penciclovir

1 INDICATIONS AND USAGE Penciclovir Cream, 1% is a deoxynucleoside analog HSV DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age or older. Penciclovir Cream, 1% is a deoxynucleoside analog HSV DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in adults and pediatric patients 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Apply Penciclovir Cream, 1% every 2 hours during waking hours for a period of 4 days. Start treatment as early as possible (i.e., during the prodrome or when lesions appear). • Apply Penciclovir Cream, 1% every 2 hours during waking hours for a period of 4 days. ( 2 ) • Start treatment as early as possible (i.e., during the prodrome or when lesions appear). ( 2 )

3 DOSAGE FORMS AND STRENGTHS Penciclovir Cream, 1% is supplied in a 5 gram tube containing 10 mg of penciclovir per gram in a cream base, which is equivalent to 1% (w/w). • Topical cream containing 1% penciclovir. ( 3 )

4 CONTRAINDICATIONS Penciclovir Cream, 1% is contraindicated in patients with known hypersensitivity to the product or any of its components. • Contraindicated in patients with known hypersensitivity to the product or any of its components. ( 4 )

6 ADVERSE REACTIONS One or more local skin reactions were reported by 3% of the subjects treated with penciclovir cream, 1% and 4% of placebo-treated patients. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies 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 two double-blind, placebo-controlled trials, 1,516 patients were treated with penciclovir cream, 1% and 1,541 with placebo. One or more local adverse reactions were reported by 3% of the patients treated with penciclovir cream, 1% and 4% of placebo-treated patients. The rates of reported local adverse reactions are shown in Table 1. Table 1: Local Adverse Reactions Reported in Phase III Trials Penciclovir N=1,516 % Placebo N=1,541 % Application site reaction 1 2 Hypesthesia/Local anesthesia <1 <1 Taste perversion <1 <1 Rash (erythematous) <1 <1 Two studies, enrolling 108 healthy subjects, were conducted to evaluate the dermal tolerance of 5% penciclovir cream (a 5-fold higher concentration than the commercial formulation) compared to vehicle using repeated occluded patch testing methodology. The 5% penciclovir cream induced mild erythema in approximately one-half of the subjects exposed, an irritancy profile similar to the vehicle control in terms of severity and proportion of subjects with a response. No evidence of sensitization was observed. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of penciclovir cream, 1%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following events have been identified from worldwide post-marketing use of penciclovir cream, 1% in treatment of recurrent herpes labialis (cold sores) in adults. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to penciclovir cream, 1%. General: Headache, oral/pharyngeal edema, parosmia. Skin: Aggravated condition, decreased therapeutic response, local edema, pain, paresthesia, pruritus, skin discoloration, and urticaria.

7 DRUG INTERACTIONS No drug interaction studies have been performed with Penciclovir Cream, 1%. Due to minimal systemic absorption of Penciclovir Cream, 1%, systemic drug interactions are unlikely.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Penciclovir cream, 1% is not absorbed systemically following topical administration and maternal use is not expected to result in fetal exposure to the drug. 8.2 Lactation Risk Summary Penciclovir cream, 1% is not absorbed systemically by the mother following topical administration and breastfeeding is not expected to result in exposure of the child to penciclovir cream, 1%. 8.4 Pediatric Use An open-label, uncontrolled trial with penciclovir cream 1% was conducted in 102 subjects, ages 12 to 17 years, with recurrent herpes labialis. The frequency of adverse events was generally similar to the frequency previously reported for adult patients. Safety and effectiveness in pediatric patients less than 12 years of age have not been established. 8.5 Geriatric Use In 74 subjects ≥ 65 years of age, the adverse events profile was comparable to that observed in younger patients.

12.1 Mechanism of Action Penciclovir is an antiviral agent active against alpha herpes viruses [see Microbiology (12.4) ] .

Mechanism of Action: Penciclovir has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1 or HSV-2, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, α-herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1 and 20 hours in HSV-2 infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.

11 DESCRIPTION Penciclovir Cream, 1% contains penciclovir, an antiviral agent active against herpes viruses. Penciclovir Cream, 1% is available for topical administration as a 1% white cream. Each gram of Penciclovir Cream, 1% contains 10 mg of penciclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water and white petrolatum. Chemically, penciclovir is known as 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine. Its molecular formula is C 10 H 15 N 5 O 3 ; its molecular weight is 253.26. It is a synthetic acyclic guanine derivative and has the following structure: Figure 1: Structural Formula of Penciclovir penciclovir Penciclovir is a white to pale yellow solid. At 20°C it has a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water. In aqueous buffer (pH 2) the solubility is 10.0 mg/mL. Penciclovir is not hygroscopic. Its partition coefficient in n-octanol/water at pH 7.5 is 0.024 (logP = -1.62). A structure of penciclovir chemical formula

10 OVERDOSAGE Since penciclovir is poorly absorbed following oral administration, adverse reactions related to penciclovir ingestion are unlikely. There is no information on overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING Penciclovir Cream is supplied in a 5 gram tube containing 10 mg of penciclovir per gram in a homogenous cream base, which is equivalent to 1% (w/w). The white cream is available as follows: NDC 13668-661-10 carton containing one 5 gram tube Store at 20oC to 25oC (68oF to 77oF) excursions permitted between 15 o C and 30 o C (59 o F and 86 o F). [See USP Controlled Room Temperature].