AHFS Class:

• Antivirals 84:04.06

Generic Name(s):

• Acyclovir

Acyclovir, a synthetic purine nucleoside analog derived from guanine, has antiviral activity in vitro against various Herpesviridae including herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).

Acyclovir is used topically as a 5% cream for the treatment of recurrent herpes labialis (perioral herpes, cold sores, fever blisters) in immunocompetent individuals.112,114 Acyclovir is used topically as a 5% ointment in the treatment of limited, non-life-threatening, mucocutaneous herpes simplex virus (HSV-1 and HSV-2) infections in immunocompromised individuals.101 The manufacturer states that acyclovir ointment may be used topically for the management of initial genital herpes;101 however, topical therapy is not usually recommended for the treatment of genital herpes.106,110 There is no evidence that topical acyclovir will either prevent transmission of HSV infections to other individuals or prevent recurrent HSV infections when applied in the absence of signs and symptoms of infection. 101 Acyclovir should not be used topically for prevention of recurrent HSV infections.101

Herpes Labialis

Acyclovir 5% cream is used topically for the treatment of recurrent herpes labialis (perioral herpes, cold sores, fever blisters) in immunocompetent adults and children 12 years of age or older.112 Efficacy of acyclovir 5% cream in immunocompromised individuals has not been established.112 In 2 randomized, double-blind, vehicle-controlled studies in immunocompetent adults with a history of recurrent herpes labialis (at least 3 episodes during the past year), self initiation of topical acyclovir 5% cream within 1 hour of onset of prodromal symptoms or the first clinical sign of herpes labialis decreased the duration of the episode and also decreased patient-assessed duration of pain.111 In these studies, the mean duration of herpes labialis episodes for patients with a known duration was 4.3-4.6 days in those treated with topical acyclovir versus 4.8-5.2 days in those treated with vehicle cream; the mean patient-assessed duration of pain was 2.9-3.1 days and 3.2-3.5 days, respectively.111 There was no evidence that use of topical acyclovir prevented the development of classic herpes labialis lesions (progression to vesicles, ulcers, and/or crusts).111

In immunocompromised adults with herpes labialis (oral and perioral herpes), topical application of acyclovir 5% ointment to the lesions has decreased the duration of viral shedding and the duration of pain.101 In one study, acyclovir was not effective in reducing total healing time or delaying the onset of recurrent infections. However, in this study, the duration of viral shedding (time from patient enrollment in the study until 2 consecutive negative cultures were obtained) was 2.5 days in acyclovir-treated patients compared with 9.5 days in placebo-treated patients; pain persisted for more than 3 weeks after onset of illness in 10% of acyclovir-treated patients and in about 50% of placebo-treated patients.

Genital Herpes

Acyclovir 5% ointment has been used in the treatment of initial episodes of genital herpes in adults.101 However, topical antiviral agents are not recommended for the treatment of genital herpes since these agents offer only minimal clinical benefit.106,110 The US Centers for Disease Control and Prevention (CDC) and some clinicians recommend that oral acyclovir, oral famciclovir, or oral valacyclovir be used for the treatment of first episodes of genital herpes, episodic treatment of recurrent infections, or suppressive therapy of recurrent infections in immunocompetent adults and adolescents.106,110

Controlled studies of first episodes of genital herpes infections, both primary and non-primary, have shown that topical therapy with acyclovir 5% ointment does not reduce the frequency or delay the time of appearance of new lesions following initiation of treatment, nor does it delay the onset of recurrent infections. However, topical therapy with acyclovir generally decreases the duration of viral shedding (time from onset of therapy until the last positive culture), the duration of pain and itching, and the time required for crusting and healing of lesions in these patients.

Studies of treatment of recurrent genital herpes infections have generally shown little if any therapeutic benefit following topical therapy with acyclovir 5% ointment. In controlled studies in patients (males and females) with recurrent infections, topical acyclovir appeared to decrease the duration of viral shedding and modestly reduce the time required for crusting and healing of lesions in males. No significant effect on healing or crusting of lesions was noted in females. No significant reduction in duration or degree of pain or itching was noted in patients of either sex. Acyclovir has not been effective in reducing the frequency or delaying the onset of subsequent recurrent infections. Similar disappointing results have occurred when topical acyclovir therapy for the prevention of recurrent genital herpes infections† was initiated immediately following the development of prodromal symptoms (e.g., itching, burning, tingling, numbness).107,109 In one large, placebo-controlled, multicenter study, the duration of viral shedding was reduced in females, but not males, and the time required for crusting was reduced in males, but not females; however, these reductions were of borderline significance only and there was no evidence of symptomatic improvement with acyclovir nor other differences compared with placebo.109

For information on current recommendations for the treatment of genital herpes, see Uses: Genital Herpes, in Acyclovir 8:18.32.

Mucocutaneous Herpes Simplex Virus (HSV) Infections

Acyclovir 5% ointment is used topically in the treatment of limited, non-life-threatening, nongenital, mucocutaneous HSV-1 and HSV-2 infections in immunocompromised adults.101,113 However, systemic therapy (e.g., oral or IV acyclovir) generally is preferred for the treatment of mucocutaneous herpes simplex infections in immunocompromised individuals.113,114

Ophthalmic HSV Infections

An ophthalmic ointment containing acyclovir 3% (not currently available) has been used in the topical treatment of HSV ophthalmic infections†; however, commercially available acyclovir 5% ointment should not be applied to the eye .

For other uses of acyclovir, see 8:18.32.

Administration

Acyclovir 5% cream is applied topically to affected areas of the lips and surrounding skin.112 The cream should not be applied to the eye, inside the mouth or nose, or to mucous membranes.112

Acyclovir 5% ointment is applied topically to the skin.101 The ointment should not be applied to the eye.101 A finger cot or rubber glove should be used when applying the ointment to prevent autoinoculation of other sites and transmission of the virus to other individuals.101

Dosage

Herpes Labialis

For the treatment of recurrent herpes labialis (perioral herpes, cold sores, fever blisters) in adults and children 12 years of age or older, therapy with acyclovir cream should be initiated at the earliest sign or symptoms of herpes labialis (i.e., during the prodrome or when lesions appear).112 The cream should be applied in sufficient quantity to cover all lesions or symptomatic areas (e.g., area with tingling).112 The cream should be rubbed gently into the affected area 5 times daily for 4 days.112 The affected area should not be covered with a dressing unless directed by a clinician.112

Genital Herpes and Mucocutaneous Herpes Simplex Virus (HSV) Infections

For the treatment of initial episodes of genital herpes in adults or mucocutaneous herpes simplex infections in immunocompromised adults, therapy with acyclovir ointment should be initiated as soon as possible following the onset of signs and symptoms of infection.101 The ointment should be applied in sufficient quantity to adequately cover all lesions.101 The usual dose of acyclovir 5% ointment varies according to the total lesion area but should be approximately a 1.25-cm (0.5-inch) ribbon of ointment per 2.5-cm² (4-inch²) surface area.101 The manufacturer recommends that the ointment be gently rubbed into the affected area every 3 hours 6 times daily for 7 days.101 Patients should be instructed to contact their physician if no improvement occurs following 7 days of therapy. The affected area should be kept clean and dry; patients should be instructed to wear loose-fitting clothing to avoid irritation of the lesions. The manufacturer states that the recommended dose, frequency of application, and duration of treatment should not be exceeded.101

Adverse Effects

Topical acyclovir generally is well tolerated.112 Based on clinical experience, spontaneously reported adverse effects associated with the use of topical acyclovir are rare.101,112

In clinical studies evaluating acyclovir 5% ointment, mild pain (including transient burning and stinging) occurred in about 30% of patients in both the active and placebo arms and treatment was discontinued in 2 of these patients.101 Local pruritus occurred in 4% of patients.101 Edema and/or pain at the application site and rash also have been reported.101 In several placebo-controlled studies, the frequency and type of these adverse effects were similar for acyclovir- and placebo-treated patients;101 therefore, these effects probably resulted from contact with or manipulation of the characteristically tender genital lesions.

In clinical studies evaluating acyclovir 5% cream, dry or cracked lips, desquamation, dry or flaking skin, burning or stinging skin, and pruritus were the most frequently reported adverse effects.112

The manufacturer states that adverse systemic effects following overdosage with topically applied acyclovir 5% cream or ointment are unlikely since the drug undergoes minimal percutaneous absorption.101,112

Precautions and Contraindications

The development of viral mutants with decreased in vitro susceptibility to acyclovir has occurred following in vitro exposure of HSV isolates to the drug and also has been observed in a small number of immunocompromised patients after repeated systemic therapy with the drug; however, the clinical importance of this decreased in vitro susceptibility is not known since the presence of these viruses did not appear to be associated with a worsening of clinical illness and, in some instances, the virus disappeared spontaneously. Although clinically important resistance has not been associated with the use of topical acyclovir, the possibility that indiscriminate use of the drug may result in such resistance should be considered.101

Patients should be instructed to avoid close contact with individuals experiencing signs or symptoms of herpes simplex (HSV) infections. There is no evidence that topically applied acyclovir will prevent transmission of HSV infections to other individuals.101 Acyclovir 5% ointment should not be used for the prevention of recurrent HSV infections; data indicating that the ointment prevents recurrent HSV infection is not available.101

The recommended dose, frequency of application, and length of treatment with topical acyclovir should not be exceeded. Commercially available acyclovir 5% cream or ointment should not be applied to the eye.101,112

The manufacturer states that acyclovir 5% cream has the potential for irritation and contact sensitization; contact dermatitis has been reported rarely during postmarketing surveillance.112

Topical acyclovir is contraindicated in patients hypersensitive to acyclovir, valacyclovir, or any ingredient in the formulation.101,112

Pediatric Precautions

Safety and efficacy of acyclovir 5% cream have not been established in children younger than 12 years of age.112 When the topical cream was used for the treatment of recurrent herpes labialis (perioral herpes, cold sores, fever blisters) in children 12-17 years of age, the safety profile was similar to that reported in adults.112

Safety and efficacy of acyclovir 5% ointment have not been established in children.101

Geriatric Precautions

Clinical studies using topical acyclovir 5% cream or ointment did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently from younger patients.101,112 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.101,112

Mutagenicity and Carcinogenicity

Mutagenic changes and chromosomal damage have occurred in vitro in human lymphocytes and mouse lymphoma cells at acyclovir concentrations at least 1000 times greater than the plasma drug concentrations achievable following topical application of the ointment in humans.

In vitro cell transformation assays have shown conflicting evidence regarding the oncogenic potential of acyclovir. However, the manufacturer states that in more definitive, long-term studies of the carcinogenic potential of acyclovir in mice and rats, no difference in the frequency of benign and malignant tumors was seen when drug-treated animals were compared with control animals; in addition, acyclovir did not appear to shorten the latency of tumors.

Because systemic absorption appears to be minimal following topical application of acyclovir, dermal carcinogenicity studies have not been conducted.101,112

Pregnancy and Lactation

Pregnancy

Acyclovir has not been shown to be teratogenic in standard tests following subcutaneous administration in rats and rabbits, IV administration in rabbits, and oral administration in mice. However, in nonstandard tests in rats, fetal abnormalities, principally involving the head and tail, were observed at higher subcutaneous acyclovir dosages, which also were associated with maternal toxicity.102,103,104 The drug crosses the placenta in humans following oral or IV administration.105,117 There are no adequate and controlled studies to date using acyclovir in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Lactation

Although it is not known whether acyclovir is distributed into milk following topical application, the drug is distributed into milk following oral or IV administration.101,112,117 Following oral administration of acyclovir in 2 nursing women, milk acyclovir concentrations were 0.6-4.1 times the simultaneous maternal plasma drug concentrations.101,112 Therefore, acyclovir ointment and cream should be used with caution in nursing women.101,112 Women who have active herpetic lesions near or on the breast should avoid nursing.101,112,113

Because systemic absorption appears to be minimal following topical application of acyclovir,101,112 drug interactions between topical acyclovir and systemically administered drugs is unlikely. The manufacturer states that drug interactions in patients receiving topical acyclovir concurrently with other topical or systemic drugs have not been reported to date.101,112

Mechanism of Action

Acyclovir exerts its antiviral effect on herpes simplex viruses (HSV) and varicella zoster virus (VZV) by interfering with DNA synthesis and inhibiting viral replication. The exact mechanisms of action against other susceptible viruses have not been fully elucidated.

In cells infected with herpesvirus in vitro, the antiviral activity of acyclovir appears to depend principally on the intracellular conversion of the drug to acyclovir triphosphate. Acyclovir is converted to acyclovir monophosphate principally via virus-coded thymidine kinase; the monophosphate is phosphorylated to the diphosphate via cellular guanylate kinase and then to the triphosphate via other cellular enzymes (e.g., phosphoglycerate kinase, pyruvate kinase, phosphoenolpyruvate carboxykinase). In uninfected cells in vitro, acyclovir is only minimally phosphorylated by cellular (host cell) enzymes. The formation of acyclovir monophosphate appears to be the rate-limiting step in the formation of acyclovir triphosphate. In vitro studies have shown that the extent of formation of acyclovir monophosphate, diphosphate, and triphosphate by both uninfected and viral-infected cells is directly related to the concentration of acyclovir in the culture medium. Acyclovir also is apparently converted to acyclovir triphosphate by other mechanisms since the drug has some activity against several viruses that apparently do not code for viral thymidine kinase (e.g., Epstein-Barr virus, cytomegalovirus). In vitro studies indicate that acyclovir triphosphate is produced in low concentrations via unidentified cellular phosphorylating enzymes in cells infected with Epstein-Barr virus and cytomegalovirus.

In vitro studies with herpes simplex viruses indicate that acyclovir triphosphate is the pharmacologically active form of the drug; the triphosphate functions as both a substrate for and preferential inhibitor of viral DNA polymerase. In herpesviruses, acyclovir triphosphate inhibits DNA synthesis by competing with deoxyguanosine triphosphate for viral DNA polymerase and incorporation principally into viral DNA. In vitro in herpesviruses, acyclovir can be incorporated into growing chains of DNA via viral DNA polymerase and to a much lesser extent via cellular α-DNA polymerase. Viral DNA polymerase exhibits a 10- to 30-fold or greater affinity in vitro for acyclovir triphosphate than does cellular α-DNA polymerase. Following incorporation of acyclovir triphosphate into the DNA chain, DNA synthesis is terminated. In vitro studies have shown that acyclovir triphosphate also partially inhibits the synthesis of γ-polypeptides within cells that are infected with herpesvirus. Acyclovir has minimal pharmacologic effects in vitro in uninfected cells since uptake of the drug into these cells is poor, phosphorylation of acyclovir and intracellular formation of acyclovir triphosphate are minimal, and cellular α-DNA polymerase has a low affinity for acyclovir triphosphate.

Non-phosphorylated acyclovir, acyclovir monophosphate, and acyclovir diphosphate are thought to have minimal or no effect on viral or cellular α-DNA polymerase and therefore, have no antiviral activity.

Spectrum

Acyclovir has antiviral activity in vitro against various Herpesviridae including herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VSV). Although the drug is active against other viruses, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpesvirus simiae, these viruses are usually not associated with dermatologic infections.

Susceptibility Testing

Various methods (e.g., cytopathic effect inhibition, plaque inhibition, dye-uptake, disk-agar diffusion) have been used to test the in vitro susceptibility of viruses to acyclovir. The results and interpretations of these tests are method dependent. Although IDs (inhibitory doses) and EDs (effective doses) of acyclovir for various viruses have been reported, a standardized method for determining these values does not currently exist. In addition, the relationship between in vitro susceptibility of viruses to acyclovir and clinical response has not been determined. In viral susceptibility testing, 1 mcg of acyclovir per mL is approximately equivalent to 4.4 µ M.

Viruses

In several studies using a cytopathic effect inhibition assay (CPE-inhibition assay), the ID₅₀ (concentration of drug required to produce 50% inhibition of viral cytopathic effect or plaque formation) of acyclovir reported for susceptible strains of HSV-1 ranged from 0.02-0.7 mcg/mL; in studies using a plaque inhibition assay, the ID₅₀ of the drug reported for susceptible HSV-1 was 0.018-0.043 mcg/mL. In several studies using a CPE-inhibition assay, the ID₅₀ of acyclovir reported for susceptible strains of HSV-2 ranged from 0.01-3.2 mcg/mL; in studies using a plaque inhibition assay, the ID₅₀ of the drug reported for susceptible HSV-2 was 0.027-0.36 mcg/mL. In several studies using a plaque inhibition assay, the ID₅₀ of acyclovir for susceptible strains of VZV ranged from 0.34-1.43 mcg/mL.

Resistance

Since the antiviral activity of acyclovir generally appears to depend on phosphorylation of the drug to acyclovir triphosphate, resistance to the drug may result from low concentrations or absence of virus-coded thymidine kinase in infected cells or from alterations in substrate specificity of virus-coded thymidine kinase. Other mechanisms of resistance to acyclovir may also exist.

Acyclovir resistance in herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VSV) may result from production of a virus-coded thymidine kinase with altered substrate specificity or from an impaired ability to produce active virus-coded thymidine kinase; either of these mechanisms may result in minimal amounts or absence of phosphorylated drug. In addition to qualitative or quantitative alterations in virus-coded thymidine kinase, resistance of herpesviruses to acyclovir may result from production of an altered DNA polymerase capable of synthesizing DNA in the presence of acyclovir triphosphate.

The development of viral mutants with decreased in vitro susceptibility to acyclovir has been observed in a small number of immunosuppressed patients after repeated systemic therapy with the drug. It has been suggested that repeated treatment of recurrent viral infections with acyclovir may favor the selection of preexisting, or development of, drug-resistant strains.

Although lack of virus-coded thymidine kinase is apparently responsible for resistance in some strains of viruses, this lack has also been associated with a loss of or decrease in virulence in some strains. In addition, in one study, inoculation of mice with acyclovir-resistant HSV-1 mutants afforded protection against infection with virulent acyclovir-susceptible HSV-1 strains.

During the course of an acute or asymptomatic herpesvirus infection, the virus usually leaves the initial site of infection and invades other cells and tissues where it establishes a site of latent infection. HSV-1, HSV-2, and VZV are thought to establish latent infections principally within the ganglia. Animal studies indicate that colonization of sensory neurons by HSV-1 may occur as soon as 24-48 hours after initial infection and latency may develop within 2-3 weeks. The exact nature of the virus during the latent state is not well understood; however, current evidence suggests that the virus is not actively replicating and, therefore, would not be susceptible to the antiviral action of drugs such as acyclovir. Despite the host's immunity, latency usually persists for life and the virus can be periodically reactivated by various stimuli (e.g., fever, stress, trauma, exposure to sunlight, menstruation, sexual intercourse, immunosuppression). Once reactivated, the virus usually reinfects the site(s) of initial infection. Acyclovir is apparently unable to eliminate an established latent infection. Acyclovir-resistant HSV mutants appear to be less capable of establishing latent infections than susceptible strains.

Some acyclovir-resistant HSV and VZV are cross-resistant to penciclovir.115,116

Pharmacokinetics

Absorption

Percutaneous absorption of acyclovir appears to be minimal following topical application of the drug to intact skin.101,112

In a pharmacokinetic study in healthy adult males that evaluated topical application of acyclovir 5% cream 5 times daily for 4 days to intact skin (area of application 710 cm²), plasma acyclovir concentrations obtained 1 hour after the last dose were undetectable or just above the limits of detection.112

In one study in immunocompromised adults, the drug was not detected in blood or urine following topical application of acyclovir 5% ointment to intact skin (25 mg of acyclovir per application) 4 times daily for 7 days.101 In another study in several patients with localized varicella-zoster, plasma acyclovir concentrations were 0.28 mcg/mL or less in patients with normal renal function and 0.78 mcg/mL or less in one patient with impaired renal function.101

Distribution

The distribution of acyclovir following topical application has not been determined. In vitro, acyclovir appears to be preferentially distributed into cells that are infected with herpesviruses.

Acyclovir crosses the placenta following oral or IV administration.105,117

It is not known if the drug or its metabolites are distributed into milk following topical application.101 However, limited data indicate that acyclovir is distributed into milk following oral administration, generally in concentrations greater than concurrent maternal plasma concentrations.100,101

Elimination

In vitro, acyclovir is metabolized in cells infected with herpesviruses, principally by intracellular phosphorylation of the drug by virus-coded thymidine kinase and several cellular enzymes. The metabolic fate of percutaneously absorbed acyclovir has not been fully determined.

Following systemic absorption, acyclovir is excreted principally in urine. When acyclovir 5% ointment was applied topically to the intact skin of healthy adult males (5 times daily for 4 days), approximately 0.04% of the total daily dose was detected in urine.112 When acyclovir 5% ointment was applied topically in immunocompromised adults with localized varicella-zoster, up to 9.4% of the total daily dose of acyclovir was excreted in urine as unchanged drug within 24 hours.101

Chemistry and Stability

Chemistry

Acyclovir is a synthetic purine nucleoside analog derived from guanine. The drug differs structurally from guanine by the presence of an acyclic side chain.

Acyclovir occurs as a white, crystalline powder and has solubilities of 1.3 mg/mL in water at 25°C and 0.2 mg/mL in alcohol. The drug has pK_as of 2.27 and 9.25. For topical use, acyclovir is commercially available as 5% cream in a vehicle that contains mineral oil, propylene glycol, sodium lauryl sulfate, and white petrolatum112 and as a 5% ointment in a polyethylene glycol vehicle.101

Stability

Acyclovir 5% cream should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.112

Acyclovir 5% ointment should be stored in a dry place at 15-25°C.101

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

100. Lau RJ, Emery MG, Galinsky RE. Unexpected accumulation of acyclovir in breast milk with estimation of infant exposure. Obstet Gynecol . 1987; 60:468-71.

101. Bioavail Pharmaceuticals, Inc. Zovirax^® (acyclovir) ointment 5% prescribing information. Bridgewater, NJ; 2004 Jan.

102. Stahlmann R, Klug S, Lewandowski C et al. Teratogenicity of acyclovir in rats. Infection . 1987; 15:261-2. [PubMed 3666969]

103. Chahoud I, Stahlmann R, Bochert G et al. Gross-structural defects in rats after acyclovir application on day 10 of gestation. Arch Toxicol . 1988; 62:8-14. [PubMed 3190462]

104. Stahlmann R, Klug S, Lewandowski C et al. Prenatal toxicity of acyclovir. Arch Toxicol . 1988; 61:468-79. [PubMed 3190444]

105. Greffe BS, Dooley SL, Deddish RB et al. Transplacental passage of acyclovir. J Pediatr . 1986; 108:1020-1. [PubMed 3012053]

106. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Morb Mortal Wkly Rep . 2006; 55(No. RR-11):1-96. [PubMed 16410759]

107. O'Brien JJ, Campoli-Richards DM. Acyclovir: an update review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs . 1989; 37:233-309. [PubMed 2653790]

108. Fawcett HA, Wansbrough-Jones MH. Prophylactic topical acyclovir for frequent recurrent herpes simplex infection with and without erythema multiforme. BMJ . 1983; 287:798-9. [PubMed 6412833]

109. Luby JP, Gnann JW, Alexander WJ et al. A collaborative study of patient-initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J Infect Dis . 1984; 150:1-6. [PubMed 6086765]

110. Anon. Drugs for sexually transmitted diseases. Med Lett Treat Guid . 2004; 2:67-74.

111. Spruance SL, Nett R, Marbury T et al. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother . 2002; 46:2238-43. [PubMed 12069980]

112. Bioavail Pharmaceuticals, Inc. Zovirax^® (acyclovir) cream 5% prescribing information. Bridgewater, NJ; 2004 Jan.

113. Committee on Infectious Diseases, American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27thed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

114. Anon. Drugs for non-HIV viral infections. Med Lett Treat Guid . 2005; 3:23-32.

115. Safrin S, Phan L. In vitro activity of penciclovir against clinical isolates of acyclovir-resistant and foscarnet-resistant herpes simplex virus. Antimicrob Agents Chemother . 1993; 37:2241-3. [PubMed 8257152]

116. Hasegawa T, Kurokawa M, Yukawa TA et al. Inhibitory action of acyclovir (ACV) and penciclovir (PCV) on plaque formation and partial cross-resistance of ACV-resistant varicella-zoster virus to PCV. Antiviral Res . 1995; 27:271-9. [PubMed 8540749]

117. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005: 23-9.