ZOVIRAX is the brand name for acyclovir, an antiviral drug active against herpes viruses. ZOVIRAX Ointment 5% is a formulation for topical administration. Each gram of ZOVIRAX Ointment 5% contains 50 mg of acyclovir in a polyethylene glycol (PEG) base.

The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6 H -purin-6-one.

Acyclovir is a white, crystalline powder with a molecular weight of 225 daltons, and a maximum solubility in water of 1.3 mg/mL.

Acyclovir is a synthetic acyclic purine nucleoside analogue with in vitro inhibitory activity against Herpes simplex types 1 and 2 (HSV-1 and HSV-2), varicella-zoster, Epstein-Barr, and cytomegalovirus. In cell cultures, the inhibitory activity of acyclovir for Herpes simplex virus is highly selective. Cellular thymidine kinase does not effectively utilize acyclovir as a substrate. Herpes simplex virus-coded thymidine kinase, however, converts acyclovir into acyclovir monophosphate, a nucleotide. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. 1 Acyclovir triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits viral DNA replication. Acyclovir triphosphate also inhibits cellular (alpha)-DNA polymerase but to a lesser degree. In vitro, acyclovir triphosphate can be incorporated into growing chains of DNA by viral DNA polymerase and to a much smaller extent by cellular (alpha)-DNA polymerase. 2 When incorporation occurs, the DNA chain is terminated. 3 Acyclovir is preferentially taken up and selectively converted to the active triphosphate form by herpesvirus-infected cells. Thus, acyclovir is much less toxic in vitro for normal uninfected cells because: 1) less is taken up; 2) less is converted to the active form; 3) cellular (alpha)-DNA polymerase is less sensitive to the effects of the active form.

The relationship between in vitro susceptibility of Herpes simplex virus to antiviral drugs and clinical response has not been established. The techniques and cell culture types used for determining in vitro susceptibility may influence the results obtained. Using a quantitative assay to determine the acyclovir concentration producing 50% inhibition of viral cytopathic effect (ID 50 ), 28 HSV-1 clinical isolates had a mean ID 50 of 0.17 mcg/mL and 32 HSV-2 clinical isolates had a mean ID 50 of 0.46 mcg/mL.* Results from other studies using different assays have yielded mean ID 50 values for clinical HSV-1 isolates of 0.018, 0.03, and 0.043 mcg/mL and for clinical HSV-2 isolates of 0.027, 0.36, and 0.03 mcg/mL, respectively. 4,5, 6

Two clinical pharmacology studies were performed with ZOVIRAX Ointment 5% in adult immunocompromised patients at risk of developing mucocutaneous Herpes simplex virus infections or with localized varicella-zoster infections. These studies were designed to evaluate the dermal tolerance, systemic toxicity, and percutaneous absorption of acyclovir.

In one of these studies, which included 16 inpatients, the complete ointment or its vehicle were randomly administered in a dose of 1-cm strips (25 mg acyclovir) four times a day for 7 days to an intact skin surface area of 4.5 square inches. No local intolerance, systemic toxicity, or contact dermatitis were observed. In addition, no drug was detected in blood and urine by radioimmunoassay (sensitivity, 0.01 mcg/mL).

The other study included 11 patients with localized varicella-zoster. In this uncontrolled study, acyclovir was detected in the blood of nine patients and in the urine of all patients tested. Acyclovir levels in plasma ranged from <0.01 to 0.28 mcg/mL in eight patients with normal renal function, and from <0.01 to 0.78 mcg/mL in one patient with impaired renal function. Acyclovir excreted in the urine ranged from <0.02% to 9.4% of the daily dose. Therefore, systemic absorption of acyclovir after topical application is minimal.

ZOVIRAX (acyclovir) Ointment 5% is indicated in the management of initial herpes genitalis and in limited nonlife-threatening mucocutaneous Herpes simplex virus infections in immunocompromised patients. In clinical trials of initial herpes genitalis, ZOVIRAX Ointment 5% has shown a decrease in healing time and, in some cases, a decrease in duration of viral shedding and duration of pain. In studies in immunocompromised patients with mainly herpes labialis, there was a decrease in duration of viral shedding and a slight decrease in duration of pain.

By contrast, in studies of recurrent herpes genitalis and of herpes labialis in nonimmunocompromised patients, there was no evidence of clinical benefit; there was some decrease in duration of viral shedding.

Diagnosis:   Whereas cutaneous lesions associated with Herpes simplex infections are often characteristic, the finding of multinucleated giant cells in smears prepared from lesion exudate or scrapings may assist in the diagnosis. 7 Positive cultures for Herpes simplex virus offer a reliable means for confirmation of the diagnosis. In genital herpes, appropriate examinations should be performed to rule out other sexually transmitted diseases.

CONTRAINDICATIONS

ZOVIRAX Ointment 5% is contraindicated for patients who develop hypersensitivity or chemical intolerance to the components of the formulation.

ZOVIRAX Ointment 5% is intended for cutaneous use only and should not be used in the eye.

PRECAUTIONS

General:   The recommended dosage, frequency of applications, and length of treatment should not be exceeded (see DOSAGE AND ADMINISTRATION ). There exist no data which demonstrate that the use of ZOVIRAX Ointment 5% will either prevent transmission of infection to other persons or prevent recurrent infections when applied in the absence of signs and symptoms. ZOVIRAX Ointment 5% should not be used for the prevention of recurrent HSV infections. Although clinically significant viral resistance associated with the use of ZOVIRAX 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 ZOVIRAX Ointment 5%.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of 50, 150, and 450 mg/kg per day given by gavage. These studies showed no statistically significant difference in the incidence of benign and malignant tumors produced in drug-treated as compared to control animals, nor did acyclovir induce the occurrence of tumors earlier in drug-treated animals as compared to controls. In two in vitro cell transformation assays, used to provide preliminary assessment of potential oncogenicity in advance of these more definitive lifetime bioassays in rodents, conflicting results were obtained. Acyclovir was positive at the highest dose used in one system and the resulting morphologically transformed cells formed tumors when inoculated into immunosuppressed, syngeneic, weanling mice. Acyclovir was negative in another transformation system.

No chromosome damage was observed at maximum tolerated parenteral doses of 100 mg/kg acyclovir in rats or Chinese hamsters; higher doses of 500 and 1000 mg/kg were clastogenic in Chinese hamsters. In addition, no activity was found in a dominant lethal study in mice. In nine of 11 microbial and mammalian cell assays, no evidence of mutagenicity was observed. In two mammalian cell assays (human lymphocytes and L5178Y mouse lymphoma cells in vitro), positive response for mutagenicity and chromosomal damage occurred, but only at concentrations at least 1000 times the plasma levels achieved in humans following topical application.

Acyclovir does not impair fertility or reproduction in mice at oral doses up to 450 mg/kg per day or in rats at subcutaneous doses up to 25 mg/kg per day. In rabbits given a high dose of acyclovir (50 mg/kg per day, SC), there was a statistically significant decrease in implantation efficiency.

Pregnancy: Teratogenic Effects: Pregnancy Category C. Acyclovir was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per day, SC and IV) or in standard tests in the rat (50 mg/kg per day, SC). In a nonstandard test in rats, fetal abnormalities, such as head and tail anomalies, were observed following subcutaneous administration of acyclovir at very high doses associated with toxicity to the maternal rat. The clinical relevance of these findings is uncertain. 8 There are no adequate and well-controlled studies in pregnant women. Acyclovir should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:   It is not known whether topically applied acyclovir is excreted in breast milk. After oral administration of ZOVIRAX, acyclovir concentrations have been documented in breast milk in two women and ranged from 0.6 to 4.1 times the corresponding plasma levels. 9,10 Caution should be exercised when ZOVIRAX Ointment is administered to a nursing woman.

Pediatric Use:   Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

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 and by 115 (31.1%) of 370 patients treated with placebo; treatment was discontinued in two of these patients. Other local reactions among acyclovir-treated patients included pruritus in 15 (4.1%), rash in one (0.3%), and vulvitis in one (0.3%). Among the placebo-treated patients, pruritus was reported by 17 (4.6%) and rash by one (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 nor were there any differences in abnormal clinical laboratory findings.

Observed During Clinical Practice: Based on clinical practice experience in patients treated with ZOVIRAX Ointment in the US, 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 which have been received since market introduction include:

General:   Edema and/or pain at the application site

Skin:   Pruritus, rash

OVERDOSAGE

Overdosage by topical application of ZOVIRAX Ointment 5% is unlikely because of limited transcutaneous absorption (see ).

DOSAGE AND ADMINISTRATION

Apply sufficient quantity to adequately cover all lesions every 3 hours, six times per day for 7 days. The dose size per application will vary depending upon the total lesion area but should approximate a one-half inch ribbon of ointment per 4 square inches of surface area. A finger cot or rubber glove should be used when applying ZOVIRAX to prevent autoinoculation of other body sites and transmission of infection to other persons. Therapy should be initiated as early as possible following onset of signs and symptoms.

HOW SUPPLIED

ZOVIRAX Ointment 5% is supplied in 15-g tubes (NDC 0173-0993-94) and 3-g tubes (NDC 0173-0993-41). Each gram contains 50 mg acyclovir in a polyethylene glycol base.

Store at 15° to 25°C (59° to 77°F) in a dry place.

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

images/pills/p01317c4.jpg

ANIMAL PHARMACOLOGY AND
ANIMAL TOXICOLOGY

Topical treatment of guinea pigs with 10% acyclovir in polyethylene glycol ointment for 3 weeks did not result in cutaneous irritation or systemic toxicity. Also, a wide variety of animal tests by parenteral routes demonstrated that acyclovir has a low order of toxicity.

Acyclovir did not cause dermal sensitization in guinea pigs.

REFERENCES

  1. Miller WH, Miller RL. Phosphorylation of acyclovir (acycloguanosine) monophosphate by GMP kinase. J Biol Chem. 1980;255:7204-7207.
  2. Furman PA, St. Clair MH, Fyfe JA, et al. Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate. J Virol. 1979; 32:72-77.
  3. Derse D, Cheng YC, Furman PA, et al. Inhibition of purified human and herpes simplex virus-induced DNA polymerases by 9-(2-hydroxyethoxymethyl)guanine triphosphate: effects on primer-template function. J Biol Chem. 1981;256:11447-11451.
  4. Collins P, Bauer DJ. The activity in vitro against herpes virus of 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine), a new antiviral agent. J Antimicrob Chemother. 1979;5:431-436.
  5. Crumpacker CS, Schnipper LE, Zaia JA, et al. Growth inhibition of acycloguanosine of herpesviruses isolated from human infections. Antimicrob Agents Chemother. 1979;15:642-645.
  6. DeClercq E, Descamps J, Verhelst G, et al. Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis. 1980;141:563-574.
  7. Naib ZM, Nahmias AJ, Josey WE, et al. Relation of cytohistopathology of genital herpesvirus infection to cervical anaplasia. Cancer Res. 1973;33:1452-1463.
  8. Stahlmann R, Klug S, Lewandowski C, et al. Teratogenicity of acyclovir in rats. Infection 1987;15:261-262.
  9. Lau RJ, Emery MG, Galinsky RE, et al. Unexpected accumulation of acyclovir in breast milk with estimate of infant exposure. Obstet Gynecol. 1987;69:468-471.
  10. Meyer LJ, deMiranda P, Sheth N, et al. Acyclovir in human breast milk. Am J Obstet Gynecol. 1988;158: 586-588.

*Data on file at Glaxo Wellcome Inc.

Glaxo Wellcome Inc., Research Triangle Park, NC 27709

©Copyright 1996 Glaxo Wellcome Inc. All rights reserved.

March 1998/RL-552