Ulipristal Acetate (ellaone )

Transcription

1 FACULTY OF SEXUAL & REPRODUCTIVE HEALTHCARE Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit A unit funded by the FSRH and supported by NHS Greater Glasgow & Clyde to provide guidance on evidence-based practice New Product Review (October 2009) Ulipristal Acetate (ellaone ) PRODUCT SUMMARY Ulipristal acetate (ellaone ) is a selective progesterone receptor modulator (SPRM) licensed for emergency contraception (EC) up to 120 hours after unprotected sexual intercourse (UPSI) or contraceptive failure. Mechanism of Action Primary mechanism is inhibition or delay of ovulation Alterations to the endometrium may also contribute to efficacy Efficacy Efficacy has been demonstrated up to 120 hours after UPSI Two randomised controlled trials have shown that ulipristal is at least as effective as progestogen-only EC (POEC) Pooled data suggest superior efficacy of ulipristal over POEC for intake within 24, 72 and 120 hours Safety Side effect profile similar to POEC No serious reactions reported Interactions Efficacy may be reduced by drugs that induce liver enzymes or increase gastric ph Potential interaction with progestogen-containing products but clinical significance unknown Cost Net price: per pack of ellaone (1 x 30 mg tablet) Background Emergency contraception (EC) is an important means of preventing unwanted pregnancy. In recent years, two methods of EC have been available in the UK: oral progestogen-only emergency contraception (POEC) containing levonorgestrel 1.5 mg (Levonelle, Bayer Schering Pharma) and the copper-bearing intrauterine device (IUD). Levonelle is licensed to be given up to 72 hours after UPSI, although there is some evidence of reducing efficacy with use after hours. 1,2 The IUD can be inserted within 120 hours (5 days) of UPSI or up to 5 days after the expected date of ovulation. 3 Despite the high efficacy of the IUD and the option to retain the device for ongoing contraception, 3 oral EC is more commonly used because it is less invasive and more easily accessible. Ulipristal (ellaone, HRA Pharma) is an oral emergency contraceptive newly launched onto the UK market and licensed for use throughout Europe. This review evaluates the available evidence and summarises the manufacturer s recommendations for use of ulipristal. Wherever possible we have accessed published literature; however, recent clinical trial data are currently only available as conference abstracts. The review is intended to inform health professionals and is not a guidance document. Existing Faculty of Sexual and Reproductive Healthcare (FSRH) guidance on EC 3 will be updated to incorporate recommendations on ulipristal in due course. FSRH

2 What is ulipristal? ellaone consists of one tablet containing 30 mg micronised ulipristal acetate (Figure 1). Ulipristal acetate (also known as CDB-2914 and VA2914) is a synthetic steroid derived from 19-norprogesterone (Figure 2). It is a selective progesterone receptor modulator (SPRM), a class of compounds that exert tissue-selective full agonist, antagonist or partial agonist effects at the progesterone receptor. 4 The Summary of Product Characteristics (SPC) indicates that ulipristal has antagonistic and partial agonistic effects. 5 Figure 1 ellaone packaging (photograph reproduced with the permission of HRA Pharma) Ulipristal acetate Mifepristone Progesterone Figure 2 Comparison of chemical structures of progesterone, ulipristal acetate and mifepristone (figure reproduced with the permission of Pharmacorama) The first SPRM, mifepristone, is licensed for use in medical abortion and is also an effective emergency contraceptive. Although a Cochrane review concluded that mifepristone is more effective than POEC up to 120 hours after UPSI, 6 it has not been developed for this indication in the UK and is not licensed as EC anywhere in Europe. Ulipristal has been described as a second-generation SPRM. In vivo, ulipristal has much weaker antiglucocorticoid activity than mifepristone as a result of differences in their active metabolites FSRH 2009

3 What is the mechanism of action for ulipristal? Ulipristal s primary mechanism of action is thought to be inhibition or delay of ovulation. A single midfollicular dose has been shown to suppress growth of lead follicles. 11 Administration just before, or in some cases just after, the luteinising hormone surge can inhibit follicular rupture. 12 Endometrial changes may also play a role. Early luteal administration of ulipristal results in delayed endometrial maturation and alterations in progesterone-dependent markers of implantation. 13 A mid-luteal dose has been shown to induce early endometrial bleeding in a dose-dependent manner. 14 It has been postulated that alterations to the endometrium may inhibit implantation by rendering the uterus less receptive to the trophoblast. However, it is not known if ulipristal has a direct endometrial effect or if the observed changes are a result of an ovarian effect. 13 How should ulipristal be used? One tablet should be taken orally as soon as possible, but no later than 120 hours after UPSI or contraceptive failure. 5 Ulipristal can be taken with or without food. 5 If vomiting occurs within 3 hours, another tablet should be taken. 5 Ulipristal is not recommended to be used more than once per cycle as the safety and efficacy of repeated exposure has not been assessed. 5 If hormonal contraception is continued after administering ulipristal, barrier contraception should be used until the next period or withdrawal bleed. 5 How effective is ulipristal? Individual studies suggest that ulipristal is as effective as levonorgestrel for EC. There have been no studies comparing the efficacy of ulipristal to the IUD for the purpose of EC. In a Phase II randomised double-blinded non-inferiority trial of women seeking EC within 72 hours of UPSI, pregnancies occurred in 7/775 ulipristal users [0.9%, 95% confidence interval (CI) ] and 13/774 levonorgestrel users (1.7%, 95% CI ). 15 Based on calculations of the risk of pregnancy on the estimated cycle day of UPSI, the study suggested that 85% of anticipated pregnancies in the ulipristal group had been avoided and 69% in the levonorgestrel group. The confidence intervals in this study were wide and no significance differences were demonstrated. The authors concluded that ulipristal was at least as effective as levonorgestrel. This trial used a 50 mg dose of non-micronised ulipristal, which is bioequivalent to 30 mg micronised ulipristal. 16 Newly presented abstract data suggests ulipristal is well tolerated and effective (pregnancy rate 2.1%, 95% CI )) when administered to women between 48 and 120 hours following UPSI. 17 A randomised trial confirmed efficacy up to 120 hours with a trend towards greater efficacy in the ulipristal group versus levonorgestrel. 18 An unpublished meta-analysis of the two comparative studies suggests ulipristal is superior to levonorgestrel when administered both within 120 and 24 hours of UPSI [odds ratio (OR) 0.55 (95% CI , p = ) and OR 0.35 (95% CI , p = ), respectively]. 16 The meta-analysis 16 suggests that regardless of the type of EC drug used, the risk of pregnancy is significantly increased with increasing body mass index (BMI) (8% per point increase in BMI). However, ulipristal acetate appears to be more efficacious compared to levonorgestrel in women who are categorised as overweight or obese (grade 1) (OR 3.1, 95% CI ). Are there any restrictions on use of ulipristal? Ulipristal is contraindicated in pregnancy or suspected pregnancy, as well as in those with a hypersensitivity to any of the excipients. 5 In the absence of specific studies to monitor safety, ulipristal is not recommended in those with severe hepatic impairment, nor is it recommended in women with severe asthma insufficiently controlled by oral glucocorticoids. 5 As it is not known whether ulipristal is excreted in breast milk, breastfeeding women are advised not to breastfeed for 36 hours after treatment. 5 FSRH

4 Are there any side effects or safety issues? The most commonly reported side effects are abdominal pain and menstrual disorders (irregular vaginal bleeding, premenstrual syndrome, uterine cramps). 5,15,17 Study data have shown that the post-treatment cycle length is on average 2.9 days longer than the expected length. 17 Some 7% of women reported a shortened cycle, and 19.2% reported an increase in cycle length of more than 7 days. 5 There have been no associated adverse outcomes in the small numbers of inadvertent pregnancies that have occurred to date. The manufacturer has put a variety of measures in place to monitor outcomes of exposure during pregnancy. 5 Does ulipristal interact with other drugs? Ulipristal is metabolised via cytochrome P450, in particular CYP3A4. 5 Liver enzyme inducers CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, ritonavir, St John s wort) may reduce plasma concentrations of ulipristal and may reduce efficacy. Liver enzyme inhibitors The effect of CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin) may increase exposure to ulipristal, but the significance is uncertain. Drugs that increase gastric ph Use of ulipristal with antacids, proton pump inhibitors and H2 receptor antagonists, or any other drugs that increase gastric ph, may reduce absorption of ulipristal and decrease efficacy. 5 Other contraceptives Ulipristal binds to progesterone receptors and so may reduce the efficacy of progestogen-containing contraceptives. Is ulipristal cost effective? There are currently no published cost effectiveness data. Comparative prices are shown in Table 1 for information. Levonelle One-Step can be bought over the counter, whereas ellaone will be available only on prescription, at least initially. In time it may become possible for nurses and pharmacists to provide ellaone by patient group direction (PGD) as currently practised for the supply of Levonelle Table 1 Cost of emergency contraceptives available in the UK* Method Cost ellaone Levonelle One-Step Levonelle Intrauterine devices *Based on British National Formulary (Vol. 57) 20 and personal communication with HRA Pharma. What does ulipristal add to the range of EC currently available? The introduction of ulipristal to the UK market marks an important development in EC. It will be the first oral emergency contraceptive to be licensed for use between 72 and 120 hours of UPSI. Its place in UK contraceptive practice will become clearer as new data are published and clinical experience increases. If ulipristal proves to be as well tolerated and effective as existing evidence suggests, the advantages are likely to justify its cost, particularly when compared to the costs of unwanted pregnancy. 4 FSRH 2009

5 References 1 von Hertzen H, Piaggio G, Ding J, Chen J, Song Si, Bartfai G, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet 2002; 360: Ngai SW, Fan S, Li S, Cheng L, Ding J, Jing X, et al. A randomized trial to compare 24h versus 12h double dose regimen of levonorgestrel for emergency contraception. Hum Reprod 2004; 20: Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit. Emergency contraception. J Fam Plann Reprod Health Care 2006; 32: [Accessed 28 September 2009]. 4 Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update 2005; 11: HRA Pharm. ellaone: Summary of Product Characteristics (SPC) [Accessed 28 September 2009]. 6 Cheng L, Gulmezoglu AM, Van Look PFA. Interventions for emergency contraception. Cochrane Database Syst Rev 2008; 2: CD Reel JR, Hild-Petito S, Blye RP. Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single, multiple or continuous doses to rats. Contraception 1998; 58: Hild SA, Reel JR, Hoffman LH, Blye RP. CDB-2914: anti-progestational/anti-glucorticoid profile and post-coital anti-fertility activity in rats and rabbits. Hum Reprod 2000; 15: Attardi BJ, Burgenson J, Hild SA, Reel JR, Blye RP. CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB Mol Cell Endocrinol 2002; 188: Attardi BJ, Burgenson J, Hild SA, Reel JR. In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124 and mifepristone. J Steroid Biochem 2004; 88: Stratton P, Hartog B, Hajizadeh N, Merina M, Lee YJ, Nieman LK. A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women. Hum Reprod 2000; 15: Croxatto HB, Brache V, Cochon L, Jesam C, Salvatierra AM, Levy D, et al. The effects of immediate pre-ovulatory administration of 30 mg ulipristal acetate on follicular rupture. Abstract presented at the 8th Congress of the European Society of Gynecology, Rome, Italy, September Stratton P, Levens ED, Hartog B, Piquion J, Wei Q, Merino M, et al. Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB Fertil Steril 2009; 5 February (Epub ahead of print). 14 Passaro MD, Piquion J, Mullen N, Sutehrland D, Zhai S, Figg WD, et al. Luteal phase dose-response relationship of the antiprogestin CDB in normally cycling women. Hum Reprod 2003; 18: Creinin MD, Schlaff WD, Archer DF, Wan L, Frezieres R, Thomas MR, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol 2006; 108: Ulmann A, Scherrer B, Mathe H, Gainer E, HRA Pharm. Meta-analysis demonstrating superiority of the selective progesterone receptor modulator ulipristal acetate versus levonorgestrel for emergency contraception. Abstract and Poster Presentation presented at the 8th Congress of the European Society of Gynecology, Rome, Italy, September Fine P, Ginde S, Morfesisi J., Mathe H, Gainer. A multicentre trial of ulipristal acetate for late-intake emergency contraception. Abstract presented at the 8th Congress of the European Society of Gynecology, Rome, Italy, September Cameron S, Glasier A, Fine P, Mathe H, Gainer E. Ulipristal aceate compared to levonorgestrel for emergency contraception within five days of unprotected intercourse: a randomised controlled trial. Abstract presented at the 8th Congress of the European Society of Gynecology, Rome, Italy, September Mansour D. EllaOne : a second-generation emergency contraceptive? J Fam Plann Reprod Health Care 2009; 35: British National Formulary, Vol. 57. March The FSRH Clinical Effectiveness Unit (CEU) has prepared the information given in this New Product Review. It is based on a structured search and review of published evidence available at the date of preparation. This New Product Review has been prepared as a service to FSRH members but is not a formal Faculty guidance document. It is not intended to be construed or to serve as a standard of medical care. Such standards are determined on the basis of all clinical data available and are subject to change as scientific knowledge advances. Members are welcome to reproduce this document by photocopying or other means, in order to share the information with colleagues. The CEU welcomes feedback on published documents, and will review all comments received and amend any significant errors. The CEU is, however, unable to respond individually to all feedback. Tel: +44 (0) Fax: +44 (0) ceu.members@ggc.scot.nhs.uk FSRH