Penciclovir (Topical)

VA CLASSIFICATION
Primary: DE103

Commonly used brand name(s): Denavir.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (topical)^{02}—

Indications

General considerations
Penciclovir is an antiviral agent used to treat infections caused by herpes viruses ^{02}. Penciclovir has in vitro inhibitory activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) ^{02}.

Accepted

Herpes labialis (treatment)—Topical penciclovir is indicated in the treatment of recurrent herpes labialis (cold sores) in adults. ^{{01} {02}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    9-[4-hydroxy-3-(hydroxymethyl) butyl]guanine. ^{{01} {02}}
Molecular weight—
    253.26 ^{{01} {02}}

Solubility
    At 20 °C 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 mg/mL. ^{{01} {02}}

Partition coefficient
    In n-octanol/water at pH 7.5 penciclovir has a partition coefficient of 0.024 (logP = -1.62). ^{{01} {02}}

Mechanism of action/Effect:

Penciclovir is phosphorylated by the enzyme thymidine kinase to a monophosphate form ^{02}. The monophosphate is converted to penciclovir triphosphate by cellular phosphokinases ^{02}. Studies show that penciclovir triphosphate inhibits herpes simplex virus polymerase competitively with deoxyguanosine triphosphate ^{02}. This effect selectively inhibits herpes viral DNA synthesis and replication. ^{{01} {02}}

Absorption:

Measurable concentrations of penciclovir have not been detected in plasma or urine following daily topical application in healthy male volunteers ^{02}. Male volunteers were given doses approximately 67 times the estimated recommended clinical dose. ^{{01} {02}}

Systemic absorption of penciclovir following topical administration has not been studied in patients younger than 18 years of age ^{02}.


Precautions to Consider

Carcinogenicity

A 2-year study in mice and rats given famciclovir (the oral prodrug of penciclovir) in doses of 600 mg per kg of body weight (mg/kg) per day showed an increased incidence of mammary adenocarcinoma in female rats ^{02}. This dose is approximately 395 times the maximum theoretical human exposure to penciclovir following application of the topical product, based on 24-hour area under the plasma concentration–time curve (AUC) comparisons. ^{{01} {02}}

A 2-year study in mice and rats given famciclovir in doses of up to 240 mg/kg per day found no increase of tumor incidence among male rats or in male and female mice at doses of up to 600 mg/kg per day ^{02}. These doses are approximately 190 times and 100 times, respectively, the maximum theoretical human AUC for penciclovir. ^{{01} {02}}

Mutagenicity

In vitro studies found that penciclovir did not cause an increase in gene mutation in the Ames test or in unscheduled DNA repair in mammalian HeLaS3 cells ^{02}. An increase in clastogenic response was seen with penciclovir in the mouse lymphoma cell assay and in human lymphocytes. ^{{01} {02}}

In vivo studies showed an increase in micronuclei in mouse bone marrow following intravenous administration of penciclovir at doses greater than or equal to 500 mg/kg, which is approximately 810 times the maximum recommended human dose. ^{{01} {02}}

Pregnancy/Reproduction
Fertility—
Adequate and well controlled studies on the effects of topical penciclovir have not been done in humans. Intravenous administration of penciclovir at doses of 160 mg/kg per day and 100 mg/kg per day resulted in testicular toxicity in rats and dogs. ^{{01} {02}}

Pregnancy—
Adequate and well-controlled studies have not been done in humans ^{02}.

Studies done in rats and rabbits given intravenous doses of 80 mg/kg per day and 60 mg/kg per day, respectively, have shown no adverse effect on the course and outcome of pregnancy or on fetal development ^{02}. The body surface area doses were 260 and 355 times, respectively, the maximum recommended human dose following topical application of penciclovir cream. ^{{01} {02}}

FDA Pregnancy Category B. ^{{01} {02}}

Breast-feeding

It is not known whether penciclovir is distributed into breast milk after topical application ^{02}.

However, penciclovir was distributed into the milk of lactating rats at concentrations higher than those seen in plasma following oral administration of famciclovir (the oral prodrug of penciclovir). ^{{01} {02}}

Pediatrics

No information is available on the relationship of age to the effects of penciclovir in pediatric patients. Safety and efficacy have not been established. ^{{01} {02}}


Geriatrics


In patients 65 years of age and older, the adverse events profile was comparable to that observed in younger patients. ^{{01} {02}}

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following problem exists:
» Immune deficiency conditions in patients who are immunocompromised^{02}    (the effect of penciclovir has not been established ^{01})


Risk-benefit should be considered when the following medical problem exists
Sensitivity to penciclovir or other components of the formulation^{01}{02}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Application site reaction ^{01}{02}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache ^{01}{02}—incidence 5.3%

Incidence less frequent
^{01}    
Hypoesthesia ^{01}{02}(abnormally decreased sensitivity, particularly to touch)
    
skin rash, erythematous ^{01}{02}(redness of the skin)
    
taste perversion (change in sense of taste)^{01}{02}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

There is no information on overdose ^{02}. Penciclovir is poorly absorbed following oral administration ^{02}. Adverse reactions related to penciclovir ingestion are unlikely. ^{{01} {02}}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Penciclovir (Topical) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to penciclovir or other components of the formulation ^{{01} {02}}
Other medical problems, especially immune deficiency conditions ^{{01} {02}}

Proper use of this medication
» Using only on herpes labialis on the lips and face ^{{01} {02}}

» Beginning as early as possible at the first signs of symptoms (during the prodrome stage or when lesion appears) ^{{01} {02}}

» Avoiding application in or near the eyes ^{{01} {02}}

» Avoiding application to mucous membranes ^{02} or within oral cavity ^{01}

» Proper dosing ^{01}
Missed dose: Applying as soon as possible; not applying if almost time for next dose

» Proper storage ^{01}


Side/adverse effects
Signs of potential side effects, especially application site reaction


General Dosing Information
Penciclovir cream is for external use only ^{02}. Contact with eyes and mucous membranes should be avoided. ^{{01} {02}}

The effect of penciclovir has not been established in immunocompromised patients. ^{{01} {02}}


Topical Dosage Forms

PENCICLOVIR CREAM

Usual adult dose
Antiviral
Topical, to cold sores every two hours during waking hours for four days. ^{{01} {02}}


Usual pediatric dose
Safety and efficacy have not been established. ^{{01} {02}}

Usual geriatric dose
See Usual adult dose . ^{01}

Strength(s) usually available
U.S.—


1% (10 mg per gram) (Rx) [Denavir (cetomacrogol 1000 BP) (cetostearyl alcohol) (mineral oil) (propylene glycol) (purified water) (white petrolatum)]^{01}{02}

Packaging and storage:
Store at or below 30 °C (86 °F) ^{02}. Protect from freezing. ^{{01} {02}}

Auxiliary labeling:
   • For external use only ^{02}.
   • Do not use in eyes ^{02}.
   • Continue medicine for full time of treatment.

Developed: 11/12/1997
Revised: 08/12/1998

References

1. Denavir package insert (SmithKline Beecham—US), New 10/96, Rec 12/96.
   

2. Denavir package insert (SmithKline Beecham—US), Rev 9/97, Rec 7/98.