Zovirax: Package Insert and Label Information

ZOVIRAX- acyclovir cream
Bausch Health US, LLC

1 INDICATIONS AND USAGE

ZOVIRAX Cream is a herpes simplex virus (HSV) deoxynucleoside analogue DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults and adolescents 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

ZOVIRAX Cream should be applied 5 times per day for 4 days. Therapy should be initiated as early as possible following the onset of signs or symptoms of herpes labialis, i.e. during the prodrome or when lesions appear.

For adolescents 12 years of age and older, the dosage is the same as in adults.

3 DOSAGE FORMS AND STRENGTHS

Each gram of ZOVIRAX Cream contains 50 mg (equivalent to 5% w/w) of acyclovir.

4 CONTRAINDICATIONS

ZOVIRAX Cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir, or any component of the formulation.

5 WARNINGS AND PRECAUTIONS

5.1 General

ZOVIRAX Cream should only be applied on the affected external aspects of the lips and face in patients with herpes labialis. Because no data are available, application to human mucous membranes is not recommended. ZOVIRAX Cream is intended for cutaneous use only and should not be used in the eye or inside the mouth or nose.

5.2 Contact Sensitization

ZOVIRAX Cream has a potential for irritation and contact sensitization [see Adverse Reactions (6.1)].

The effect of ZOVIRAX Cream has not been established in immunocompromised patients.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in clinical practice.

In five double-blind, placebo-controlled trials, 1124 patients were treated with ZOVIRAX Cream and 1161 with placebo (vehicle) cream. Local application site reactions were reported by 5% of patients receiving ZOVIRAX Cream and 4% of patients receiving placebo. The most common adverse reactions at the site of topical application were dry lips, desquamation, dryness of skin, cracked lips, burning skin, pruritus, flakiness of skin, and stinging on skin; each adverse reaction occurred in less than 1% of patients receiving ZOVIRAX Cream and placebo. Three patients on ZOVIRAX Cream and one patient on placebo discontinued treatment due to an adverse event.

An additional study, enrolling 22 healthy adults, was conducted to evaluate the dermal tolerance of ZOVIRAX Cream compared with vehicle using single occluded and semi-occluded patch testing methodology. Both ZOVIRAX Cream and placebo showed a high and cumulative irritation potential. Another study, enrolling 251 healthy adults, was conducted to evaluate the contact sensitization potential of ZOVIRAX Cream using repeat insult patch testing methodology. Of 202 evaluable subjects, possible cutaneous sensitization reactions were observed in the same 4 (2%) subjects with both ZOVIRAX Cream and placebo, and these reactions to both ZOVIRAX Cream and placebo were confirmed in 3 subjects upon rechallenge. The sensitizing ingredient(s) has not been identified.

The safety profile in patients 12 to 17 years of age was similar to that observed in adults.

6.2 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of acyclovir cream. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to acyclovir cream.

General: Angioedema, anaphylaxis.

Skin: Contact dermatitis, eczema.

7 DRUG INTERACTIONS

Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with ZOVIRAX Cream. Due to minimal systemic absorption of ZOVIRAX Cream, systemic drug interactions are unlikely.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Acyclovir is minimally absorbed systemically following topical route of administration, and maternal use is not expected to result in fetal exposure to the ZOVIRAX Cream [see Clinical Pharmacology (12.3)]. Experience with topical acyclovir use in pregnant women over several decades, based on published literature including observational studies, has not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies with systemic exposure of acyclovir have been conducted. Refer to acyclovir prescribing information for additional details.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

Risk Summary

Acyclovir is minimally absorbed systemically following topical route of administration, and breastfeeding is not expected to result in exposure of the child to ZOVIRAX Cream [see Clinical Pharmacology (12.3)]. There are no data on the effects of ZOVIRAX on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOVIRAX Cream and any potential adverse effects on the breastfed child from ZOVIRAX Cream or from the underlying maternal condition.

8.4 Pediatric Use

An open-label, uncontrolled trial with ZOVIRAX Cream was conducted in 113 patients aged 12 to 17 years with recurrent herpes labialis. In this trial, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults. Safety and effectiveness in pediatric patients less than 12 years of age have not been established.

8.5 Geriatric Use

Clinical studies of acyclovir cream 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 (12.3)].

10 OVERDOSAGE

Overdosage by topical application of ZOVIRAX Cream is unlikely because of minimal systemic exposure [see Clinical Pharmacology (12.3)]. There is no information available for overdose.

11 DESCRIPTION

ZOVIRAX is the brand name for acyclovir, a synthetic deoxynucleoside analogue active against herpes viruses. ZOVIRAX Cream 5% is a formulation for topical administration.

The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy) methyl]-6H -purin-6-one; it has the following structural formula:

Acyclovir Chemical Structure

Acyclovir is a white, crystalline powder with the molecular formula C8 H11 N5 O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pKa’s of acyclovir are 2.27 and 9.25.

Each gram of ZOVIRAX Cream contains 50 mg (equivalent to 5% w/w) of acyclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water and white petrolatum.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Acyclovir is an antiviral drug active against α-herpesviruses [see Microbiology (12.4)].

12.3 Pharmacokinetics

A clinical pharmacology study was performed with ZOVIRAX Cream in adult volunteers to evaluate the percutaneous absorption of acyclovir. In this study, which included 6 male volunteers, the cream was applied to an area of 710 cm2 on the backs of the volunteers 5 times daily at intervals of 2 hours for a total of 4 days. The weight of cream applied and urinary excretion of acyclovir were measured daily. Plasma concentration of acyclovir was assayed 1 hour after the final application. The average daily urinary excretion of acyclovir was approximately 0.04% of the daily applied dose. Plasma acyclovir concentrations were below the limit of detection (0.01 μM) in 5 subjects and barely detectable (0.014 μM) in 1 subject. Systemic absorption of acyclovir from ZOVIRAX Cream is minimal in adults.

The systemic absorption of acyclovir following topical application of cream has not been evaluated in patients <18 years of age.

12.4 Microbiology

Mechanism of Action: Acyclovir is a synthetic purine deoxynucleoside analogue with cell culture and in vivo inhibitory activity against HSV types 1 (HSV-1) and 2 (HSV-2) DNA polymerases. It inhibits HSV-1 and HSV-2 replication in cell culture and in vivo.

The inhibitory activity of acyclovir is selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV. This viral enzyme converts acyclovir into acyclovir monophosphate, a deoxynucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral DNA. This inhibition 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.

Antiviral Activity

The quantitative relationship between the susceptibility of herpes viruses to antivirals in cell culture 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 (EC50 value), vary greatly depending upon a number of factors. Using plaque-reduction assays on Vero cells, the EC50 values of acyclovir against herpes simplex virus isolates range from 0.09 to 59.9 μM (0.02 to 13.5 μg/mL) for HSV-1 and from 0.04 to 44.0 μM (0.01 to 9.9 μg/mL) for HSV-2.

Resistance

In Cell Culture

Acyclovir-resistant HSV-1 and HSV-2 strains were isolated in cell culture. Acyclovir-resistant HSV resulted from mutations in the viral thymidine kinase (TK; pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture the following resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 1).

Table 1: Summary of Acyclovir (ACV) Resistance-associated Amino Acid Substitutions in Cell Culture

HSV-1

TK

P5A, H7Q, L50V, G56V, G59A, G61A, K62N, T63A, E83K, P84S, D116N, P131S, R163H, A167V, P173L, Q185R, R216S, R220H, T245M, R281stop, T287M, M322K

HSV-2

TK

L69P, C172R, T288M

HSV-1

POL

D368A, Y557S, E597D, V621S, L702H, N815S, V817M, G841C

HSV-2

POL

In HSV-Infected Patients

Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their α-herpesvirus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 2). HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Table 2: Summary of ACV Resistance-associated Amino Acid Substitutions Observed in Treated Patients

HSV-1

TK

G6C, R32H, R41H, R51W, Y53C/D/H, Y53stop, D55N, G56D/S, P57H, H58/N/R/Y, G59R, G61A, K62N, T63I, Q67stop, S74stop, Y80N, E83K, P84L, Y87H, W88R, R89Q/W, E95stop, T103P, Q104H, Q104stop, H105P, D116N, M121L/R, S123R, Q125H, M128L, G129D, I143V, A156V, D162A/H/N, R163G/H, L170P, Y172C, P173L, A174P, A175V, R176Q/W, R176stop, L178R, S181N, V187M, A189V, V192A, G200C/D/S, T201P, V204G, A207P, L208F/H, R216C/H, R220C/H, R221H, R222C/H, L227F, T245M/P, L249P, Q250Stop, C251G, R256W, E257K, Q261R, T287M, L288Stop, L291P/R, L297S, L315S, L327R, C336Y, Q342Stop, T354P, L364P, A365T

HSV-2

TK

R34C, G39E, R51W, Y53N, G59P, G61W, S66P, A72S, D78N, P85S, A94V, N100H, I101S, Q105P, T131P, D137stop, F140L, L158P, S169P, R177W, S182N, M183I, V192M, G201D, R217H, R221C/H, Q222stop, R223H, Y239stop, R271V, P272S, D273R, T287M, C337Y

HSV-1

POL

K532T, Q570R, L583V, A605V, A657T, D672N, V715G, A719T/V, S724N, F733C, E771Q, S775N, L778M, E798K, V813M, N815S, G841S, I890M, G901V, V958L H1228D

HSV-2

POL

E250Q, D307N, K533E, A606V, C625R, R628C, E678G, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, N820S, Y823C, Q829R, T843A, M910T, D912N/V, A915V, F923L, T934A, R964H

Note: Additional substitutions to acyclovir resistance may exist.

Cross-resistance

Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) [Table 3].

Table 3: Summary of Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOS

Cross-resistant to PCV/FCV

HSV-1 TK

G6C, R32H, R51W, Y53C/H, H58N, G61A, S74Stop, E83K, P84L, T103P, Q104Stop, D116N, M121R, I143V, R163H, L170P, Y172C, A174P, R176Q/W, Q185R, A189V, G200D, L208H, R216C, R220H, R222C/H, T245M, Q250Stop, R256W, R281Stop, T287M, L315S, M322K, C336Y

Cross-resistant to PCV/FCV

HSV-1 POL

A657T, D672N, V715G, A719V, S724N, E798K, N815S, G841S

Cross-resistant to PCV/FCV

HSV-2 TK

G39E, R51W, Y53N, R177W, R221H, T288M

Cross-resistant to PCV/FCV

HSV-2 POL

K533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A, N820S, F923L, T934A

Cross-resistant to FOS

HSV-1 POL

D368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S, V817M, G841C/S, I890M

Cross-resistant to FOS

HSV-2 POL

K533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, Y823C, D912V, F923L, T934A, R964H

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