Docosanol: OTC treatment for herpes labialis

Antiviral agents prevent viral replication through their competitive inhibition of viral DNA polymerase. In contrast, docosanol appears to inhibit replication by blocking viral entry into cells.

Herpes labialis affects 1 in 5 Americans each year and accounts for the largest reservoir of herpes simplex virus (HSV) infections. The frequency of recurrence of herpes labialis has been estimated to be approximately 33%. In the United States, penciclovir (Denavir, Novartis) is the only FDA-approved topical treatment option. Topical acyclovir is also used, but is not FDA approved. Abreva (docosanol 10% cream, GlaxoSmithKline) is an over-the-counter (OTC) alternative to these agents. It is currently the only FDA approved nonprescription medication available for the treatment of cold sores.

Mechanism of action

Antiviral agents such as acyclovir and penciclovir prevent viral replication through their competitive inhibition of viral DNA polymerase. In contrast, docosanol appears to inhibit replication by blocking viral entry into cells. Incorporation of docosanol into the plasma membrane is believed to alter the normal membrane to inhibit the fusion of virons to the host cell. Unlike the nucleoside analogue agents, acyclovir and penciclovir, docosanol does not block replication shared by the virus and the infected target cell. This may possibly prevent the induction of drug-resistant viral mutant strains that can possible occur with the use of nucleoside analogues

Cost of Topical HSV Drugs  

The following costs are 2001 average wholesale pricing.

 

(docosanol 10%) cream, 2 g

$14.99

 

(penciclovir 1%) cream, 1.5 g

$25.41

 

(acyclovir 5%) ointment, 3 g

$21.31

 
Source: Jessica Kill, PharmD  

Docosanol is a 22-carbon saturated fatty alcohol. In vitro data have indicated that the inhibitory effect of docosanol against HSV-1 has a half-life of approximately 3 hours. In the same study, antiviral activity was increased in target cells incubated with docosanol prior to the addition of HSV-1. HSV-1 induced plaque formation was inhibited by 28% in cells where docosanol was added simultaneously with, or 3 hours prior to the virus. The percentage of inhibition increased to approximately 42% when docosanol was added 15 hours prior to HSV-1, and to 68% when added 24 hours prior to the virus.

The onset of action in the treatment of herpes labialis is 2.5-3.5 days. The amount of systemic exposure that would occur with the use of docosanol during the treatment of a recurrent episode has been estimated to be 0.4 mg/kg/day.

Clinical Trials

The efficacy of docosanol has been tested in a randomized, double-blind, parallel group, placebo-controlled study. Sixty-three patients aged 17-60 years with recurrent herpes labialis were enrolled in this study. Recurrent herpes was defined as at least 3 episodes annually. A total of 98 herpes episodes were treated, 48 with docosanol 10% cream and 50 with placebo. Patients were instructed to begin using the cream at the first sign or symptom of infection. The stage of the disease was assessed as prodrome, erythrema, papule, vesicle, ulcer, scab, healing, healed. The cream was applied five times daily until the lesion healed and could not exceed a maximum of 10 days. Onset of treatment was defined as “early” if it coincided with the prodromal or erythema stage, and “late” if it had been initiated at the papule stage or later. The overall mean healing time of all episodes was reduced by 1.6 days in the docosanol group (5.7 days) as compared with placebo (7.3 days) (P=0.02). A total of 20 episodes were classified as “early” treatment. Mean healing time in this subgroup was reduced by 3.3 days (P=0.05). No statistical difference was found between docosanol and placebo in those episodes defined as “late” treatment.

A recent placebo-controlled study compared the efficacy of docosanol cream, penciclovir cream of acyclovir ointment for the treatment herpes labialis using the dorsal cutaneous guinea pig model. The backs of guinea pigs were infected with HSV-1 in four different areas. Treatments were initiated 24 hours after inoculation with the virus and compared with corresponding vehicle controls. The maximum tolerated frequency of application of docosanol cream was 3 times daily. The corresponding vehicle control provided by the manufacturer contained stearic acid to help maintain the appearance of the active treatment. This formulation was highly irritating and could only be applied once daily. Therefore, in the first experiment, 10% docosanol cream applied 3 times daily was compared with untreated infection sites. Acyclovir applied 4 times daily per day for a total of 3 days was compared with an ointment vehicle control.

Efficacy measures included the number of lesions, total lesion area, and the lesion virus titer. Acyclovir exhibited significant reductions in all parameters, 5% (P=0.008), 22% (P=0.004), and 12% (P=0.002) respectively. An 8% reduction in total lesion area was seen with docosanol, which approached statistical significance (P=0.07). Nonsignificant reductions in number of lesions and total virus titer were seen. A second experiment compared 12% n-docosanol cream with 12% stearic acid control. Treatment was applied 3 times daily for 5 days and efficacy parameters were assessed on days four, five and six. Acyclovir exhibited a significant reduction in the mean lesion area of 28%. This was the only significant result seen. No statistically significant benefit was seen with docosanol.

The animal model used to evaluate the efficacy of docosanol was designed primarily to test compounds that exhibit antiviral activity. The authors of the study acknowledge that docosanol may have beneficial effects through other mechanisms. Since docosanol is not classified as an antiviral, its efficacy may not be fairly assessed in this model. The dosage frequencies used were not the same as the recommended doses used in humans. In addition, animal models may not match what is seen in human disease. Unfortunately, the large patient populations needed to compare relative efficacies of available treatments and the associated cost may prevent larger trials from being conducted.

Safety

Since systemic absorption is very limited, the majority of adverse events associated with docosanol are local. Dermatologic reactions may include application site reaction, rash, pruitis and dry skin. Burning and stinging upon application of the cream have also been reported. Headache was the most common adverse event experienced in clinical trials. The frequency of headache did not differ between placebo and active treatment group. The FDA has classified docosanol as pregnancy category B.

Dosage and administration

Docosanol is approved for use in adults and children older than 12 years. For best results, it is recommended to start use of docosanol at the prodrome of a recurrent herpes labialis episode, when a tingle, redness, itch or a bump is detected. Use should be restricted to herpes simplex on the face and lips. Ocular administration of docosanol is not recommended. Docosanol should be used five times daily until the cold sore is healed.

Docosanol is the first FDA-approved OTC alternative for the treatment of herpes labialis. OTC availability has several potential advantages to prescription only products. These include increased patient accessibility, which allows more rapid initiation of treatment. Early administration of therapy is recommended for all treatments to increase treatment success. Although animal data have indicated docosanol may be less effective than comparable prescription options, human data supports that docosanol reduces lesion healing time. Docosanol is more affordable than other topical options for the recurrence of herpes labialis, and it’s unique mechanism of action may prevent the induction of drug-resistant viral mutant strains.

For more information:
  • Vaner Straten M, Carrasco D, Lee P, Tyring S. A review of antiviral therapy for herpes labialis. Arch Dermatol. 2001;137:1232-35.
  • Pope, et al. The anti-herpes simplex virus activity of n-docosanol includes inhibition of the viral entry process. Antiviral Research. 1998; 40:85-94.
  • Micromedex Healthcar Series. Docosanol: Drug Evaluation. Micromedex, Inc. 2001.
  • Habbema L, De Boule K, Roders G, Katz D. n-docosanol 10% cream in the treatment of recurrent herpes labialis. Acta Derm Venereol (Stockh). 1996;76:479-81.
  • McKeough M, Spruance S. Comparison of new topical treatments for herpes labialis. Arch Dermatol. 2001;137:1153-58.

Herpes labialis affects 1 in 5 Americans each year and accounts for the largest reservoir of herpes simplex virus (HSV) infections. The frequency of recurrence of herpes labialis has been estimated to be approximately 33%. In the United States, penciclovir (Denavir, Novartis) is the only FDA-approved topical treatment option. Topical acyclovir is also used, but is not FDA approved. Abreva (docosanol 10% cream, GlaxoSmithKline) is an over-the-counter (OTC) alternative to these agents. It is currently the only FDA approved nonprescription medication available for the treatment of cold sores.

Mechanism of action

Antiviral agents such as acyclovir and penciclovir prevent viral replication through their competitive inhibition of viral DNA polymerase. In contrast, docosanol appears to inhibit replication by blocking viral entry into cells. Incorporation of docosanol into the plasma membrane is believed to alter the normal membrane to inhibit the fusion of virons to the host cell. Unlike the nucleoside analogue agents, acyclovir and penciclovir, docosanol does not block replication shared by the virus and the infected target cell. This may possibly prevent the induction of drug-resistant viral mutant strains that can possible occur with the use of nucleoside analogues

Cost of Topical HSV Drugs  

The following costs are 2001 average wholesale pricing.

 

(docosanol 10%) cream, 2 g

$14.99

 

(penciclovir 1%) cream, 1.5 g

$25.41

 

(acyclovir 5%) ointment, 3 g

$21.31

 
Source: Jessica Kill, PharmD  

Docosanol is a 22-carbon saturated fatty alcohol. In vitro data have indicated that the inhibitory effect of docosanol against HSV-1 has a half-life of approximately 3 hours. In the same study, antiviral activity was increased in target cells incubated with docosanol prior to the addition of HSV-1. HSV-1 induced plaque formation was inhibited by 28% in cells where docosanol was added simultaneously with, or 3 hours prior to the virus. The percentage of inhibition increased to approximately 42% when docosanol was added 15 hours prior to HSV-1, and to 68% when added 24 hours prior to the virus.

The onset of action in the treatment of herpes labialis is 2.5-3.5 days. The amount of systemic exposure that would occur with the use of docosanol during the treatment of a recurrent episode has been estimated to be 0.4 mg/kg/day.

Clinical Trials

The efficacy of docosanol has been tested in a randomized, double-blind, parallel group, placebo-controlled study. Sixty-three patients aged 17-60 years with recurrent herpes labialis were enrolled in this study. Recurrent herpes was defined as at least 3 episodes annually. A total of 98 herpes episodes were treated, 48 with docosanol 10% cream and 50 with placebo. Patients were instructed to begin using the cream at the first sign or symptom of infection. The stage of the disease was assessed as prodrome, erythrema, papule, vesicle, ulcer, scab, healing, healed. The cream was applied five times daily until the lesion healed and could not exceed a maximum of 10 days. Onset of treatment was defined as “early” if it coincided with the prodromal or erythema stage, and “late” if it had been initiated at the papule stage or later. The overall mean healing time of all episodes was reduced by 1.6 days in the docosanol group (5.7 days) as compared with placebo (7.3 days) (P=0.02). A total of 20 episodes were classified as “early” treatment. Mean healing time in this subgroup was reduced by 3.3 days (P=0.05). No statistical difference was found between docosanol and placebo in those episodes defined as “late” treatment.

A recent placebo-controlled study compared the efficacy of docosanol cream, penciclovir cream of acyclovir ointment for the treatment herpes labialis using the dorsal cutaneous guinea pig model. The backs of guinea pigs were infected with HSV-1 in four different areas. Treatments were initiated 24 hours after inoculation with the virus and compared with corresponding vehicle controls. The maximum tolerated frequency of application of docosanol cream was 3 times daily. The corresponding vehicle control provided by the manufacturer contained stearic acid to help maintain the appearance of the active treatment. This formulation was highly irritating and could only be applied once daily. Therefore, in the first experiment, 10% docosanol cream applied 3 times daily was compared with untreated infection sites. Acyclovir applied 4 times daily per day for a total of 3 days was compared with an ointment vehicle control.

Efficacy measures included the number of lesions, total lesion area, and the lesion virus titer. Acyclovir exhibited significant reductions in all parameters, 5% (P=0.008), 22% (P=0.004), and 12% (P=0.002) respectively. An 8% reduction in total lesion area was seen with docosanol, which approached statistical significance (P=0.07). Nonsignificant reductions in number of lesions and total virus titer were seen. A second experiment compared 12% n-docosanol cream with 12% stearic acid control. Treatment was applied 3 times daily for 5 days and efficacy parameters were assessed on days four, five and six. Acyclovir exhibited a significant reduction in the mean lesion area of 28%. This was the only significant result seen. No statistically significant benefit was seen with docosanol.

The animal model used to evaluate the efficacy of docosanol was designed primarily to test compounds that exhibit antiviral activity. The authors of the study acknowledge that docosanol may have beneficial effects through other mechanisms. Since docosanol is not classified as an antiviral, its efficacy may not be fairly assessed in this model. The dosage frequencies used were not the same as the recommended doses used in humans. In addition, animal models may not match what is seen in human disease. Unfortunately, the large patient populations needed to compare relative efficacies of available treatments and the associated cost may prevent larger trials from being conducted.

Safety

Since systemic absorption is very limited, the majority of adverse events associated with docosanol are local. Dermatologic reactions may include application site reaction, rash, pruitis and dry skin. Burning and stinging upon application of the cream have also been reported. Headache was the most common adverse event experienced in clinical trials. The frequency of headache did not differ between placebo and active treatment group. The FDA has classified docosanol as pregnancy category B.

Dosage and administration

Docosanol is approved for use in adults and children older than 12 years. For best results, it is recommended to start use of docosanol at the prodrome of a recurrent herpes labialis episode, when a tingle, redness, itch or a bump is detected. Use should be restricted to herpes simplex on the face and lips. Ocular administration of docosanol is not recommended. Docosanol should be used five times daily until the cold sore is healed.

Docosanol is the first FDA-approved OTC alternative for the treatment of herpes labialis. OTC availability has several potential advantages to prescription only products. These include increased patient accessibility, which allows more rapid initiation of treatment. Early administration of therapy is recommended for all treatments to increase treatment success. Although animal data have indicated docosanol may be less effective than comparable prescription options, human data supports that docosanol reduces lesion healing time. Docosanol is more affordable than other topical options for the recurrence of herpes labialis, and it’s unique mechanism of action may prevent the induction of drug-resistant viral mutant strains.

For more information:
  • Vaner Straten M, Carrasco D, Lee P, Tyring S. A review of antiviral therapy for herpes labialis. Arch Dermatol. 2001;137:1232-35.
  • Pope, et al. The anti-herpes simplex virus activity of n-docosanol includes inhibition of the viral entry process. Antiviral Research. 1998; 40:85-94.
  • Micromedex Healthcar Series. Docosanol: Drug Evaluation. Micromedex, Inc. 2001.
  • Habbema L, De Boule K, Roders G, Katz D. n-docosanol 10% cream in the treatment of recurrent herpes labialis. Acta Derm Venereol (Stockh). 1996;76:479-81.
  • McKeough M, Spruance S. Comparison of new topical treatments for herpes labialis. Arch Dermatol. 2001;137:1153-58.