ULIPRISTAL ACETATE (ESMYA )

Transcription

1 Page 1 London New Drugs Group APC/DTC Briefing Document ULIPRISTAL ACETATE (ESMYA ) Contents Summary 1 Background 3 Ulipristal 3 Clinical efficacy 4 PEARL I 4 PEARL II 5 Adverse events 8 Budget Impact model 9 References 10 Appendices 11 Summary The drug and the review In April 2012 ulipristal acetate (Esmya ), was launched in the UK for pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. Ulipristal, a selective progesterone receptor modulator, reduces fibroid volume by inhibiting cell proliferation and inducing apoptosis. The aim of this review is to critically evaluate the main trials submitted for the marketing authorisation. Background Uterine fibroids are the most common benign, hormone-sensitive tumours occurring in 20-40% of women of reproductive age. They are nine times more common in Black women as in Caucasian women. Clinical intervention is required in 20-50% of cases, and includes pharmacological therapies such as NSAIDs, tranexamic acid and GnRH agonists, or, if medical management cannot control symptoms, surgery is warranted. Literature Two pivotal PIII studies (PEARL I and II) have been identified. Efficacy studies The two PEARL studies enrolled women aged with a score on the pictorial blood-loss assessment chart (PBAC) of >100 during days 1-8 of menstruation, an enlarged myomatous uterus and at least one fibroid 3cm diameter, but none >10cm diameter. Exclusion criteria included prior or current treatment with a GnRH agonist, tranexamic acid or mefenamic acid. Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: nwlh-tr.medinfo@nhs.net Further copies of this document are available from URL: PEARL I The aim of PEARL I was to compare the efficacy and safety of ulipiristal 5mg (n=96), 10mg (n=98) or placebo (n=48), given daily for 3 months, on uterine bleeding and fibroid volume. After week 13, patients could have surgery according to their clinical response. There were two primary endpoints: Reduction in uterine bleeding (PBAC <75) was seen in 91% of the 5mg and 92% of the 10mg ulipristal groups, compared with 19% of the placebo group (p<0.001 for both ulipristal groups vs. placebo). Statistically and clinically significant reductions in fibroid volume occurred with ulipristal therapy (-21% with 5mg and -12% with 10mg), compared with placebo (-3%) (p=0.002 and vs. placebo respectively). There were a number of secondary endpoints. Excessive bleeding was controlled in >75% of patients receiving ulipristal by day 8, compared with 6% receiving placebo. Approximately 50% treated with 5mg and 70% treated with 10mg ulipristal became amenorrhoeic within the first 10 days. Greater reductions in fibroid and uterine volume occurred with ulipristal compared with placebo treatment. PEARL II PEARL II assessed the efficacy and safety of ulipristal vs. leuprorelin acetate for treating symptomatic fibroids prior to surgery. Patients were randomised to treatment with ulipristal 5mg (n=98) or 10mg (n=104) daily plus a monthly intramuscular (IM) saline injection, or placebo tablets and a monthly leuprorelin 3.75mg IM injection (n=101), for 3 months. The primary endpoint, the proportion of patients with uterine bleeding at week 13 (PBAC <75) was achieved in similar proportions of patients in each group (89-98%), indicating non-inferiority of ulipristal to leuprorelin. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 There were a number of secondary endpoints. All three treatments reduced fibroid and uterine size, with greatest reductions seen with leuprorelin therapy. Excessive bleeding was controlled more rapidly with ulipristal, with bleeding attenuated up to 2 weeks earlier than with leuprorelin. All three groups showed similar improvements in pain and quality of life. For those patients who did not undergo surgery, a more sustained effect on fibroid volume was seen up to six months after stopping treatment in those who had been treated with ulipristal. Safety The rate of adverse events did not differ significantly between ulipristal and placebo treatment. Most common adverse events in the ulipristal treatment groups were headache, and pain/discomfort/tenderness in the breasts, but these did not occur to a significantly greater extent than in the placebo group. Moderate-to-severe hot flushes occurred in four times as many patients treated with leuprorelin than with ulipristal. No significant differences between the ulipristal and leuprorelin groups were seen in the proportion of patients reporting other adverse events. Endometrial thicknesses were greater in patients treated with ulipristal than with leuprorelin, but no dysplasia or neoplasia were identified. Ulipristal should not be given with CYP34 inducers or inhibitors, which will increase or decrease its blood levels. Ulipristal can inhibit P-glycoprotein and should not be used with P-gp substrates such as dabigatran. Medicinal products containing progesterone should not be used during ulipristal treatment and for 12 days after stopping ulipristal: ulipristal has inhibitory effects on the progesterone receptor and progesterones in e.g. hormonal contraceptives will compete with ulipristal for this receptor. Critical evaluation The PEARL studies showed that ulipristal is an effective treatment for controlling excessive bleeding and fibroid size in women with uterine fibroids prior to surgery. Both studies are limited by the short duration of treatment; more data are required to assess the long-term safety and efficacy of ulipristal. The length of duration of PEARL II may be limited by the licensed duration of treatment of leuprorelin for this indication in the US, which is 3 months. Neither study assessed treatment-related differences in surgical outcomes. Potential benefits over existing technologies Other current treatments prior to surgery to remove fibroids are GnRH agonists, which have side effects such as hot flushes and reduced bone mineral density. Ulipristal has been shown to have a lower incidence of these side effects in the studies. Ulipristal is an oral therapy; GnRH agonists are given by monthly intramuscular injections for 3-6 months. Potential disadvantages over existing technologies Ulipristal will initially be licensed for use up to 3 months based on available trial data. Leuprorelin and triptorelin can be used for up to 6 months. Health Economics The total cost of treatment per person per treatment cycle, including administration, is estimated as for ulipristal (3 months treatment) vs for leuprorelin (Prostap SR, 4 months) and for goserelin (Zoladex, 3 months). Various assumptions have been made, which are listed in the full budget impact, later in this document. Issues for consideration Ulipristal will be the first orally administered option for reducing excessive bleeding and uterine fibroid size prior to surgery, compared with GnRH analogues which need to be given subcutaneously. This will give patients a choice which they may find preferable. Oral therapy will reduce the time and cost of doctors and nurses who currently administer the subcutaneous treatments. There are only efficacy data for the use of ulipristal for up to 3 months. [Note that the GnRH agonist goserelin is only licensed for 3 months and leuprorelin and triptorelin are licensed for up to 6 months of treatment for reducing uterine fibroids]. Reduction in fibroid volume was maintained for a longer period of time with ulipristal than with leuprorelin in patients who did not undergo surgery. There are no data on the use of ulipristal following a GnRH agonist, or followed by a GnRH agonist. The PEARL studies did not assess surgical outcomes following ulipristal therapy. This document reflects the views of the London New Drugs Group and may not reflect those of the reviewers.

3 Page 3 Background In April 2012 ulipristal acetate (Esmya ), was launched in the UK for pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. The duration of treatment is limited to 3 months. 1 Uterine fibroids (leiomyomas) are the most common benign, hormone-sensitive tumours in women of reproductive age, occurring in 20-40%. 2;3 Fibroids are at least nine times more common in black women than in Caucasian women, and Asian women have the lowest incidence. 2 Many are undiagnosed and while most women with fibroids do not have symptoms, 20-50% require clinical intervention. 4 The most common symptoms are pelvic pain, pelvic pressure and menorrhagia, which can result in irondeficiency anaemia. 2;4 Women may also experience infertility, miscarriage, pre-term deliveries and complications in late pregnancy. 4 Management is pharmacological or surgical. NSAIDs are used to reduce menstrual blood loss and dysmenorrhoea by antagonising prostaglandins which cause the uterus to contract, leading to pain. 5 Tranexamic acid and danazol reduce heavy bleeding. Tranexamic acid inhibits fibrinolysis. Danazol creates a high androgen and low oestrogen environment, leading to fibroid shrinkage, but use is limited by undesirable side effects such as acne, hirsutism and weight gain. 5 Oral contraceptive pills are used to control menorrhagia and dysmenorrhoea but can increase fibroid size because they are oestogendependent. 5 GnRH agonists reduce hormonal stimulation of fibroids and can reduce fibroids to approximately 25-50% of their size within 3 months, but the fibroids regrow to their former size within 3-6 months of stopping treatment. GnRH agonists also cause amenorrhoea, menopausal symptoms and bone loss. 4 NICE guidance recommends that GnRH agonists are used for 3-4 months prior to a hysterectomy or myomectomy when fibroids are causing an enlarged or distorted uterus. 6 Some GnRH agonists are licensed for the reduction of uterine fibroids in women with heavy bleeding, prior to surgery, but can only be used for up to 3 months (goserelin) and up to 6 months (triptorelin and leuprorelin). 7 Surgery is indicated when the uterus is greatly enlarged, pressure symptoms are present, medical management cannot control the symptoms and fertility is an issue. 2 A hysterectomy is the only definitive procedure for the permanent removal of fibroids, but for women who want to have children or retain their uterus, a myomectomy (removal of fibroids) is the alternative procedure. 4;6 A concern with a myomectomy is that the fibroids may reappear and require further surgery. 6 Uterine artery embolisation (UAE) avoids major surgery and preserves the uterus. In UAE, an embolic agent (such as polyvinyl alcohol) is injected into the uterine arteries, flowing preferentially into the fibroid vessels, and ultimately limiting the blood supply to the fibroids, causing them to shrink. 4;5 Ulipristal Ulipristal is a selective progesterone receptor modulator which has a tissue-specific partial progesterone antagonist effect, acting on progesterone receptors in myometrial and endometrial tissue and depriving uterine fibroids of growth stimulation due to progesterone. 3;8 Ulipristal reduces fibroids through inhibition of cell proliferation and induction of apoptosis. 1 Treatment with ulipristal (Esmya ) is 5mg daily started during the first week of a menstrual cycle, for up to 3 months. 1 There are no data for using ulipristal for longer than 3 months, or for repeat courses. 1 A missed dose should be taken as soon as possible, unless the dose was missed by more than 12 hours, in which case the missed dose should not be taken and the usual dosing schedule resumed the next day. 1 Most patients will complete their first menstruation but will not menstruate again until after treatment is stopped; menstrual cycles generally resume within 4 weeks. 1 Special populations No dose adjustment is required in patients with mild or moderate renal impairment or mild hepatic impairment. 1 Due to the lack of data in patients with severe renal impairment and moderate-severe hepatic impairment, ulipristal should not be used in these patients. The safety and efficacy of ulipristal has only been established in women aged 18 years and over. Ulipristal should not be used in patients with uterine, cervical, ovarian or breast cancer, in those with genital bleeding of unknown cause or in those who are pregnant/breast feeding. Interactions Contraceptive methods containing progestagens should not be used concomitantly; non-hormonal methods of contraception are recommended. 1

4 Page 4 Ulipristal acts as a selective progesterone receptor modulator and has inhibitory effects on the progesterone receptor; hormonal contraceptives are likely to compete with ulipristal for this receptor. Medicinal products containing progesterone should not be taken within 12 days of stopping ulipristal treatment. Concomitant use with P-glycoprotein substrates (e.g. dabigatran or digoxin) is not recommended because ulipristal may inhibit P-gp and increase plasma levels of medications that are P-gp substrates. 1 Concomitant use with moderate/potent CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, ritonavir) or inducers (e.g. rifampicin, carbamazepine, phenytoin) is not recommended because these will increase or decrease ulipristal blood levels. 1 Clinical efficacy There are two main randomised, parallel-group, double-blind phase III, 13-week studies: PGL4001 (Ulipristal acetate) Efficacy Assessment in Reduction of Symptoms due to Uterine Leiomyomata (PEARL I and PEARL II). These studies have been classed as class A data in the New England Journal of Medicine. Inclusion criteria for women aged were a score on the pictorial blood-loss assessment chart (PBAC, see Appendix 1) higher than 100 during days 1-8 of menstruation (range 0-500, higher score indicating more bleeding), a myomatous uterus with a size equivalent to a uterus of 16 weeks gestation, at least one fibroid 3cm diameter but none >10cm diameter, and a body-mass index of ;9 In PEARL I, an additional inclusion criterion was fibroidrelated anaemia (Hb 10.2g/dL). 3 Uterine bleeding was assessed using the PBAC; menorrhagia was defined as a PBAC score of >100 during a menstrual period, corresponding to a blood loss of 80mL. Exclusion criteria included: history of uterine surgery (except Caesarean section or cervical conisation), endometrial ablation or uterine artery embolisation, history of or current gynaecological cancer, current endometrial hyperplasia, haemoglobinopathy, severe coagulation disorder, uterine polyp >2cm, previous or current treatment for fibroids with a GnRH agonist, treatment with agents that affect CYP3A4 or those taking progestins, aspirin, mefenamic acid, anticoagulants, antifibrinolytic drugs or systemic glucocorticoids. 10;11 PEARL I The aim of PEARL I was to assess the efficacy of ulipristal 5mg and 10mg daily on uterine bleeding and fibroid volume in 242 women with symptomatic fibroids who were planning to undergo surgery. 3 Patients were randomised to treatment with 5mg (n=96), 10mg (n=98) or placebo (n=48) per day, stratified by haematocrit level ( or >28%) and race (black or other). Treatment started during the first 4 days of menstruation, and all patients received 80mg iron supplementation. Patients could have surgery after week 13 according to their clinical response, but no further pharmacologic treatment of fibroids was given. At baseline, median PBAC scores ranges from 330 to 376. The median fibroid volume (cm 3 ) was smaller in the placebo group, (61.9, range 24.8 to 158.9) than in the 5mg (100.7, range 40 to 205.3) and 10mg (96.7, range 31.7 to 181.3) groups. Pain, as assessed by the Visual Analogue Scale, was rated higher in the placebo group (49.5) than in the 5mg and 10mg groups (39.0 for both). Efficacy analyses were carried out in the intention-to-treat population (ITT). The efficacy outcome for each dose group was considered to be successful only if there were significant improvements over placebo in both co-primary endpoints. The last observation carried forward method was used for missing values. The study would have 90% power to show a significant between-group difference if 240 patients were randomised. The co-primary endpoints were the percentage of patients with a reduction in uterine bleeding at week 13, defined as a PBAC score (summed over the preceding 28 days) of <75, and the change in total fibroid volume from screening to week 13. Menstrual bleeding was controlled in 91% of the 5mg group and 92% of the 10mg group, compared with 19% of the placebo group (further results in Table 1). Clinically and statistically significant reductions in uterine fibroid size was seen in both ulipristal groups (-21% in the 5mg and -12% in the 10mg groups) compared with the placebo group (-3%). There were a number of secondary endpoints, details of which are in table 1: The median PBAC scores during weeks 9-12 were significantly lower with ulipristal treatment compared with placebo treatment. Excessive bleeding was controlled in >75% of patients receiving ulipristal by day 8, compared with 6% receiving placebo.

5 Page 5 Amenorrhoea (PBAC 28-day score 2 at weeks 9 and 13) was achieved in significantly more patients treated with ulipristal than with placebo. Approximately 50% treated with 5mg and 70% treated with 10mg became amenorrhoeic within the first 10 days. Significantly greater reductions in uterine and fibroid volume (at least a 25% reduction) were achieved with ulipristal treatment. Changes in haemoglobin were significantly greater with ulipristal treatment. Pain, as assessed by the Short-Form McGill Pain Questionnaire, (range 0-45, higher scores indicating more pain), Visual Analogue Scale (0=none, 100=worst) and discomfort associated with fibroids (score 0-28, higher indicating more discomfort, see Appendix 2) were significantly improved with ulipristal treatment. Approximately half the patients in each group had fibroid surgery after completing the study. Menstruation occurred on average 30 days after stopping ulipristal treatment. In summary: the use of ulipristal was effective in controlling excessive bleeding and reducing fibroid size in women with severe bleeding and associated anaemia at baseline. Bleeding was controlled within 8 days of starting treatment. Self-reported pain and discomfort due to fibroids was also improved significantly with ulipristal therapy. The side effect profile of ulipristal was similar to that of placebo. The study is limited by the short duration of treatment: more data are required to assess long-term benefits and risks of ulipristal treatment. The study did not assess treatment-related differences in surgical outcomes. Only the 5mg strength is available and licensed for use in the UK. PEARL II The aim of PEARL II was to assess the efficacy and side effects of ulipristal versus leuprolide acetate (leuprorelin) for treating symptomatic uterine fibroids prior to surgery. 9 Patients were randomised to 5mg (n=98) or 10mg (n=104) ulipristal daily plus an intramuscular saline injection once a month, or placebo tablets plus a 3.75mg leuprorelin acetate injection once a month (n=101). Randomisation was stratified to avoid imbalance with respect to race or ethnic group. Treatment was started within 4 days after the start of the menstrual period and continued until week 13, when patients could have surgery. Approximately 10% of enrolled patients were black. The me- Table 1: Results from PEARL I 3;10 Primary endpoints Placebo (n=48) Ulipristal 5mg (n=95) Ulipristal 10mg (n=94) PBAC <75 9/48 (19%) 86/94 (91%), p< /93 (92%), p<0.001 Median % change in total fibroid volume (range) Secondary endpoints 3.0 (-19.7 to 23) (-41.2 to -1.1), p= (-39.1 to 4.3), p=0.006 Median PBAC score, wk 9-12 (range) 336 (115 to 543) 0 (0 to 5) 0 (0 to 0) Median change from baseline in PBAC, to wk (-216 to 58) -329 (-571 to -205), p< (-527 to -226), p<0.001 Amenorrhoea, PBAC 2, weeks /48 (6%) 69/94 (73%), p< /93 (82%), p< % total reduction in fibroid vol, wk 13 8/45 (18%) 35/85 (41%), p= /80 (41%), p= % reduction in uterine volume, wk 13 3/47 (6%) 30/88 (34%), p< /85 (28%), p=0.006 Changes from baseline to week 13 Haemoglobin, g/dl +3.10± ±1.90, p< ±1.83, p<0.001 Pain assessment: SF McGill , p= , p=0.04 Visual analogue scale , p= , p=0.08 Discomfort questionnaire -6.0 (-9 to -2) -9.0 (-13 to -6), p= (-14 to -5), p<0.001 P values: ulipristal vs. placebo

6 Page 6 dian total volume (cm 3 ) of the three largest fibroids at baseline was greatest in the 5mg group (79.6, range 30.3 to 151.0) and smallest in the 10mg group (47.6, range 24.1 to 110.6). Efficacy analyses were carried out in the modified ITT and per-protocol populations. The sample size (95 per group) was based on the requirement to show non-inferiority of ulipristal to leuprorelin with a power of 90% and a pre-specified non-inferiority margin of -20%. The per-protocol population (mitt excluding patients with major protocol deviations and <80% compliance) was the primary interest for the non-inferiority analysis. The last observation carried forward method was used for missing values. The primary endpoint was the proportion of patients with uterine bleeding at week 13 defined as a PBAC score <75 for the preceding 4 weeks. In the perprotocol population, similar proportions of patients in each group reached the primary endpoint, indicating non-inferiority for both doses of ulipristal in controlling bleeding (see table 2, page 7, for further results). [The lower limit of the confidence interval was more than the prespecified non-inferiority margin of -20%.] A subsequent superiority analysis showed that ulipristal 10mg was superior to leuprorelin (p=0.03). There were a number of secondary endpoints (see table 2). All three treatments reduced the volume of the three largest fibroids and uterine volume, with the greatest reductions seen with leuprorelin treatment. Median PBAC scores at week 13 were 0 in all three groups. Excessive bleeding was controlled more rapidly with ulipristal than with leuprorelin (p<0.001, both doses vs. leuprorelin). Amenorrhoea was induced more quickly in ulipristal-treated patients, with bleeding attenuated up to 2 weeks earlier than with leuprorelin treatment (p<0.001). All three groups showed similar improvements in pain, quality of life and haemoglobin levels. Approximately half the patients had surgery and for those who did not have surgery, bleeding, pain and quality of life improvements were sustained during follow-up (up to week 38) without treatment. 11 Menstruation returned on average days and 43 days after end of treatment with ulipristal and leuprorelin respectively. treatment, but volume reduction was maintained for 6 months in those who had been treated with ulipristal (see figure 1, page 8 11 ). The investigators suggest that this is due to apoptosis of the leiomyoma cells. In summary: The efficacy of ulipristal to reduce bleeding associated with fibroids was non-inferior to that of leuprorelin. All three treatments groups responded well to treatment, with the majority of patients achieving PBAC scores <75% at 13 weeks. Reduction in fibroid volume was maintained for a longer time after stopping ulipristal than after stopping leuprorelin; this was based on exploratory analysis of patients who did not undergo surgery (approximately half). The incidence of hot flushes was significantly higher with leuprorelin treatment, and there may be a higher incidence of bone resorption with leuprorelin, compared with ulipristal. The study has limitations which are the same to those of PEARL I. Surgical outcomes were not assessed, though the numbers and types of surgery were similar in the three groups. Treatment was given for only 13 weeks, so long-term efficacy and safety data are lacking. The duration of the study is likely to be based on the licensed duration of treatment of leuprorelin: in the US, leuprorelin can be used for up to 3 months to treat excessive bleeding caused by uterine fibroids, prior to surgery. 12 In the UK, leuprorelin can be used for up to 6 months. 7 Exploratory analysis of the women who did not undergo surgery showed that fibroids began to enlarge approximately 1 month after stopping leuprorelin

7 Page 7 Table 2: Results from PEARL II 9;11 Endpoints at week 13 Ulipristal 5mg (n=93) Ulipristal 10mg (n=95) Leuprorelin (n=93) PBAC <75 84/93 (90%) 93/95 (98%) 82/92 (89%) Difference vs. leuprorelin %, 95% CI 1.2 (-9.3 to 11.8) 8.8 (0.4 to 18.3) - Median % change in total fibroid volume (range) -36 (-58 to -11) -42 (-69 to -14) -53 (-69 to -36) Difference vs. leuprorelin %, 95% CI 1.23 (0.99 to 1.52) 1.12 (0.91 to 1.38) - Amenorrhoea, PBAC 2 70/93 (75%) 85/95 (89%) 74/92 (80%) Median time to amenorrhoea 7 days, p< days, p< days Uterine volume, % change from baseline, median -20 (-40 to -3) -22 (-45 to 0) -47 (-57 to -35) Haemoglobin, g/dl 12.8± ± ±1.6 SF McGill, score, median (range) 2.0 (0 to 4) 1 (0 to 3) 0 (0 to 4) SF McGill change from baseline, median -5 (-11 to -2) -6 (-14 to -1) -5.5 (-14.5 to 2) Uterine fibroid symptom and QoL questionnaire 76.4± ± ±23.0 Serum oestradiol, picogram/ml (median) 64, p< , p< , p<0.001 Adverse events Moderate to severe hot flushes 11/97 (11%), p< /103 (10%), p< /101 (40%) Headache 25/97 (25.8%) 19/103 (18.4%) 29/101 (28/7%) Mean endometrial thickness 9.4mm, p< mm, p< mm Non-physiological endometrial changes 58% 59% 12% Endpoints at week Ulipristal 5mg (n=43) Ulipristal 10mg (n=45) Leuprorelin (n=43) Patients who did not have surgery PBAC, median 236 (143 to 387) 141 (103 to 311) 239 (103 to 458) PBAC, median change from baseline -73 (-242 to 65) -96 (-155 to -6) -115 (-161 to 19) Total volume of 3 largest fibroids, median 29.1 (9.5 to 55.4) 17.7 (7 to 47.6) 32.7 (17 to 65.3) % change from baseline, median -44.8% (-75.1 to -12) -54.8% (-75 to 1.8) -16.5% (-41.1 to 19.3) Uterine volume, % change from baseline, median -21.8% (-37.7 to -5.6) (-24.6 to 4.7) (-22.9 to -1.0) SF McGill score, median 2 (0 to 6) 2.0 (0.0 to 6.0) 1.0 (0.0 to 5.0) SF McGill change from baseline, median -3.0 (-9 to -1) -4.0 (-10 to -1) -2.0 (-8 to 1) VAS score, median 8.0 (0 to 34) 9.0 (0 to 24) 3.0 (0 to 32) VAS change from baseline, median -20 (-43 to -1) -27 (-46 to -8) -23 (-43 to 0) UFS QoL, mean 38.7± ± ±24.9 UFS QoL, change from baseline, mean -25.4± ± ±25.8 A lower limit of the CI of more than -20% indicates non-inferiority. A lower limit of the CI of more than zero indicates superiority. P values: ulipristal vs. leuprorelin UFS-QoL: uterine fibroid symptom and quality of life questionnaire, symptom score 0-100, higher score indicating increased severity

8 Page 8 Adverse events In PEARL I, the rate of adverse events did not differ significantly between the three groups. 3 The most common adverse events in the ulipristal group were headache (4-10%) and pain, discomfort or tenderness in the breasts (2-6%), but these events did not occur to a significantly greater extent than in the placebo group. Less than 3% of patients experienced hot flushes. There was no significant difference between the treatments in mean endometrial thickness. Two serious adverse events: one event of a fibroid protruding through the cervix (placebo group) and one event of uterine haemorrhage (10mg group). Three serious adverse events occurred within 1 month of follow up: one case of breast cancer (placebo group) and one event each of ovarian haemorrhage and uterine haemorrhage (5mg group). One case of menometrorrhagia (excessive, prolonged uterine bleeding at irregular, frequent intervals, placebo group) and one of uterine haemorrhage (10mg group) occurred during follow-up to 6 months. Oestradiol levels after ulipristal treatment were consistent with midfollicular-phase levels for a premenopausal woman (60-150picogram/mL). In PEARL II, moderate to severe hot flushes occurred in four times as many patients treated with leuprorelin than ulipristal. No significant differences between the ulipristal and leuprorelin groups were seen in the proportion of patients reporting other side effects, or discontinuing treatment because of adverse effects. Endometrial thicknesses were greater in patients treated with ulipristal but biopsy examinations gave no reason for concern; there was no dysplasia or neoplasia identified. Non-physiological endometrial changes occurred in five times as many patients treated with ulipristal than with leuprorelin, but after 6 months of treatment-free follow-up in women who did not have surgery, the changes were low and similar in all three study groups (6-7%). Median levels of one of the four markers of bone turnover monitored during the study (CTX) were significantly lower at the end of treatment in the ulipristal groups than in the leuprorelin group (158 to 175 vs. 258 mcg/mmol, p< ), which may indicate a higher rate of bone resorption in patients receiving leuprorelin.

9 Page 9 Health economics / budget impact model PreGlem UK have provided the follow budget impact model. 13 An interactive model is available from them; local data can be inputted into this model. Produced by the London New Drugs Group. Correspondence to Alexandra Denby, Regional MI Manager, London Budget Impact Model 13 Cost per treatment cycle Leuprorelin (Prostap SR) Goserelin (Zoladex) Ulipristal (Esmya ) Service provision costs Specialist diagnosis (20 mins) Initial of treatment Follow-on administration (GP consultation) Total cost of treatment administration Follow-up by specialist (20 mins) Total service provision costs Drug cost per injection per injection per month 4 injections given 3 injections given 3 months treatment Total drug cost Total cost Cost to Acute Trust (2 x specialist consults plus drug costs) Cost to Primary Care (GP consults plus drug costs) x = x x x = x x x = Budget impact considering patient 25 patients 25 patients 25 patients numbers Total cost 12, , , Assumptions made in model: First initiation of GnRH agonist is made by the consultant as part of the diagnosis. Subsequent administrations are made in primary care. No GP consultation for ulipristal prescription. 4 months treatment with Prostap SR is compared with 3 months of Zoladex and of ulipristal, based on customer insight to the average number of months of GnRH agonist treatment used. All default consultation/administration costs are based on actual costs estimated by the Personal Social Services Research Unit, not on National Tariff Prices which would be the commissioning cost. Tariff prices are likely to be higher. GPs will receive a fee for administering GnRH agonist. Table 3: Basic NHS costs Treatment Dose Cost Ulipristal (Esmya ) 5mg orally daily for a maximum of 3 months. Goserelin (Zoladex) Leuprorelin acetate (Prostap SR DCS) Triptorelin (Decapeptyl SR) Cost of hysterectomy 3.6mg by SC injection every 28 days for a maximum of 3 months, in women who have anaemia due to uterine fibroids, prior to surgery mg by SC or IM injection every month for 3-4 months (max 6 months), to reduce size of uterine fibroids and associated bleeding prior to surgery. 7 3mg by IM injection every 4 weeks for at least 3 months, max 6 months, to reduce size of uterine fibroids. 7 Without major cc: 2,599 x MFF With major cc: 3,684 x MFF per 3.6mg injection per 3.75mg injection per 3mg injection7

10 Page 10 Produced by the London New Drugs Group. Correspondence to Alexandra Denby, Regional MI Manager, London Medicines Information Centre, Northwick Park Hospital, Watford Road, Harrow, Middlesex. HA1 3UJ. This document reflects the views of the LNDG and may not reflect those of the reviewers. The LNDG would like to thank Dr Alvan Priddy, Consultant Gynaecologist, NWLH NHS Trust for his comments on this review. PregLem UK has commented on this review. Embase: ULIPRISTAL/ AND UTERUS MYOMA Medline: ulipristal.af and LEIOMYOMA/ Reference List (1) Summary of Product Characteristics. Esmya 5 mg Tablets (ulipristal acetate). Date of first authorisation: 23 February Preglem UK (2) Fibroids. Document ID: 1236, version 25. Last checked 04/01/12. Willacy, H. (3) Donnez J, Tatarchuk TF, Bouchard P et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. (PEARL I). N Engl J Med 2012; 366(5): (4) McCarthy-Keith DM, Armstrong AY. Innovations in uterine fibroid therapy. Therapy 2011; 8(2): (5) Duhan N. Current and emerging treatments for uterine myoma - an update. International Journal of Women's Health 2011; 3: (8) Summary of opinion (initial authorisation). Esmya, ulipristal acetate. EMA/679632/2011. Committee for Medicinal Products for Human Use (CHMP). (9) Donnez J, Tomaszewski J, Vázquez F et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. (PEARL II). N Engl J Med 2012; 366(5): (10) Donnez J, Tatarchuk TF, Bouchard P et al. Supplementary appendix: Ulipristal acetate versus placebo for fibroid treatment before surgery. (PEARL I). N Engl J Med 2012; 366 (5). (11) Donnez J, Tomaszewski J, Vázquez F et al. Supplementary appendix: Ulipristal acetate versus leuprolide acetate for uterine fibroids. (PEARL II). N Engl J Med 2012; 366(5). (12) Lupron Depot 3.75mg (leuprolide acetate for depot suspension). Rev 1/2012. Abbott Laboratories prescribing-information.cfm (13) Esmya Budget Impact Model. April PG -ADV 12/0018. Preglem UK (14) Department of Health, Welsh Government. National Health Service England and Wales. Drug Tariff April TSO, London., April_2012/mindex.htm (6) Clinical Guideline 44. Heavy menstrual bleeding. National Collaborating Centre for Women's and Children's Health (7) British National Formulary 63rd edition. March Ryan, RSM. editor. British Medical Association and Royal Pharmaceutical Society of Great Britain.

11 Page 11 Appendix 1: PBAC score 3 The pictorial blood-loss assessment chart (PBAC) is a validated method used to assess menstrual blood loss. 3 Monthly scores ranged from 0 to >500, with higher scores indicating more bleeding. Patients record the number of tampons or sanitary pads they use and the extent of soiling with blood. Menorrhagia was defined as a PBAC score of >100 during one menstrual period, corresponding to a blood loss of >80mL. A PBAC score of 400 corresponds to a blood loss of approximately 300mL, or the use of approximately 80 tampons or pad. Appendix 2: Measurement of Discomfort due to Uterine Fibroids Questionnaire 10 Seven symptoms evaluated: bleeding, abdominal pressure, urination frequency, daily activity, fatigue, mood, sexual activity. Minimum score 0, maximum worst score 28. This was developed by the study sponsor using questions from other validated questionnaires, because there was no disease specific quality of life questionnaire validated in the languages in the participating countries.