FDA eyes LNG ECP label change in light of research on weight impact
February 1, 2014
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FDA eyes LNG ECP label change in light of research on weight impact
European drug label now states lower efficacy in women 165 pounds-plus
EXECUTIVE SUMMARY
Labeling for the European levonorgestrel (LNG) emergency contraceptive pill NorLevo has been revised due to data indicating lower drug efficacy in women weighing 165 pounds and above. This move has led U.S. regulators to assess data on similar products.
- NorLevo, marketed by HRA Pharma, is a single pill that contains 1.5 mg of levonorgestrel. The same formulation is found in Plan B One-Step, Next Choice One Dose, and My Way.
- The effect of a women's weight on levonorgestrel efficacy was identified in 2011 during a study of another emergency contraceptive drug, ulipristal acetate. Results suggested that levonorgestrel pills start losing effectiveness in women weighing above 165 pounds and are no different than placebo in women weighing above 176 pounds.
Labeling for the European levonorgestrel (LNG) emergency contraceptive pill (ECP) NorLevo has been revised in light of data indicating lower drug efficacy in women weighing 165 pounds and above.1 This move has led U.S. regulatory officials to assess data on similar products in this country.
NorLevo, marketed by Paris, France-based HRA Pharma, contains 1.5 mg of levonorgestrel. The same formulation is found in products marketed by different manufacturers in the U.S.: Plan B One-Step (Teva Women's Health, North Wales, PA), Next Choice One Dose (Actavis, Parsippany, NJ), and My Way (Gavis Pharmaceuticals, Somerset, NJ).
The Food and Drug Administration (FDA) is reviewing available and related scientific information on this issue, including the publication upon which the NorLevo labeling change was based, states Erica Jefferson, deputy director of the FDA Office of Media Affairs. The agency will then determine what, if any, labeling changes to approved emergency contraceptives are warranted, says Jefferson.
"As background, the original approval of Plan B for use in the U.S. did not include an assessment specific to weight," states Jefferson. "NorLevo is not approved under this brand name in the U.S."
What prompted the NorLevo label change? The effect of a women's weight on levonorgestrel efficacy was first identified in 2011 during the development of an alternative emergency contraceptive product (ulipristal acetate) in the context of a clinical trial, says Erin Gainer, MPH, chief executive officer of HRA Pharma. Ulipristal acetate is marketed by Actavis in the United States as ella. (Contraceptive Technology Update reported on ella. See "Add ella to options for emergency contraception," October 2010, p. 112.)
1.5 to 3 times greater risk of pregnancy
Compared with women with a BMI under 25 kg/m2, which is normal weight or underweight, according to the World Health Organization (WHO), the risk of pregnancy was more than three times greater (OR [odds ratio], 3.60; 95% CI [confidence interval], 1.966.53; p less than 0001) for obese women (BMI of 30 kg/m2 and above according to WHO) and 1.5 times greater (OR, 1.53; 95% CI, 0.752.95) for overweight women (BMI between 25 and 30 kg/m2 ), whichever drug was taken, the researchers note.1
However, when the pregnancy rates were compared within the two treatment groups, the effect of BMI was more pronounced in women treated with levonorgestrel than with ulipristal acetate, the scientists note. The relative risk of becoming pregnant was doubled when overweight women taking LNG were compared with normal-weight or underweight women (OR, 2.09; 95% CI, 0.864.87; ns ) using LNG, whereas the risk was not different when women taking UPA were compared (OR, 0.97; 95% CI, 0.272.83). Moreover, obese women who took levonorgestrel were at more than four times greater risk to get pregnant (OR, 4.41; 95% CI, 2.059.44; p=.0002) in comparison with normal-weight or underweight women. For women treated with ulipristal acetate, the same odds ratio comparing obese women to normal or underweight women was estimated to be 2.62 (95% CI, 0.897.00), the researchers report.1
"Based on the spline cubic smoothing method applied to the logistic model, levonorgestrel showed a rapid decrease of efficacy with increasing BMI, reaching the point where it appeared no different from pregnancy rates expected among women not using emergency contraception at a BMI of 26 kg/m2 compared with 35 kg/m2 for ulipristal acetate," the scientists conclude. (CTU reported on the study findings in "Hope vs. reality — Access to EC pills doesn't work," January 2013, p. 8.)
"As a result, HRA Pharma has performed further analyses in 2012, which enabled it to put together a safety variation which was presented to European regulatory authorities at the start of 2013," says Gainer. "By sharing the data in this manner, it demonstrates a clear obligation by the company to be transparent with the healthcare community and provide regulators with the most up-to-date information to inform women."
Based on the presented material, Gainer says European authorities involved in the process decided to include the following statement in the NorLevo labeling: "In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg [165 pounds] or more and levonorgestrel was not effective in women who weighed more than 80 kg [176 pounds]."
HRA Pharma is not marketing levonorgestrel in the United States and is therefore not involved in any process of label change for levonorgestrel in the United States, says Gainer. The company is recommending that women affected by the change in labeling discuss alternative emergency contraceptive options, such an intrauterine device (IUD) or an alternate oral emergency contraceptive, with their clinician or pharmacist, says Gainer.
Company upholds efficacy
Another European ECP manufacturer, Budapest, Hungary-based Gedeon Richter, stands by the efficacy of its similar LNG product, marketed in Europe as Levonelle, Postinor, Escapelle, and Upostelle. In a statement issued Nov. 29, 2013, the company points to its company's 30-year history in manufacturing levonorgestrel drugs and its post-marketing surveillance.
"During an approximately 16-year period since post-marketing data on patient exposure and on spontaneous safety reports are available for Gedeon Richter, the company's levonorgestrel-containing emergency contraceptive products were used in almost 400 million occasions worldwide," the statement reads. "Regarding this period, 61 inefficacy cases were reported for each 10 million drug intake, irrespectively of the patient's weight. Unwanted pregnancies in presumably overweight or obese patients (BMI equal or above 25) were reported in four cases out of 10 million occasions when the company's levonorgestrel products were used."
According to the company, based on the analysis of its validated safety database, which incorporates all spontaneous case reports received by the Gedeon Richter regarding its levonorgestrel emergency contraceptive products, "no such results became available for the company, which would suspect an increased risk for emergency contraceptive failure resulting in an unwanted pregnancy when the product is used in overweight or obese women."2
How should clinicians incorporate this data in their practice regarding emergency contraception? According to a "Contraceptive Pearl" from the New York City-based Reproductive Health Access Project, keep these facts in mind:
- "Levonorgestrel EC becomes less effective over time following unprotected intercourse. Levonorgestrel EC's efficacy decreases with high BMI as well. For women with a BMI over 26, levonorgestrel EC is no better than placebo.
- Ulipristal acetate EC retains full efficacy up to five days after sexual intercourse. Ulipristal EC has lower efficacy among obese women. Compared with levonorgestrel, ulipristal has a higher BMI threshold. Ulipristal retains its efficacy for women with BMI up to 35.
- The copper IUD can be inserted up to five days after unprotected intercourse and reduce the risk of pregnancy by 99%. It retains full efficacy over time and with obesity. Best of all, it provides ongoing contraception for up to 12 years."3
Emergency contraceptive of choice
The copper T380A IUD (ParaGard, Teva Women's Health) is the emergency contraceptive of choice for all women, regardless of their weight, concludes Robert Hatcher, MD, MPH, professor emeritus of gynecology and obstetrics at Emory University School of Medicine in Atlanta.
Also, check results of a recently published study that looked at ulipristal acetate and levonorgestrel's capacity to inhibit follicular rupture days just prior to ovulation, the most crucial period for emergency contraception (EC) efficacy.4 Based on the data, researchers say that while no EC treatment is 100% effective in inhibiting follicular rupture when administered in the late follicular phase, ulipristal acetate is the most effective treatment and delays ovulation for at least five days in 59% of the cycles. In the study, levonorgestrel was no different from placebo in inhibiting follicular rupture at this advanced phase of the cycle. No treatment was effective in postponing rupture when administered on the day of luteinizing hormone peak, researchers note.4
Data suggests that obesity might have an impact on how well EC works, noted Anne Burke, MD, MPH, associate professor in the Department of Gynecology and Obstetrics at the Johns Hopkins University of School of Medicine in Baltimore. Burke spoke on the effect of obesity on contraceptive efficacy at the November 2013 Contraceptive Technology Quest for Excellence conference in Atlanta.5
When it comes to contraception, long-acting reversible contraceptives such as the IUD and contraceptive implant are better for preventing pregnancy in all women, no matter their weight, said Burke. For emergency contraception, use ulipristal acetate in obese women and possibly in all women, she noted.
REFERENCES
- Glasier A, Cameron ST, Blithe D, et al. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception 2011; 84(4):363-367.
- Gedeon Richter. Levonorgestrel containing emergency contraceptive products are effective in overweight and obese women as well, assures Gedeon Richter Plc. Press statement. Nov. 29, 2013. Available at http://bit.ly/1bZwUsM.
- Brache V, Cochon L, Deniaud M, et al. Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens. Contraception 2013; 88(5):611-618.
- Reproductive Health Access Project. Emergency contraception: timing, weight, and efficacy. November 2013. Accessed at http://bit.ly/18GsqnV.
- Burke A. The effect of obesity on contraceptive efficacy: what we now know. Presented at the 2013 Contraceptive Technology Quest for Excellence conference. Atlanta; November 2013. n
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