Acyclovir

1 INDICATIONS AND USAGE Acyclovir cream, 5% 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. Acyclovir cream, 5% 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. (1)

2 DOSAGE AND ADMINISTRATION Acyclovir 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. • Apply 5 times a day for 4 days. ( 2 ) • Administer immediately following the onset of cold sore lesions. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Each gram of acyclovir cream contains 50 mg (equivalent to 5% w/w) of acyclovir, USP. Cream, 50 mg (equivalent to 5% w/w) acyclovir, USP. ( 3 )

4 CONTRAINDICATIONS Acyclovir cream is contraindicated in patients with known hypersensitivity to acyclovir USP, valacyclovir, or any component of the formulation. Acyclovir cream is contraindicated in patients with known hypersensitivity to acyclovir USP, valacyclovir or any component of the formulation. (4)

6 ADVERSE REACTIONS The most common adverse reactions reported were local skin reactions at the application site. ( 6.1 ) Angioedema, anaphylaxis, contact dermatitis and eczema have been reported. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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, 1,124 patients were treated with acyclovir cream and 1,161 with placebo (vehicle) cream. Local application site reactions were reported by 5% of patients receiving acyclovir 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 acyclovir cream and placebo. Three patients on acyclovir 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 acyclovir cream compared with vehicle using single occluded and semi-occluded patch testing methodology. Both acyclovir 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 acyclovir 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 acyclovir cream and placebo, and these reactions to both acyclovir 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 acyclovir cream. Due to minimal systemic absorption of acyclovir cream, systemic drug interactions are unlikely. • Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir cream. Due to minimal systemic absorption of acyclovir cream, systemic drug interactions are unlikely. ( 7 )

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 acyclovir 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 acyclovir cream [see Clinical Pharmacology ( 12.3 )] . There are no data on the effects of acyclovir cream 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 acyclovir cream and any potential adverse effects on the breastfed child from acyclovir cream or from the underlying maternal condition. 8.4 Pediatric Use An open-label, uncontrolled trial with acyclovir 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 )].

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

11 DESCRIPTION Acyclovir is a synthetic deoxynucleoside analogue active against herpes viruses. Acyclovir cream 5% is a formulation for topical administration. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6 H -purin-6-one; it has the following structural formula: Acyclovir, USP is a white to off-white, crystalline powder with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225.20. The maximum solubility in water at 37°C is 2.5 mg/mL. It is soluble in diluted hydrochloric acid; slightly soluble in water; and insoluble in alcohol. The pKa's of acyclovir are 2.27 and 9.25. Each gram of acyclovir Cream contains 50 mg (equivalent to 5% w/w) of acyclovir, USP and the following inactive ingredients: cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water, and white petrolatum. Acyclovir Cream

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

16 HOW SUPPLIED/STORAGE AND HANDLING Acyclovir cream is a white, odorless, smooth homogeneous cream. Each gram of acyclovir cream contains 50 mg (equivalent to 5% w/w) of acyclovir in an aqueous cream base. Acyclovir cream, 5% is supplied as follows: 5 g tubes NDC 72162-2327-2 Store at or below 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504