Solvay's Androgel REMS Proposal May Need More Restrictions - Cmte.

Solvay may need a more restrictive Risk Evaluation and Mitigation Strategy for AndroGel 1% to adequately warn against the danger of secondary transfer of the testosterone gel, according to some members of FDA's Pediatric Advisory Committee.

At the panel's June 23 meeting, Solvay presented the REMS it had developed, which includes an FDA-ordered boxed warning, package insert and Medication Guide as well as its own timetable to assess awareness. The meeting was a review of pediatric safety for several products, as mandated by the Best Pharmaceuticals for Children Act.

But some committee members believe the language of the warnings is still too vague and the REMS may need to include more restrictive distribution.

FDA brought the pediatric safety issue to public attention in advance of the advisory committee, with a MedWatch alert and press conference May 7, warning of the serious consequences of secondary exposure to testosterone, especially to children (¹ (Also see "Testosterone Gel Makers Brace For REMS, Black Box Warning" - Pink Sheet, 7 May, 2009.)).

Androgel is the most-prescribed product in that category, followed by Ipsen's Testim 1%. FDA said at the time that it would require the makers of the two products to include a boxed warning and other changes to the labels to ensure that the benefits of the products continue to outweigh the risks.

Though the potential for secondary exposure was already known, and has been included in labeling since approval, the severity of the effects in pediatric patients warranted the stronger steps for risk management.

Between 2000 and May 2009, Solvay reported 25 pediatric and 137 adult cases of secondary exposure. Pediatric cases include age-inappropriate enlargement of the penis or clitoris, premature pubic hair development, advanced bone age and increased erections as well as psychosocial and behavioral aberrations.

At the advisory committee meeting, FDA medical officer Paul Reed set out several actions the agency will require for the drug class, including a MedGuide, additional analysis of adverse events, a boxed warning specific to secondary exposure, inclusion in the Highlights section under both Warnings and Precautions and Adverse Reactions, and other additions to the full prescribing information.

The committee voted 10-3 to concur with FDA's stated strategy for class labeling changes, but those who voted no said it is not enough and a few who voted yes gave the caveat that it is only "a good first step."

Voting member Leon Dure, a pediatric neurologist at the University of Alabama, voted yes but emphasized that more should be done. "The language needs to be direct, very descriptive; we need to avoid terms like 'virilization' in all the publications."

Virilization is the term used by the regulators to refer to the abnormal development of male characteristics in a female. But that's just one aspect of the problem. Precocious puberty would be a better term, but it's still too vague, noted Ellen Leschek, a pediatric endocrinologist at NIH.

Committee Chair Marsha Rappley, Michigan State University, summarized the panel's comments by suggesting the language in the boxed warning and MedGuide be more clear and easier to understand, perhaps by "eliminating the passive voice and speaking to what we do know - that there is an inadvertent exposure and it is not safe for children who are so exposed."

Solvay's proposal is in line with FDA's request for the drug class.

Solvay Chief Medical Officer Elizabeth Mutisya told the committee that the goals of Solvay's REMS are to increase awareness of the risk of secondary exposure, importance of appropriate use and the need for precautionary measures. In addition to the MedGuide, labeling changes and assessments, the REMS includes a variety of communication and education tools, most importantly the use of Web sites, Mutisya noted.

Mutisya said the warning will be the first thing patients see when they go onto the ² Androgel Web site. Currently, the site includes only a passing reference to the occurrence of secondary exposure. Along with a statement of indications and contraindications, a box at the bottom of the home page says, "Patients should be advised to cover the application site with clothing once dry and wash hands to prevent transfer of testosterone to others."

FDA-required revised labeling will have an increased emphasis on secondary exposure, with details of post-marketing reports and bolded instructions to minimize transfer. It will include additional signs and symptoms of virilization and instructions to read the MedGuide.

For evaluation of the impact of the REMS, Solvay will use sample surveys and focus groups of providers and patients to assess understanding of the risk of secondary exposure, awareness of ways to minimize that risk and recognition of signs and symptoms of exposure, Mutisya explained.

Too Much Prescribing Going On?

Some panel members suggested that there may be more off-label prescribing of Androgel than is acceptable.

"I do believe this drug is being prescribed a little bit more frequently than it should be. I see it all the time," said Lescheck. She suggested that prescribers and patients could sign a statement that they understand the risks, or that prescribing could be restricted to subspecialists.

There should be "some sort of signed statement to make sure patients are aware of the risks," Dure agreed.

Mutisya said physicians have written 10 million prescriptions for Androgel and 3.7 million patients have used the drug.

For a product that's been on the market nearly a decade, Androgel sales have significant momentum. At €102 million, sales of Androgel were up 31 percent (15 percent at constant exchange rates) in the first quarter of 2009 over first quarter 2008. Total 2008 sales were €337 million.

The products are commonly used off-label for treatment of hypoactive sexual desire in women. An article in the July 2009 issue of the Journal of Sexual Medicine notes a sharp increase in testosterone prescriptions in recent years and that 21 percent of scripts are for use by women. The article calls for FDA approval to replace growing off-label use.

Solvay has supplemental applications pending in the U.S. for AndroGel PD for treatment of constitutional delay in growth and puberty and treatment of hypogonadism in adolescent males (13-17 years old) with a deficiency or absence of endogenous testosterone, regardless of etiology.

- Pamela Taulbee ([email protected])