Pharmacology
Acyclovir, an acyclic nucleoside analog, is a substrate specific for herpesvirus-specified thymidine kinase. It inhibits replication of these viruses. Normal cellular thymidine kinase does not effectively utilize acyclovir as a substrate. Herpes virus-specified thymidine kinase transforms acyclovir to its monophosphate, which is then transformed by 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 preferentially taken up and selectively converted to its active form by herpesvirus-infected cells. Thus, acyclovir has a very much lower toxic potential 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 affinity for the active form of the drug.
Indications
For the management of initial episodes of genital herpes simplex infections. It is also indicated in the management of non life-threatening cutaneous herpes simplex virus infections in immunocompromised patients. The prophylactic use of this preparation has not been established.
In genital herpes, appropriate examinations should be performed to rule out other sexually transmitted diseases.
These indications are based on the results of a number of double-blind, placebo-controlled studies which examined changes in virus excretion, healing of lesions and relief of pain. Because of the wide biological variations inherent in herpes simplex infections, the following summary is presented merely to illustrate the spectrum of responses observed to date. As in the treatment of any infectious disease, the best response may be expected when therapy is begun at the earliest possible moment.
In immunocompromised patients, 93% were virus negative after 5 days of topical acyclovir therapy, whereas only 35% of placebo recipients were virus negative at the same time. In patients with herpes labialis, there was a significantly greater decrease in the amount of virus excreted after one day of therapy in those receiving acyclovir within 8 hours of the onset of cold sores when compared to identically treated placebo recipients.
Because complete re-epithelialization of herpes-disrupted integument necessitates recruitment of several complex repair mechanisms, the physician should be aware that the disappearance of visible lesions is somewhat variable and will occur later than the cessation of virus shedding. All immunocompromised patients who received topical acyclovir had healed their lesions 23 days after the initiation of a 10-day course of therapy; 75% of placebo patients had healed lesions at that point. Some placebo patients continued to have visible lesions for more than 30 days.
Pain associated with herpes infections is highly variable in frequency and intensity. 100% of the acyclovir-treated immunocompromised patients were pain-free by day 23 versus 70% of placebo-treated patients.
Whereas cutaneous lesions associated with herpes simplex infections are often pathognomonic, Tzanck smears prepared from lesions 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 known interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir ointment 5%.
Acyclovir, when given systemically, is known to be excreted into human milk. Although evidence suggests that absorption of acyclovir through the skin is minimal, caution should be exercised when acyclovir is administered to a nursing mother.
Safety of use of acyclovir ointment 5% in children has not been established.
The recommended dosage, frequency of application and duration of treatment of acyclovir ointment 5% should not be exceeded (see Dosage).
There exist no data, at this time, which demonstrate that the use of acyclovir ointment 5% will prevent transmission of infection to other persons.
Since most cutaneous herpes simplex virus infections result from reactivation of latent virus, is is unlikely that acyclovir ointment 5% will prevent recurrence of infections when applied in the absence of signs and symptoms. Acyclovir ointment 5% 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 ointment 5% has not been observed, this possibility exists.
All animal studies carried out to date on reproduction and teratology have been negative. However, since animal reproduction studies are not always predictive of human response, acyclovir ointment 5% should be used during pregnancy only if the physician feels the benefit will outweight the possible harm to the fetus.
A postmarketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulations 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 significant effect on sperm count, motility or morphology.
Supplied
Each g contains: acyclovir 50 mg in a polyethylene glycol base. Tubes of 4, 15 and 30 g. Store between 15 to 25°C and keep dry.
Contraindications
Hypersensitivity or chemical intolerance to any of the components of the formulation, such as polyethylene glycol.
Warnings
5% is intended for topical use only and should not be used in the eye or on mucous membranes.
Adverse Effects
Because ulcerated genital lesions are characteristically tender and sensitive to any contact or manipulation, patients may experience discomfort upon application of ointment. In the controlled clinical trials, mild pain (including transient burning and stinging) was reported by 103 (28.3%) of 364 patients treated with acyclovir ointment 5% and by 115 (31.1%) of 370 patients treated with placebo; treatment was discontinued in 2 of these patients. Other local reactions among acyclovir-treated patients included pruritus in 15 (4.1%), rash in 1 (0.3%) and vulvitis in 1 (0.3%). Among the placebo-treated patients, pruritus was reported by 17 (4.6%) and rash by 1 (0.3%).
In all studies, there was no significant difference between the drug and placebo group in the rate or type of reported adverse reactions.
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 ointment 5% is unlikely because of limited transcutaneous absorption.
Dosage
Apply acyclovir ointment 5% liberally to the affected area 4 to 6 times daily for up to 10 days. A sufficient quantity of ointment should be applied to adequately cover all lesions. A finger cot or rubber glove should be used while applying acyclovir in order to prevent: (1) autoinoculation of other body sites or (2) transmission of infection to other persons. Therapy should be initiated as early as possible following onset of signs and symptoms.
