the topical management of initial episodes of genital herpes simplex infections. The prophylactic use of this preparation has not been established.
In the treatment of genital herpes, appropriate examinations should be performed to rule out other sexually transmitted diseases. Therapy should begin as early as possible after the start of an infection.
Two multicentre, double-blind, placebo-controlled studies were performed with acyclovir cream in immunocompetent patients with initial genital herpes. The cream was applied for up to 10 days or until healing had occurred. Results showed that acyclovir cream significantly reduced the duration of viral shedding, the formation of new lesions, the time to crusting and healing of lesions, and the duration of pain.
Whereas cutaneous lesions associated with herpes simplex infections are often pathognomonic, Tzanck smears prepared from lesion exudate or scrapings may assist in the diagnosis. Positive cultures for herpes simplex virus offer the only absolute means for confirmation of the diagnosis.
Precautions
Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir cream.
Acyclovir, when given systemically, is known to be excreted into human milk. No information is available on levels of acyclovir which may appear in breast milk after administration of acyclovir cream. Caution should be exercised when acyclovir is administered to a nursing mother.
Safety of use of acyclovir cream in children has not been established.
Acyclovir cream is not recommended for application to mucous membranes such as the mouth or vagina.
The recommended dosage, frequency of application and duration of treatment of acyclovir cream should not be exceeded (see Dosage).
There exist no data, at this time, which demonstrate that the use of acyclovir cream will prevent transmission of infection to other persons.
Since most cutaneous herpes simplex virus infections result from reactivation of latent virus, it is unlikely that acyclovir cream will prevent recurrence of infections when applied in the absence of signs and symptoms. Acyclovir cream should not be applied in an attempt to prevent recurrences; application should commence only at the earliest prodromal sign of disease onset.
Although clinically significant viral resistance associated with the use of acyclovir cream has not been observed, this possibility exists.
Teratology studies carried out to date in animals have been negative in general. However, in a non-standard test in rats, there were fetal abnormalities such as head and tail anomalies, and maternal toxicity; since such studies are not always predictive of human response, acyclovir should not be used during pregnancy unless the physician feels the potential benefit justifies the risk of possible harm to the fetus. The potential for high concentrations of acyclovir to cause chromosome breaks in vitro should be taken into consideration in making this decision.
A postmarketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of acyclovir. The registry findings have not shown an increase in the number of birth defects amongst acyclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause.
There is no information on the effect of acyclovir oral formulations on human female fertility. In a study of 20 male patients with normal sperm count, oral acyclovir administered at doses of up to 1 g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.
Supplied
Each g of cream contains: acyclovir 50 mg. Nonmedicinal ingredients: cetostearyl alcohol, paraffin, poloxamer, propylene glycol and sodium lauryl sulfate. Tubes of 5 g. Store between 15 and 25°C and keep dry.
Contraindications
For patients who develop hypersensitivity or chemical intolerance to acyclovir, valacyclovir or any of the components of the formulation, such as propylene glycol.
Warnings
Acyclovir cream is intended for topical use only and should not be used in the eye.
Adverse Effects
Because ulcerated genital lesions are characteristically tender and sensitive to any contact or manipulation, patients may experience discomfort upon application of acyclovir cream. Table 1 shows the number of initial genital herpes patients who reported adverse reactions in the 2 controlled clinical trials.
Table 1: Zovirax CreamAdverse Effects | Adverse Reaction | Zovirax
(n=54) | Placebo
(n=47) |
| Burning/stinging on application | 3 | 7 |
| Rash | 0 | 3 |
| Itching | 1 | 0 |
| Retention of urine | 2 | 2 |
| Meningism | 0 | 2 |
| Paronychia | 0 | 1 |
| Total No. (%) of patients | 6 (11%) | 15 (32%) |
Observed During Clinical Practice: Based on worldwide clinical practice experience in patients treated with acyclovir cream, the adverse events most commonly reported include contact dermatitis, application site reaction, eczema, allergic reaction, pain, and rash.
Less common events include pruritus, skin discoloration, urticaria, vesiculobullous rash, and facial edema.
There have been very rare reports of immediate hypersensitivity reactions including angioedema with topical acyclovir.
Overdose
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Overdosage by topical application of acyclovir cream is unlikely because of limited transcutaneous absorption.
Dosage
Apply liberally to the affected area 4 to 6 times daily for up to 10 days. A sufficient quantity of cream should be applied to adequately cover all lesions. A finger cot or rubber glove should be used while applying acyclovir cream, in order to prevent autoinoculation of other body sites or transmission of infection to other persons. Therapy should be initiated as early as possible following onset of signs and symptoms.
