FDA Panel: Oral Single-Agent Levonorgestrels Safe in Teens

Emma Hitt, PhD

February 02, 2012

February 2, 2012 — In a pediatric-focused safety review, the US Food and Drug Administration (FDA) Pediatric Advisory Committee recommended that levonorgestrel (Plan B One-Step, Teva Women's Health Inc) tablets and related products be returned to routine monitoring.

The 2-day meeting of the committee was held in Gaithersburg, Maryland, earlier this week.

Amy Taylor, MD, medical officer, pediatric and maternal health staff, Office of New Drugs, Center for Drug Evaluation and Research, FDA, presented the latest safety data on Plan B One-Step and similar products.

Plan B One-Step is a 1.5 mg, oral use progestin-only emergency contraceptive indicated for prevention of pregnancy after unprotected intercourse or a known or suspected contraceptive failure. The agent is available only by prescription for women younger than 17 years and available over the counter for women aged 17 years and older.

Other oral single-agent levonorgestrel products include Plan B and Next Choice (Watson), said Dr. Watson during the meeting.

In 2010, 106,000 patients received prescriptions for Next Choice; 85,000 patients received prescriptions for Plan B One-Step; and 3800 patients received prescriptions for Plan B. According to Dr. Taylor, most patients receiving these products — about 90% — were 18 years of age or older.

Dr. Taylor reviewed the postmarketing adverse events for levonorgestrel received by the FDA from January 1, 2002, to December 31, 2010. A total of 15 pediatric reports (after 3 were excluded) were reported in young women aged 15 to 17 years. None were fatal.

Levonorgestrel (Plan B One-Step)

Adverse events included hematemesis (4 cases), loss of consciousness/syncope (4 cases), abdominal pain, and vaginal bleeding. In total, there were 23 reports of hematemesis among all ages (adult and pediatric), and the rate of loss of consciousness and syncope was also similar across age groups.

"There were no new pediatric safety signals identified and FDA recommends returning to routine monitoring," Dr. Taylor said. The committee voted in favor of this action, with the exception of 1 abstention.

During the discussion of the data, Robert Dracker, MD, from Summerwood Pediatrics, Pediatric InfusaCare Services in Liverpool, New York, commented that the "concern I have is use of a product…as a form of delayed-onset birth control when they've missed their period," whereas "the use of other forms of birth control in adolescents isn't even considered despite the fact that it's readily available," he said.

However, Paula Hillard, MD, professor of obstetrics and gynecology at Stanford University of Medicine in California, countered by saying, "I think it's pretty clear that this product does not have the effect of interrupting a preexisting pregnancy. It just doesn't work (when there's a preexisting pregnancy), and there are not data to indicate risks…I'm not concerned about the safety in that situation."

She added that this product is "so safe that it is outrageous that it is not available for women of all ages over the counter."

Bridgette Wiefling, MD, acting consumer representative, president and CEO of the Anthony L. Jordon Health Center in Rochester, New York, pointed out that she would like to see added to the label, regardless of age, not only the names of medications that can interact with levonorgestrel-containing products, but also the diseases that they are used to treat. Patients "might be familiar only with brand names that are on their bottle," she said. Dr. Weifling added that the packaging also does not do a good job of explaining what to do if the medication is taken while taking birth control pills.

Panelist Jeffrey Wagener, MD, professor of pediatrics at the University of Colorado Medical School in Aurora, questioned why hematemesis and syncope, unlabeled events, were not being added to the label.

Adrienne Rothstein, PharmD, from the FDA's Division of Pharmacovigilance, responded by saying that there is just a "handful of clinical reports" regarding these effects. "There is very little information in these reports to directly link these to the product," she said. But the FDA will continue to monitor, and "if we feel it should be added to the label we would do so," she said.

On the day 2 of the meeting, a levonorgestrel-intrauterine releasing system (Mirena, Bayer) underwent an abbreviated review process led by Dr. Wagener.

"I agree with the FDA's assessment of no new pediatric safety issues of interest," he said. "This drug is used less than 1% of the time in children…and seems to have no added safety problems in children."

Dr. Wagener recommended that Mirena be returned to routine monitoring.

The FDA's abbreviated pediatrics review process is intended for products that have caused no deaths and have shown no or very few serious adverse events. In addition, products must have very little or no pediatric use or no longer be marketed, and there must have been no new safety signals.

The first day of the 2-day meeting also included pediatric-focused safety reviews for several drugs, including dexmethylphenidate (Focalin, Novartis), quetiapine fumarate (Seroquel, AstraZeneca), and omalizumab (Xolair, Genentech and Novartis).

The committee also reviewed a pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein; Prevnar 13, Wyeth Pharmaceuticals) and a human papillomavirus bivalent, types 16 and 18, recombinant vaccine (Cervarix, GlaxoSmithKline).

The FDA usually follows the advice of advisory panels, but not always.

Pediatric Advisory Committee Meeting. Presented January 30-31, 2012.

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