Management of Cold Sores by Prescription

Introduction

Recurrent herpes labialis (RHL), or the recurrent expression of herpes simplex virus type 1 (HSV-1), is a commonly occurring viral infection of the mouth and perioral soft tissues. Commonly known as "cold sores" or "fever blisters," RHL typically manifests through reactivation of initial exposure to HSV-1, often triggered by stimuli such as sunlight, stress, menses, or trauma to the affected area.¹ The seroprevalence of HSV-1 in the United States has been estimated at 57.7% in those aged 14 to 49 years, and RHL has been found to affect 32.9% of the population.^2,3

Viral Origin and Pathology of the Cold Sore

The most common form of HSV-1 infection is primary gingivostomatitis; however, only about 1% of those exposed to HSV-1 develop clinical symptoms of primary gingivostomatitis.⁴ The infection may be subclinical in nature, and symptoms may be overlooked.⁴ Primary infection usually occurs in preschool or kindergarten-aged children, adolescents, and young adults, then re-expresses as cold sores throughout adulthood.⁵ Viral shedding is greatest during the primary infection, though the quantity of viral shedding appears to have no correlation to the severity of the attack.⁶ Patients experiencing primary infection may present with fever, malaise, loss of appetite, or multiple intraoral vesicles that burst, leaving painful ulceration. Because of the pain associated with swallowing, children especially may become dehydrated.⁵ Recurrences are typically less severe than the primary infection.⁵

After ascending the dorsal root ganglion during primary infection, the virus lies dormant in the form of chronic latent infection in trigeminal, facial, vagal, and other various ganglia. Evidence suggests that latent infection also develops in epithelial lip tissue.^5,7 Upon reactivation, many patients experience a prodrome such as itching, burning, or tingling at the location where a lesion will appear.⁵ RHL can recur frequently or infrequently.⁸ Depending on the frequency and severity of outbreaks, recommended therapy can be classified as either episodic or suppressive, and while there are no specific guidelines that specify when to initiate suppressive therapy, suppressive therapy may be considered when a patient has 6 or more RHL episodes a year.¹ Currently, topical agents are not indicated for use as suppressive therapy.

Nonprescription Treatments for RHL

Although not an antiviral like prescription treatments, OTC products occupy a significant place in therapy. The only FDA-approved OTC drug to treat RHL is docosanol (Abreva). Evidence suggests that docosanol interferes with early intracellular events, rendering target cells less susceptible to viral fusion or entry.⁹ Docosanol is not considered to be a true antiviral agent because it does not work by inhibiting viral replication.¹⁰

Other OTC palliative topical therapies often contain analgesics or anesthetics such as camphor, benzyl alcohol, pramoxine, phenol, menthol, tetracaine, or benzocaine. Protectants such as white petrolatum, allantoin, calamine, zinc oxide, and cocoa butter relieve dryness and cracking. Patients should be counseled against the use of products containing salicylic acid because it can erode compromised skin.¹¹

Topical Prescription Treatments for RHL

Acyclovir 5% Cream (ZOVIRAX)

An FDA-approved antiviral, acyclovir cream has demonstrated reduced lesion healing time and duration of pain.¹

Spruance et al conducted 2 identical, independent, randomized, double-blind, vehicle-controlled, multicenter studies in 686 and 699 adult patients with RHL (studies 1 and 2, respectively) comparing acyclovir 5% cream with vehicle control. Patients were told to self-initiate treatment and apply cream 5 times daily for 4 days beginning within 1 hour of onset of the recurrent episode. The mean episode duration was 4.3 days versus 4.8 days for those treated with acyclovir cream versus vehicle control (study 1) and 4.6 days versus 5.2 days (study 2), both differences reaching statistical significance (P = .007 and P = .006, respectively).Whether initiated early or late, therapeutic efficacy was apparent, and there was also a significant reduction in duration of lesion pain in both studies.¹²

Penciclovir 1% Cream (Denavir)

This FDA-approved topical antiviral has also shown that it can reduce healing time and pain duration when compared with placebo.^1,13,14 When compared with topical acyclovir in a randomized trial (n = 124 in each group), topical penciclovir showed no significant difference in cure rate, resolution time, or side effects.¹⁵

Acyclovir 5% Plus Hydrocortisone 1% Cream (XERESE)

The FDA approved this antiviral/corticosteroid combination in August 2009 based on a double-blind, randomized study looking at early treatment with acyclovir plus hydrocortisone (initiated at the first sign of a cold sore). This study was a multicenter study of 1443 patients who suffered at least 3 cold sore episodes in the past year. In this study, acyclovir plus hydrocortisone prevented the development of ulcerative cold sores in 42% of patients (254 of 601) who were treated (primary end point).¹⁶ In the same study, early treatment with acyclovir plus hydrocortisone reduced healing time by 1.4 days and reduced cumulative lesion area by approximately 50% compared with placebo (secondary end points).¹⁶ The overall frequency of adverse events was similar across treatment groups. The most common adverse events considered to be related to topical treatment were dry lips, chapped lips, and application site dryness/irritation.¹⁶

Role of the Pharmacist

With the widespread availability of OTC products, and a general lack of awareness about the pathophysiology of cold sores, many patients may not realize there is an opportunity to treat cold sores with antiviral agents. Pharmacists are in a unique position to counsel patients regarding treatment options for patients with cold sores, and can help optimize outcomes by bridging both nonprescription and prescription options and advising appropriate patients to speak to a physician in a timely manner. After all, the best outcomes for cold sore treatment are achieved when drug administration is started immediately at the first sign of prodromal symptoms.¹

About XERESE

XERESE is the first and currently the only available product that combines an antiviral (acyclovir) with an anti-inflammatory (hydrocortisone). XERESE (acyclovir and hydrocortisone) Cream 5%/1% for topical use is indicated for the early treatment of RHL to reduce the likelihood of ulcerative cold sores and shorten the lesion time in adults and adolescents 12 years of age and older.¹⁷ XERESE is the only product with data demonstrating the prevention of progression of a cold sore to ulceration. The safety and efficacy of XERESE were demonstrated in a double-blind, randomized study in 1443 adult patients. Comparable safety and efficacy was observed in 134 adolescent patients enrolled in an open-label study.¹⁷ In a double-blind randomized study, early treatment with XERESE prevented the development of ulcerative cold sores in 42% of patients (254 of 601).¹⁶ XERESE is applied 5 times per day for 5 days. There are no contraindications to XERESE.¹⁷

XERESE Indication and Important Safety Information

XERESE (acyclovir and hydrocortisone) Cream 5%/1% is indicated for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and adolescents (12 years of age and older).

XERESE Cream is intended for cutaneous use only, on the lips and around the mouth. XERESE should not be used in the eye, inside the mouth or nose, or on the genitals. Patients should be encouraged to seek medical advice when a cold sore fails to heal within 2 weeks. The effect of XERESE Cream has not been sufficiently established in immunocompromised patients. XERESE Cream has a potential for irritation and contact sensitization. In clinical trials, the most common adverse reactions in the area of the application site included drying or flaking of the skin; burning or tingling following application; erythema; pigmentation changes; and application site reaction including signs and symptoms of inflammation. Each event occurred in less than 1% of patients.

ZOVIRAX Indication and Important Safety Information

ZOVIRAX Cream 5% is indicated for the treatment of recurrent herpes labialis (cold sores) in adults and adolescents (12 years of age and older).

ZOVIRAX Cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir, or any component of the formulation. ZOVIRAX Cream is intended for cutaneous use only and should not be used in the eye or inside the mouth or nose. ZOVIRAX Cream does not prevent transmission of HSV infections, and its effect has not been established in immunocompromised patients. ZOVIRAX Cream has a potential for irritation and contact sensitization. In clinical trials, the most common adverse reactions at the site of topical application included dry lips, desquamation, dryness of skin, cracked lips, burning skin, pruritus, flakiness of skin, and stinging on skin. Each event occurred in less than 1% of patients.

Click here to see Full Prescribing Information for XERESE Cream.

Click here to see Full Prescribing Information for ZOVIRAX Cream.

References

• St Pierre SA, Bartlett BL, Schlosser BJ. Practical management measures for patients with recurrent herpes labialis. Skin Therapy Lett. 2009;14:1-3.
• Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964-973.
• Young TB, Rimm EB, D’Alessio DJ. Cross-sectional study of recurrent herpes labialis: prevalence and risk factors. Am J Epidemiol. 1988;127(3):612-625.
• Siegel MA. Diagnosis and management of recurrent herpes simplex infections. J Am Dent Assoc. 2002;133:1245-1249.
• Raborn GW, Grace MG. Recurrent herpes simplex labialis: selected therapeutic options. J Can Dent Assoc. 2003;69:498-503.
• Spruance SL, Overall JC, Kern ER, et al. The natural history of recurrent herpes simplex labialis. N Engl J Med. 1977;297:69-75.
• Hill TJ, Blyth WA. An alternative theory of herpes-simplex recurrence and a possible role for prostaglandins. Lancet. 1976;7956(1):397-399.
• Ship II, Morris AL, Durocher RT, Burkett LW. Recurrent aphthous ulcerations and recurrent herpes labialis in a professional school student population. Oral Surg Oral Med Oral Pathol. 1960;13:1191-1202.
• Katz DH, Marcelletti JF, Khalil MH, Pope LE, Katz LR. Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex. Proc Natl Acad Sci U S A. 1991;88:10825-10829.
• GlaxoSmithKline. Abreva FAQs. Abreva website. www.abreva.com/FAQ.aspx. Accessed January 23, 2012.
• Pray WS. Preventing and treating cold sores. US Pharm. 2007;32:16-23.
• Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother. 2002;46:2238-2243.
• Spruance SL, Rea TL, Thoming C, et al; Topical Penciclovir Collaborative Study Group. Penciclovir cream for the treatment of herpes simplex labialis: a randomized, multicenter, double-blind, placebo-controlled trial. JAMA. 1977;277(17):1374-1379.
• Boon R, Goodman JJ, Martinez J, et al; Penciclovir Cream Herpes Labialis Study Group. Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial. Clin Ther. 2000;22(1):76-90.
• 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(2):67-72.
• Hull CM, Harmenberg J, Arlander E, et al; ME-609 Study Group. Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial. J Am Acad Dermatol. 2011;64(4):696.e1-696.e11.
• Xerese [prescribing information]. Mississauga, Ontario, Canada: Meda Pharmaceuticals Inc; 2010.