OTC Antiviral Agents For Herpes Cold Sores Disfavored By FDA

The future of potential OTC antiviral treatments for herpes labialis, including Avanir Pharmaceuticals' docosanol 10% cream, is questionable in light of FDA's announcement that it disfavors use of such antiviral drugs in a nonprescription setting.

In a draft guidance published in the Federal Register March 8, the agency cites concerns related to OTC antiviral drug misuse and resulting herpesvirus resistance in concluding "at present, based on a public health-based risk/benefit assessment...antiherpes agents should not be made available OTC."

In response, Avanir, which has a pending new drug application for the antiviral docosanol 10% cream as an OTC cold sore treatment, maintained its product does not fall within the group of antiviral drugs FDA disfavors and has a different mode of action making emergence of drug resistant strains unlikely. The firm expects agency action on the NDA by June 3.

FDA notes antiviral agents currently effective in treating all types of herpes infections are members of a single drug class - the acyclic guanosine analogue class. Rx drugs within this class include acyclovir (Glaxo Wellcome's Zovirax) and penciclovir (SmithKline Beecham's Denavir).

"The emergence of herpesvirus (HSV) isolates that are resistant to each of the marketed acyclic guanosine analogues has been documented," the guidance says. "Because of a common mechanism of action, it is also generally believed that the rate of cross-resistance between the available acyclic guanosine analogues is nearly complete."

"The agency is concerned that misuse of these drugs could hasten the development of HSV resistance, jeopardizing the usefulness of the entire class of agents for treatment of serious and life-threatening herpes infections," the notice says.

"Because there are outstanding issues related to the potentially inappropriate use of OTC antiviral products and the unknown potential implications for cross-resistance to other members of this class of drugs, the Center for Drug Evaluation & Research believes that antiviral drugs for the treatment of herpes labialis should not be sold OTC in the United States at this time."

The agency says it announced its position "because of the interest on the part of individuals, professional groups and drug manufacturers in marketing antiviral agents for OTC treatment of herpes labialis."

FDA last year rejected SmithKline's Rx-to-OTC switch application for topical 1% penciclovir cream for the treatment of cold sores.

The agency's action followed a December 1998 meeting of the Nonprescription and Antiviral Drugs Advisory Committees, which voted 5-7 against a switch. Chief among the committee members' concerns was the potential for an increased incidence of viral resistance resulting from broader access to the drug (¹ (Also see "OTC Denavir Advisory Cmte. Members Uncomfortable With Risk/Benefit Ratio" - Pink Sheet, 7 Dec, 1998.)).

SmithKline nevertheless has said it would continue to pursue a Denavir switch. In announcing the proposed merger of Glaxo Wellcome and SmithKline in January, company reps cited herpes as a potential switch area for Glaxo SmithKline (² (Also see "Glaxo SmithKline OTC Switch Potential Seen As Merger Catalyst" - Pink Sheet, 24 Jan, 2000.)).

On Dec. 20, SmithKline signed a letter of intent with Avanir for North American rights to market docosanol 10% cream OTC as a treatment for recurrent oral-facial herpes. The companies continue to negotiate details of the licensing agreement.

Avanir originally sought to market the product as an Rx but received two "not approvable" letters. According to the company, FDA said in November 1999 that clinical data submitted would be sufficient for approval as an OTC, provided the agency finds no serious discrepancies from a site audit at a clinical study site overseas. The firm is awaiting FDA's assessment of this audit, conducted in December, and has submitted proposed OTC product labeling.

Docosanol is not an acyclic guanosine analog and has a distinctly different mode of action from such products, which work after the virus has entered the cell and begun replicating, Avanir said.

"Docosanol does not act directly on the virus; rather, it modulates the host cell to prevent entry of the virion," Avanir said, citing language in its NDA. "Most drug resistant viral strains arise from a mutation in a single gene. For example, acyclovir-resistant mutants commonly arise from mutation in the viral thymidine kinase gene."

"In contrast, docosanol may not target a single viral protein, and the emergence of drug-resistant mutants is therefore improbable," Avanir maintained.

The San Diego, Calif.-based firm noted although it has not conducted clinical studies demonstrating misuse would lead to development of resistant strains, the mechanism of action places no genetic pressure on the reproductive process of the virus.

In the guidance, FDA suggests sponsors who are considering proposing OTC use of antiviral products for herpes labialis "should thoroughly evaluate issues related to misuse and resistance before submitting an application for marketing."

The document lists six areas of concern identified by the agency and the Denavir joint advisory committee.

These issues include how appropriately would an OTC antiviral product be applied compared to a prescription product used with a healthcare provider's oversight; potential consequences of HSV resistance resulting from inappropriate use of an OTC antiviral; and public health effects of transmitting drug-resistant HSV.

Other items for consideration include the pathogenic potential of drug-resistant HSV; effect of HSV latency on the ability to evaluate the effects of selective drug pressure on the prevalence of HSV resistance; and reliability and standardization of methods for susceptibility testing. Comments on the draft guidance are due by May 8.

The guidance marks the second time in recent years FDA has sua sponte announced its opposition to OTC availability for certain categories of drugs.

In an October 1997 guidance, CDER said it agreed with the recommendations of the Nonprescription Drugs and Endocrinologic & Metabolic Drugs Advisory Committees that hypercholesterolemia treatment requires both preliminary and ongoing medical management and, consequently, is not suitable as an OTC condition.

The advisory committees' findings and guidance stemmed from Bristol-Myers Squibb's failed attempt to switch Questran (cholestyramine) over-the-counter. The agency issued the guidance, in part, to advise companies against expending resources to switch cholesterol-lowering drugs.

At a Food, Drug & Law Institute meeting in December, CDER Director Janet Woodcock, MD, said FDA would reexamine the guidance in 2000.