GAITHERSBURG, Maryland (EGMN) – A U.S. Food and Drug Administration advisory panel on June 17 unanimously agreed that the selective progesterone receptor modulator ulipristal acetate is an effective emergency contraceptive with an acceptable safety profile, when used within 5 days of unprotected intercourse or a known or suspected contraceptive failure.
The FDA’s Reproductive Health Drugs Advisory Committee voted 11 to 0 that the manufacturer, HRA Pharma, had provided enough information to conclude that the proposed 30 mg dose of micronized ulipristal “reduces the likelihood of pregnancy” when taken as soon as possible within 120 hours after unprotected intercourse or a known or suspected contraceptive failure. The primary mechanism of action of ulipristal, which has a potent affinity for the progesterone receptor, is presumed to be the inhibition or the delay of ovulation, according to the company.
If approved by the FDA, the company plans to market it as a prescription-only product under the trade name “ella.” Ulipristal was approved as an emergency contraceptive in Europe in May 2009 and has been marketed there since October, under the trade name “ellaOne.” The FDA usually follows the recommendations of its advisory panels.
Currently, the levonorgestrel-based emergency contraceptive marketed as Plan B or Next Choice, is the only available emergency contraceptive in the United States. It is recommended for use for up to 72 hours within unprotected intercourse or contraceptive failure; it is available by prescription and – for women aged 18 years and older – over the counter, in a 1.5 mg single-dose (Plan B One-Step) and two 0.75 mg doses to be taken 12 hours apart (Plan B or Next Choice).
Ulipristal was evaluated in two phase III prospective, multicenter studies of women aged 18 years and older (in the United States) or aged 16 years and older (in Europe), who received 30 mg of micronized ulipristal within 48-120 hours of unprotected intercourse.
The first trial was an open-label study conducted in the United States of 1,241 women, who were give a dose of ulipristal within 48-120 hours after unprotected intercourse. The pregnancy rate was 2.10%, which was significantly lower than the expected pregnancy rate of 5.53%.
The second study was a randomized, controlled, inferiority study in which ulipristal was compared with levonorgestrel in women in the United States and Europe. Among the 1,694 women who took either medication within 72 hours of unprotected intercourse, the pregnancy rate was 1.78% among those who took ulipristal, which was significantly lower than the expected pregnancy rate of 5.54%. The pregnancy rate among those who received the levonorgestrel emergency contraceptive was 2.59%.
The pregnancy rate was higher among women with a higher body mass index (BMI), in a pooled analysis of the two studies: The pregnancy rate was 3.13% among those with a BMI above 30 mg/m2. The panel agreed that it should not be restricted in women with higher BMIs, but split on whether to recommend that the label include information about the lower efficacy in that population.
Among more than 4,700 women in ulipristal studies who received single doses up to 200 mg, including 2,700 women who received the 30-mg proposed dose, the most common side effects reported were headache, nausea, dysmenorrhea, and abdominal pain, according to the company. The one serious adverse event associated with ulipristal was in an 18 year old, who experienced severe dizziness after taking the drug. No ectopic pregnancies were reported; two ruptured ovarian cysts were reported in women who received the 30-mg dose in phase II/III and phase III studies.
The limited data on pregnancies exposed to ulipristal suggest that the miscarriage rate is not increased with exposure, according to the company. Only 21 exposed pregnancies have been reported to date; of those, 14 are ongoing normal pregnancies, 2 were elective terminations, 1 was a miscarriage and 4 were lost to follow-up. The company is planning a postmarketing study in Europe, which will follow up with 1,000 health care practitioners to collect detailed clinical data on the course of pregnancies and outcomes among patients who get pregnant despite treatment with ulipristal. The FDA has proposed that if approved, this be expanded to include health care providers in the United States.
Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
马里兰州盖瑟斯堡(EGMN)——6月17日，美国食品药品管理局(FDA)顾问专家组得出一致结论，即在无保护性行为或已知(或怀疑)避孕失败5天内应用选择性孕酮受体调节剂醋酸ulipristal是一种安全性可接受的有效紧急避孕药。
FDA生殖健康药品顾问委员会以11︰0的投票结果认为，此药的制造商HRA制药公司已经提供了足够的资料来得出以下结论：在无保护性行为或已知(或怀疑)避孕失败120 h内尽早地使用，则ulipristal 30 mg建议使用量(粉剂)“降低了妊娠的几率”。据HRA制药公司说，ulipristal对孕酮受体具有强亲和力，其主要作用机制被认定是抑制或者延缓排卵。
如果能够得到FDA的批准，则此公司计划将其仅作为处方药上市，商品名为“ella”。Ulipristal已于2009年5月在欧洲获批作为紧急避孕药，并于10月份开始销售，商品名为“ellaOne”。FDA通常会遵循其顾问专家组的推荐意见。
当前，基于左炔诺孕酮的紧急避孕药B计划或备用药是美国仅有的可用紧急避孕药，其被推荐在无保护性行为或避孕失败后72 h内应用。它是处方药，对于18岁或以上女性也可以作为非处方药，每次1.5 mg(单次B计划)或者两次0.75 mg间隔12 h服用(B计划或备用药)。
两项针对美国18岁及以上(欧洲16岁及以上)女性的前瞻性、多中心、Ⅲ期临床试验对ulipristal进行了评估，研究受试者在无防护性生活结束后48~120 h服用了30 mg的粉剂。
第一项临床试验是在美国进行的一项开放性研究，包含1,241名女性，这些女性在无防护性生活后48~120 h接受单剂ulipristal治疗。结果显示，妊娠率为2.10%，显著低于预期的5.53%。
第二项研究是一项随机、对照、劣效性研究，其在美国和欧洲女性中将ulipristal与左炔诺孕酮进行比较。在1,694例无保护性生活后72 h内应用了任意此两种药之一的女性中，服用ulipristal者妊娠率为1.78%，比预期的5.54%显著降低。服用紧急避孕药左炔诺孕酮者的妊娠率是2.59%。
对此两项研究的汇总分析发现，体重指数(BMI) 较高者的妊娠率较高：BMI>30 mg/m2的女性妊娠率是3.13%。顾问专家组一致认为不应限制BMI较高者使用该药，但对于是否建议药品标签中包含此人群效果较差的信息尚存在分歧。
据HRA制药公司的研究，在4,700余例接受ulipristal单剂量高达200 mg的女性(包括2,700例接受30 mg建议剂量者)中，所报告的最常见不良反应是头痛、恶心、痛经和腹痛。与ulipristal相关的1例严重不良事件是一名18岁女性服药后出现了数次头晕。未见异位妊娠的病例报道。在Ⅱ/Ⅲ期和Ⅲ期临床试验中，有两例应用30 mg剂量的女性出现了卵巢囊肿破裂。
据此公司报道，关于妊娠后服用ulipristal的有限数据显示，流产率并没有因服用ulipristal而增加。截至目前，只有21例已孕者用药的报道，其中，14例处于正常妊娠状态，2例选择终止妊娠，1例出现自然流产，4例失访。该公司正在计划在欧洲进行一项上市后研究，准备与1,000位卫生保健工作人员一同去跟踪收集有关使用ulipristal后仍怀孕者妊娠过程及转归的详细临床数据。FDA已建议，如获批准，则美国的卫生保健工作人员也将参与到此类研究中。
FDA顾问专家组成员在会议召开前已确定不存在潜在利益冲突，但有时，FDA会准许某位存在利益冲突的顾问专家组成员弃权。
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