Warner Lambert FemPatch approved Dec. 3; estradiol patch manufacturers to add adhesion data to labeling.

WARNER-LAMBERT FEMPATCH ESTRADIOL PATCH ADHESION DATA will be submitted as supplemental labeling revisions to the NDA, which was approved by FDA on Dec. 3. Warner-Lambert will also pursue labeling revisions to include efficacy results from clinical studies on the estradiol transdermal system.

All estradiol patch manufacturers could be subject to conducting further "wear" studies on their skin patches. FDA indicated in its approval letter to Warner-Lambert that it is asking manufacturers to submit labeling revisions that include adhesion data from studies; if they do not have the information, they must generate it. Currently marketed estradiol patches include Berlex' Climara and CibaGeneva's Estraderm and Vivelle.

"Based on the fact that the adhesion of transdermal systems to the skin in vivo is a critical factor directly related to its therapeutic effect and possibly to its compliance, the agency is requesting that the sponsors of estradiol transdermal delivery systems update their respective product's labeling to incorporate in vivo adhesion (lifting and detachment) information generated during the pharmacokinetic and clinical studies," FDA says in the letter.

FDA's Division of Reproductive & Urologic Drug Products is "standardizing the labeling of already approved and to-be-approved estradiol transdermal systems to include in the `Pharmacokinetics' section of the labeling, the subheading `Adhesion,'" the letter states. Information to be included under the subheading includes the importance of adhesion as related to efficacy; pharmacokinetic and therapeutic implications of patch lifting and detachment; and information on the percentage of systems that lifted and were replaced during the clinical and pharmacokinetic studies. In addition, the "Dosage and Administration" section "should clearly indicate `what to do' if the system falls off."

"To avoid any marketing disadvantages," FDA's letter says, "the agency has requested that the recommended labeling changes regarding adhesion be included in the labeling of all similar products at the same time." The division is asking manufacturers to submit revised labeling including in vivo adhesion data by May. FDA expects all estradiol transdermal systems on the market to have properly updated labeling by September.

"If a drug manufacturer did not collect appropriate adhesion data during the clinical and pharmacokinetic studies, they should conduct an adequate wear study to generate such information. This protocol should be submitted for review and comments before the initiation of the study," FDA states.

Warner-Lambert says less than 2% of FemPatch users during clinical trials discontinued due to adhesion failure. Current FemPatch labeling addresses adhesion only under "Dosage and Administration."

Warner-Lambert is touting its product as a "low-dose" transdermal estrogen replacement alternative; the patch delivers .025 mg of estradiol per day. While the company claims the vasomotor symptom relief from FemPatch is "comparable to that achieved with a .05 mg transdermal dose of 17 beta-estradiol," it makes no claim of a superior side effect profile. Product labeling contains the same warnings, contraindications and general adverse event descriptions as other estradiol patches.

Labeling mentions that in studies of 324 postmenopausal women, nine users (seven on placebo, two on FemPatch) discontinued because of a skin effect. "A total of five (2.8%) patients treated with FemPatch withdrew from the controlled studies due to an adverse event (bloating, swelling, dizziness, depression, breast pain)," labeling adds. Four (2.8%) patients receiving placebo withdrew because of AEs.

"Treatment should be initiated with one FemPatch system applied to the skin on the buttocks once weekly," labeling says. "If symptoms are not relieved after four to six weeks, two FemPatch systems may be applied weekly. FemPatch was not studied in women with a uterus. It is recommended that FemPatch therapy be given continuously to patients who do not have a uterus. FemPatch may be given on a continuous or cyclic schedule (e.g., 21 days on drug followed by seven days off) to patients who have a uterus."

Warner Lambert submitted NDA 20-417 for its seven-day, 10.3 mg estradiol transdermal system on Dec. 22, 1993. FDA sent the company a "not approvable" letter on Sept. 27, 1995, to which Warner Lambert responded with an amendment on May 31, 1996.