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Denavir

Generic Name: Penciclovir
Class: Antivirals
VA Class: DE103
Molecular Formula: C10H15N5O3
CAS Number: 39809-25-1

Introduction

Antiviral; acyclic guanine nucleoside analog.1 2 5 11 14 25 27 28 29

Uses for Denavir

Herpes Labialis

Topical treatment of recurrent herpes labialis (orofacial or orolabial herpes, cold sores, fever blisters) in immunocompetent adults and children ≥12 years of age.1 2 6 7

Efficacy not established in immunocompromised patients.1 20

In HIV-infected individuals, oral antivirals (e.g., acyclovir, famciclovir, valacyclovir) usually recommended for treatment of orolabial lesions caused by herpes simplex virus (HSV).155 Topical treatment of herpes labialis generally less effective than oral treatment.22 23

Denavir Dosage and Administration

Administration

Topical Administration

Apply 1% cream topically to herpes labialis lesions on the lips and surrounding symptomatic skin on the face (e.g., areas with tingling).1

Do not apply in or near the eyes.1 Do not apply to mucous membranes.1 (See Administration Precautions under Cautions.)

Clean and dry face prior to application.1

Apply sufficient amount of cream to adequately cover all lesions on the lips and surrounding symptomatic skin on the face (e.g., areas with tingling);1 rub gently until cream disappears.1

Wash hands with soap and water prior to and after applying the cream.1

Dosage

Pediatric Patients

Herpes Labialis
Topical

Children ≥12 years of age: Apply 1% cream to affected areas every 2 hours while awake, for 4 days.1 Use amount sufficient to cover all lip lesions and surrounding symptomatic skin on the face (e.g., areas with tingling).1

Initiate at the earliest sign or symptom of herpes labialis (i.e., tingling, redness, itching, presence of a bump).1

If lesions worsen or do not improve, evaluate for secondary bacterial infection.1 Also consider possibility of resistance to penciclovir.1

Adults

Herpes Labialis
Topical

Apply 1% cream to affected areas every 2 hours while awake, for 4 days.1 Use amount sufficient to cover all lip lesions and surrounding symptomatic skin on the face (e.g., areas with tingling).1

Initiate at the earliest sign or symptom of herpes labialis (i.e., tingling, redness, itching, presence of a bump).1

If lesions worsen or do not improve, evaluate for secondary bacterial infection.1 Also consider possibility of resistance to penciclovir.1

Special Populations

No special population dosage recommendations.1

Cautions for Denavir

Contraindications

  • Hypersensitivity to penciclovir or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Induced mild erythema in about 50% of healthy individuals in vehicle-controlled dermal tolerance studies performed using repeated, occluded patch testing with 5% cream (fivefold higher concentration than commercially available cream);1 irritancy profile was similar to that of the vehicle control.1

No evidence that topical penciclovir causes sensitization.1

Postmarketing reports of local edema, pain, paresthesia, pruritus, skin discoloration, and urticaria.1

Administration Precautions

For topical use only on the lips and surrounding symptomatic skin on the face (e.g., areas with tingling).1

Do not apply in or near the eyes;1 irritation may occur.1

Do not apply to mucous membranes;1 data not available regarding use at these sites.1

Individuals with Altered Immunocompetence

Efficacy not established in immunocompromised patients.1

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether distributed into human milk after topical application.1 Penciclovir is distributed into milk in rats after oral administration of famciclovir (oral prodrug of penciclovir).1

Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1 Data not available regarding safety in neonates.1

Frequency of adverse reactions in children and adolescents 12–17 years of age is similar to that reported in adults.1

Geriatric Use

Adverse effects profile in adults ≥65 years of age is similar to that in younger adults.1

Common Adverse Effects

Application site reactions (localized irritation, hypesthesia/local anesthesia).1 2

Interactions for Denavir

No formal drug interaction studies;1 clinically important interactions unlikely since systemic absorption is minimal after topical application of penciclovir 1% cream to skin.1

Denavir Pharmacokinetics

Absorption

Bioavailability

Not appreciably absorbed into systemic circulation after topical application to skin.1 5

Not detected in plasma or urine of healthy adults after single or repeated application of 1% penciclovir cream at a dosage of 180 mg daily (about 67 times the estimated usual topical dosage).1 5 Systemic absorption not evaluated in children and adolescents <18 years of age.1

In vitro study using cadaver skin indicates that penciclovir penetrates the skin after topical application of 1% cream;24 approximately 3% of the topical dose is found in the stratum corneum and epidermis layers.24

Elimination

Metabolism

Converted in vivo to penciclovir triphosphate, the pharmacologically active metabolite.1 5 11 14 25 27 Intracellular conversion to the triphosphate is necessary for antiviral activity.1 5 11 14 25 27

Half-life

Intracellular half-life of active triphosphate metabolite is 10 or 20 hours in HSV types 1 or 2 (HSV-1 or HSV-2), respectively;1 clinical importance unknown.1

Stability

Storage

Topical

Cream

20°–25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Nucleoside analog antiviral;1 2 5 11 14 25 27 28 29 structurally and pharmacologically related to acyclovir.5 11 14 27 28 29

  • Converted in vivo to a pharmacologically active triphosphate metabolite.1 5 11 14 25 27

  • Active against various Herpesviridae,1 5 9 11 14 25 27 28 29 including HSV-1 and HSV-21 5 14 25 27 and varicella-zoster virus (VZV).5 10 13 Also has some in vitro activity against Epstein-Barr virus (EBV),5 9 10 11 but only limited activity in vitro against cytomegalovirus (CMV).5 11

  • Exerts antiviral effects on HSV and VZV by interfering with DNA synthesis and inhibiting viral replication.1 9 Acts as a viral DNA polymerase inhibitor and stops replication of viral DNA by competing with deoxyguanosine triphosphate for viral DNA polymerase and inhibiting viral DNA chain elongation.1 27

  • Mechanism of action is similar to that of acyclovir.27 28 Although penciclovir has higher affinity for HSV thymidine kinase than acyclovir and penciclovir triphosphate is more stable than acyclovir triphosphate in HSV-infected cells, HSV DNA polymerases have higher affinity for acyclovir triphosphate than for penciclovir triphosphate;27 net effect is that these nucleoside analogs have similar antiviral potencies.27

  • Intermittent topical use of penciclovir does not appear to be associated with emergence of resistance to the drug.25 26 27 However, HSV resistant to penciclovir have been produced in vitro and penciclovir-resistant clinical isolates have been reported rarely.1 25 26 27

  • HSV clinical isolates resistant to acyclovir because of deficiency in viral thymidine kinase (i.e., thymidine kinase-negative mutants) generally are cross-resistant to penciclovir.1 5 8 14 15 27 28 Some viral thymidine kinase- or DNA polymerase-altered strains resistant to acyclovir have been susceptible to penciclovir in vitro.5 8 11 13 14 27

Advice to Patients

  • Importance of using penciclovir cream only for treatment of recurrent herpes labialis (orofacial or orolabial herpes, cold sores, fever blisters) on the lips and surrounding symptomatic skin on the face (e.g., areas with tingling).1

  • Importance of avoiding application in or near the eyes.1

  • Advise patients that the cream is not a cure for cold sores and that not all patients respond to treatment with the cream.1

  • Importance of starting treatment at the earliest sign of a cold sore (i.e., tingling, redness, itching, bump).1

  • Advise patients to ensure that their face is clean and dry prior to application of the cream and to wash their hands with soap and water prior to and after application.1

  • Advise patients not to use the cream if they have had an allergic reaction to the drug or any ingredient in the formulation.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Penciclovir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Cream

1%

Denavir

Prestium

AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions February 23, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Prestium Pharma, Inc. Denavir (penciclovir) topical cream 1% prescribing information. Newtown, PA; 2013 Sep.

2. Spruance SL, Rea TL, Thoming C et al. Penciclovir cream for the treatment of herpes simplex labialis. JAMA. 1997; 277:1374-79. [IDIS 384117] [PubMed 9134943]

5. Alrabiah FA, Sacks SL. New antiherpesvirus agents. Drugs. 1996; 52:17-32. [PubMed 8799682]

6. Lin L, Chen XS, Cui PG et al. Topical application of penciclovir cream for the treatment of herpes simplex facialis/labialis: a randomized, double-blind, multicentre, aciclovir-controlled trial. J Dermatolog Treat. 2002; 13:67-72. [PubMed 12060504]

7. Raborn GW, Martel AY, Lassonde M et al. Effective treatment of herpes simplex labialis with penciclovir cream: combined results of two trials. J Am Dent Assoc. 2002; 133:303-9. [PubMed 11934185]

8. Boyd MR, Safrin S, Kern ER. Penciclovir: a review of its spectrum of activity, selectivity and cross-resistance patterns. Antiviral Chem Chemother. 1993; 4(Suppl 1): 3-11.

9. Bacon TH, Boyd MR. Activity of penciclovir against Epstein-Barr virus. Antimicrob Agents Chemother. 1995; 39:1599-1602. [IDIS 350501] [PubMed 7492112]

10. Gnann JW Jr. New antivirals with activity against varicella-zoster virus. Ann Neurol. 1994; 34:S69-72.

11. Kulikowski T. Structure-activity relationships and conformational features of antiherpetic pyrimidine and purine nucleoside analogues: a review. Pharm World Sci. 1994; 16:127-138. [IDIS 331981] [PubMed 8032338]

13. Hasegawa T, Kurokawa M, Yukawa TA et al. Inhibitory action of acyclovir (ACV) and penciclovir (PCV) on plaque formation and partial cross-resistance of ACV-resistant varicella-zoster virus to PCV. Antiviral Res. 1995; 27:271-9. [PubMed 8540749]

14. Safrin S, Phan L. In vitro activity of penciclovir against clinical isolates of acyclovir-resistant and foscarnet-resistant herpes simplex virus. Antimicrob Agents Chemother. 1993; 37:2241-3. [IDIS 320621] [PubMed 8257152]

15. Talarico CL, Phelps WC, Biron KK. Analysis of the thymidine kinase genes from acyclovir-resistant mutants of varicella-zoster virus isolated from patients with AIDS. J Virol. 1993; 67:1024-33. [PubMed 8380452]

20. FDA summary basis of approval.

22. Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007; 57:737-63; quiz 764-6. [PubMed 17939933]

23. Usatine RP, Tinitigan R. Nongenital herpes simplex virus. Am Fam Physician. 2010; 82:1075-82. [PubMed 21121552]

24. Hasler-Nguyen N, Shelton D, Ponard G et al. Evaluation of the in vitro skin permeation of antiviral drugs from penciclovir 1% cream and acyclovir 5% cream used to treat herpes simplex virus infection. BMC Dermatol. 2009; 9:3. [PubMed 19341466]

25. Sarisky RT, Bacon T, Boon R et al. Penciclovir susceptibilities of herpes simplex virus isolates from patients using penciclovir cream for treatment of recurrent herpes labialis. Antimicrob Agents Chemother. 2002; 46:2848-53. [PubMed 12183237]

26. Shin YK, Weinberg A, Spruance S et al. Susceptibility of herpes simplex virus isolates to nucleoside analogues and the proportion of nucleoside-resistant variants after repeated topical application of penciclovir to recurrent herpes labialis. J Infect Dis. 2003; 187:1241-5. [PubMed 12696003]

27. Bacon TH, Levin MJ, Leary JJ et al. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev. 2003; 16:114-28. [PubMed 12525428]

28. Piret J, Boivin G. Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management. Antimicrob Agents Chemother. 2011; 55:459-72. [PubMed 21078929]

29. De Clercq E, Field HJ. Antiviral prodrugs - the development of successful prodrug strategies for antiviral chemotherapy. Br J Pharmacol. 2006; 147:1-11. [PubMed 16284630]

155. Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (September 17, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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