Denavir
DENAVIR- penciclovir cream
Mylan Pharmaceuticals Inc.
1 INDICATIONS AND USAGE
DENAVIR 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.
2 DOSAGE AND ADMINISTRATION
Apply DENAVIR 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).
3 DOSAGE FORMS AND STRENGTHS
DENAVIR 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).
4 CONTRAINDICATIONS
DENAVIR is contraindicated in patients with known hypersensitivity to the product or any of its components.
5 WARNINGS AND PRECAUTIONS
5.1 General
DENAVIR should only be used on herpes labialis on the lips and face. Because no data are available, application to human mucous membranes is not recommended. Particular care should be taken to avoid application in or near the eyes since it may cause irritation. Lesions that do not improve or that worsen on therapy should be evaluated for secondary bacterial infection. The effect of DENAVIR has not been established in immunocompromised patients.
6 ADVERSE REACTIONS
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 DENAVIR (penciclovir cream) and 1,541 with placebo. One or more local adverse reactions were reported by 3% of the patients treated with DENAVIR and 4% of placebo-treated patients. The rates of reported local adverse reactions are shown in Table 1.
| 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 DENAVIR. 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 DENAVIR 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 DENAVIR.
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 DENAVIR. Due to minimal systemic absorption of DENAVIR, systemic drug interactions are unlikely.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
DENAVIR 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
DENAVIR is not absorbed systemically by the mother following topical administration and breastfeeding is not expected to result in exposure of the child to DENAVIR.
8.4 Pediatric Use
An open-label, uncontrolled trial with penciclovir cream 1% was conducted in 102 subjects, ages 12-17 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.
10 OVERDOSAGE
Since penciclovir is poorly absorbed following oral administration, adverse reactions related to penciclovir ingestion are unlikely. There is no information on overdose.
11 DESCRIPTION
DENAVIR (penciclovir) cream 1% contains penciclovir, an antiviral agent active against herpes viruses. DENAVIR is available for topical administration as a 1% white cream. Each gram of DENAVIR 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 C10 H15 N5 O3 ; 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 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).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Penciclovir is an antiviral agent active against alpha herpes viruses [see Microbiology (12.4)].
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