ESMYA - ESMYA - CT 12237 - Version anglaise
Description
Présentation ESMYA 5 mg, comprimé B/28 - Code CIP : 2225789 Mis en ligne le 02 avr. 2013 Substance active (DCI) ulipristal (acétate d') Gynécologie - Nouveau médicament Progrès thérapeutique mineur par rapport à la leuproréline dans le traitement pré-opératoire des symptômes modérés à sévères des fibromes utérins ESMYA a l’AMM dans le traitement pré-opératoire des symptômes modérés à sévères des fibromes utérins chez la femme en âge de procréer.Il diminue l’abondance des saignements avant chirurgie, mais ne doit pas pour autant être utilisé comme traitement médical des fibromes utérins.Il représente un progrès thérapeutique mineur par rapport à la leuproréline en termes de tolérance. Pour en savoir plus, téléchargez la synthèse ou l'avis complet ESMYA. Code ATC G03AD02 Laboratoire / fabricant GEDEON RICHTER FRANCE ESMYA 5 mg, comprimé B/28 - Code CIP : 2225789 Mis en ligne le 02 avr. 2013
Informations
| Publié par | haute-autorite-sante-maladies-appareil-genital |
| Publié le | 18 juillet 2012 |
| Nombre de lectures | 38 |
| Licence : |
En savoir + Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
|
| Langue | English |
Extrait
The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 18 July 2012 ESMYA 5 mg, tablet B/28 (CIP code: 222 578-9) Applicant: GEDEON RICHTER FRANCE Ulipristal acetate ATC code (year 2011): not yet allocated List I Special conditions for prescribing and dispensing: prescription restricted to specialists in medical gynaecology or gynaecology-obstetrics Date of Marketing Authorisation and of its amendments: 23 February 2012 (centralised procedure) Reason for the request: Inclusion on the list of medicines reimbursed by National Health Insurance and approved for hospital use. Medical, Economic and Public Health Assessment Division
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1.
CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient Ulipristal acetate 1.2. Indication(s) “Ulipristal acetate is indicated 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. 1.3. Dosage “The treatment consists of one tablet of 5 mg to be taken orally once daily for up to 3 months. Treatment should be started during the first week of a menstrual cycle. There are no data available on treatment with a duration longer than 3 months or on repeat courses of treatment, therefore, treatment duration should not exceed 3 months. If a patient misses a dose the patient should take ulipristal acetate as soon as possible. If the dose was missed by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule. Special populations Renal impairment No dose adjustment is recommended in patients with mild or moderate renal impairment. In the absence of specific studies, ulipristal acetate is not recommended in patients with severe renal impairment, unless the patient is closely monitored. Hepatic impairment No dose adjustment is recommended for patients with mild hepatic impairment. In the absence of specific studies, ulipristal acetate is not recommended in patients with moderate or severe hepatic impairment unless the patient is closely monitored. Paediatric population There is no relevant use of ulipristal acetate in the paediatric population. The safety and efficacy of ulipristal acetate was only established in women of 18 years and older.
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2.
SIMILAR MEDICINAL PRODUCTS
2.1. ATC Classification Not yet allocated. 2.2. Medicines in the same therapeutic category 2.2.1 Strictly comparator medicines Not applicable. 2.2.2 Non-strictly comparator medicines Proprietary medicinal product AB (INN) IAB Route of administration Inclusion of the extension of indication for pre-operative treatment of uterine fibroids, 1999: ENANTONE L.P. High AB -3.75 mg - IAB III, if a reduction in fibroid size is (leuprorelin) required to facilitate or change the operative S.C. or I.M technique (endoscopic myomectomies) Renewed inclusion, 2002 - High AB Inclusion of the extension of indication for pre-operative treatment of uterine fibroids, 2000: DECAPEPTYL - High AB L.P. 3 mg - IAB III, if a reduction in fibroid size is (tripteorlin) required to facilitate or change the operative I.M technique (endoscopic myomectomies) Renewed registration, 2011 - High AB GONAPEPTYL Registration, 2002: 3.75 mg - High AB (triptorelin) - No IAB compared to comparator S.C. or I.M medicines. 2.3. Medicines with a similar therapeutic aim None.
Indication
Pre-operative treatment of uterine fibroids: - associated with anaemia (with a haemoglobin of 8 g/dl or lower), - when reduction in fibroid size is required to facilitate or change the operative technique, endoscopic surgery, transvaginal surgery. Duration of treatment is limited to 3 months.
Pre-operative reduction in the size of the fibroid to reduce bleeding and pain from symptomatic uterine fibroids.
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3.
ANALYSIS OF AVAILABLE DATA
The applicant submitted two comparative clinical studies: one placebo-controlled study (PGL07-021) and one study against a GnRH analogue (PGL07-022). 3.1. Efficacy Study PGL07-021 Primary objectives: To demonstrate the efficacy of two doses (5 mg and 10 mg) of the proprietary medicinal product ESMYA: - on reducing excessive bleeding from uterine fibroids before surgery. Excessive bleeding was defined as a PBAC score1> 100 (cf. illustrated grid to be completed by patients in the appendix). - on reduction in fibroid volume. Secondary objectives: - demonstrating the efficacy of the proprietary medicinal product ESMYA in correcting anaemia as a result of bleeding. Method: Double-blind, randomised study on three parallel groups (2/2/1 randomisation), comparing two dosages of ESMYA to a placebo. Primary efficacy endpoints: - Proportion of patients with a PBAC score < 75 at the end of treatment. - change in total fibroid volume measured by MRI between the start and end of the study. Secondary efficacy endpoints: - change in haemoglobin, ferritin and haematocrit compared to inclusion. The efficacy of ESMYA was not deemed to have been demonstrated unless a significant difference was found in the two primary efficacy endpoints compared to placebo for at least one of the two treatment groups. Main inclusion criteria: - non-menopausal women from 18 to 50 years old - with a bleeding score (PBAC) > 100 from D1 to D8 of their menstrual bleed before the inclusion visit - with anaemia due to a fibroma defined by a haemoglobin of≤ 10.2 g/dL without macrocytosis (mean cell volume≤104 fL) - with a myomatous uterus of volume≤16 weeks of pregnancy - with at least one fibroid diameter≥3 cm and no fibroids of diameter >10 cm - eligible for one of the following surgical procedures: hysterectomy myomectomy, uterine artery embolisation or resection of the endometrium during the 14 weeks following the inclusion visit. Main non-inclusion criteria: - past history of uterine surgery (except for Caesarian section and cervical cone biopsy). - haemoglobin concentration < 6 g/dL or any condition requiring transfusion.
1 Pictorial Bleeding Assessment Chart
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Treatments: - study treatment: ESMYA 5 mg/day for 12 or 13 weeks ESMYA 10 mg/day for 12 or 13 weeks - concomitant treatment: All patients received 80 mg/day of iron for 13 weeks. Results: The major characteristics of the patients included are shown intable 1. Table 1: main characteristics of patients at inclusion Placebo ESMYA 5 mg ESMYA 10 mg n=48 n=95 n 98 = Mean age (years) 41.6 ± 5.6* 41.2 ± 5.9* 42 ± 5.5* Mean weight (kg) 64.7 ± 12.5* 70.1 ± 13 6* 67.1 ± 10.3* . Mean BMI (kg/m2 25.9 ± 4.6*) 24.6 ± 4.4* 25.0 ± 3.9* Median PBAC score (D1 to D8) (119 - 1284) 376 (118 1645) 366 (102 1570) 325 Mean total fibroid volume (cm3) 136.0 ± 191.4* (n=45) 142.5 ± 133.3* (n=89) 134.3 ± 151.0* (n=82) *: standard deviation; : ITT population , cf table2) The main efficacy results are shown intables 2and3. Table 2: efficacy, primary efficacy endpoints, modified ITT population* Endpoint Placebo ESMYA 5 mg ESMYA 10 mg n=48 n=95 n=94 PBAC score < 75, at W13 (% of patients)18.8 91.5 92.5 Difference versus placebo [55.1; 83.2] 72.7 [56.2; 84.0] 73.7 p 0.001 p < 0.001 < % change in total fibroid volume - median - difference versus placebo 3 - 21.2 -12.3 -22.6 [-36.1; -8.2] -18.2 [-33.0; -5.2] p < 0.002§ < 0,006 p§ *: patients who received at least one dose of the study treatment and had a result for at least one of the endpoints; : calculated from last observed values;: Cochran Mantel Haenszel test with Bonferroni corection; §: Van Elteren test with Bonferroni correction; Table 3: efficacy results, secondary efficacy endpoints, modified ITT ESMYA 5 mg ESMYA 10 mg Endpoint P8aln4=ec 5 =9onb n=94 Hb (g/dL): mean change at W13 3.1 ± 0.20 4.1 ± 0.15 4.1 ± 0,15 Hct (%): mean change at W13 7.4 ± 0.60 10.0 ± 0.45 10.0 ± 0.45 Ferritin ( ± 2.60 ± 2.60 26.4 21. 21.1g/L): mean change at W13 4 ± 3.50 Hb: blood haemoglobin; Hct: haematocrit; Note that the percentage change in total fibroid volume was available for 45 patients in the placebo group, 85 in the ESMYA 5 mg group and 80 in the ESMYA 10 mg group.
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Study PGL07-022 Primary efficacy objective: - To demonstrate non-inferiority of ESMYA compared to a GnRH agonist (intramuscular leuprorelin) in reducing excessive bleeding from a uterine fibroid before surgery. Secondary objectives: - To evaluate improvement in symptoms from fibroids: impact on quality of life and on pain, - To evaluate the efficacy of ESMYA in reducing uterine volume and total volume of the three largest fibroids. Primary safety objective - To demonstrate improved safety of ESMYA compared to leuprorelin on symptoms of castration: hot flushes and estradiol concentrations. Method: Double-blind, randomised placebo-controlled study on three parallel groups (1/1/1 randomisation) comparing two dosages of ESMYA to intramuscular leuprorelin. Primary efficacy endpoint - proportion of patients with a PBAC score of < 75 at the end of treatment (Pictorial Bleeding Assessment Chart). The secondary efficacy endpoints included: - change in uterine volume and total volume of the three largest fibroids at the end of treatment (W13) measured by ultrasound, - change in symptoms from uterine fibroids and UFS-QOL quality of life score at week 13 - Change in the PBAC score at W5, W9 and W13 - Change in haemoglobin, haematocrit and ferritin at W5, W9 and W13. Primary safety endpoints: - Serum estradiol concentration at week 13 - Percentage of patients with moderate or severe hot flushes on treatment. Main inclusion criteria: - non-menopausal women from 18 to 50 years old. - with a bleeding score (PBAC) > 100 from D1 to D8 of their menstrual bleed before the inclusion visit - with a myomatous uterus of volume≤16 weeks of pregnancy - with at least one fibroid diameter≥3 cm and no fibroid diameter >10 cm - eligible for one of the following surgical procedures: hysterectomy myomectomy, uterine artery embolisation or resection of the endometrium during the 14 weeks following the inclusion visit. Main non-inclusion criteria: - past history of uterine surgery (except for Caesarian section and cervical cone biopsy) haemoglobin concentration < 6 g/dL or any condition requiring transfusion. -
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Treatments: - ESMYA 5 mg/day for 12 or 13 weeks - ESMYA 10 mg/day for 12 or 13 weeks - leuprorelin 3.75 mg, one intramuscular injection at the start of the study and at weeks 5 and 9. Statistics: A non-inferiority margin of 20% was chosen as the primary efficacy endpoint. Each treatment group was tested separately against the reference treatment. Non-inferiority was deemed to have been achieved if it was found in at least 1 of the 2 groups tested. Results: The major characteristics of the patients included are shown intable 4. Table 4: main characteristics of patients at inclusion ESMYA 5 mg ESMYA 10 mg Leuprorelin 3.75 mg n=97 n=103 n=101 Mean age (years) 40.1 ± 6.2* 40.7 ± 6.3* 40.3 ± 6.2 * Mean weight (kg) 68.3 ± 12.3* 68.8 ± 12.7* 67.9 ± 1 2.2* Mean BMI (kg/m2 ± 4.1* 26.2) 25.4 ± 4.1* ± 4.7* 24.9 Median PBAC score (D1 to D8) 288 (120 1809) 271 (109 - 1960) (102 2104) 275 Mean volume of the 3 largest 126 ± 139.0 93.9 ± 103.5 101.7 ± 100.0 fibroids (cm3) *: standard deviation; NA: not available; : PP population, cf table 4) The primary efficacy results are shown intables 5and6. Table 5: efficacy results, primary efficacy endpoint, PP population* ESMYA ESMYA leuprorelin Endpoint 5 mg 10 mg 3.75 mg n=93 n=95 n=101 PBAC score <75, at W13 (% of patients) 90.3 97.9 89.1 Difference versus leuprorelin1.2 8.8 Lower limit of 95% CI 0.4 9.3 - *: patients who had received at least 80% of the treatment with no protocol violation; : calculated from the last observed values; : Newcombe-Wilson score method with Bonferroni correction;
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Table 6: efficacy results, secondary efficacy endpoints, PP population. Endpoint ESMYA 5 mg ESMYA 10 mg Leuprorelin n=93 n=95 3.75 mg - n=93 % change in uterine volume at W13 - 1.27 ± 123.8* - 13.03 ± 50.3* - 39.0 ± 38.6* % mean change in total volume of the 3 largest - 33.3 ± 56.6* - 53.3 ± 33.9* - 39.6 ± 92.9* fibroids at W13 PBAC score: median change - at W5 -23.0 -31.0 33.0 - at W9 -278.0 -267.0 -269.0 - at W13 -268.0 -268.0 -273.5 Hb (g/dL): mean change at W5 ± 0.1 0.5 ± 0.1 ± 0.1 0.1 0.2 - - W9 0.5 ± 0.1 0.4 ± 0.1 0.3 ± 0.1 - W13 ± 0.1 0.6 ± 0.1 0.5 0.5 ± 0.1 Hct (%): mean change - at W5 0.5 ± 0.3 0.3 ± 0.3 1.4 ± 0.3 - at W9 1.2 1.6 ± 0.3 1.2 ± 0.3 ± 0.3 - at W13 1.6 ± 0.3 2.0 ± 0.3 1.6 ± 0.3 Ferritin (g/L): mean change at - W5 ± 1.6 -2.2 ± 1.6 -1.2 0.9 ± 1.6 -- W9 ± 2.0 1.1 ± 2.0 2.6 ± 2.0 0.9 - W13 2.2 ± 2.2 8.1 ± 2.2¶ 2.7 ± 2.2¶ Change in UFS-QOL score at the end of (n = 56) (n = 67) (n = 50) treatment at W13 - symptom severity -28.2 ± 3,2 - 33. 8 ± 3.0 -27.2 ± 3.4 - total score 20.3 ± 3.3 23.4 ± 3.2 17.8 ± 3.4 *: standard deviation; UFS-QOL: Uterine Fibroid Symptom and health-related quality of life score thescore increases with severity of symptoms; : calculated from the last observed values; : least squares method; Hb: blood haemoglobin; Hct: haematocrit; The ESMYA EPAR states2 that the UFS-QOL questionnaire was administered in six of the seven countries in which the study was performed. 3.2. Adverse effects Study PGL07-021 Adverse events which occurred from treatment start until week 17 (i.e. 4 weeks after the end of treatment) were included. The most common adverse events which occurred during the study are shown intable 7. Table 7: adverse events occurring during the study* Adverse events (% of patients affected) Placebo ESMYA 5 mg ESMYA 10 mg n=48 n=95 n=98 At least 1 AE 45.8% 49.5% 53.1% AE leading to treatment being stopped. 2.1% 1.1% 1.0% The most common adverse events (% of patients concerned) Headache 4.2% 4.2% 10.2% Mastodynia/swollen breasts 0% 2.1% 6.1% Dysmenorrhoea 4.2% 0% 0% Abdominal pain 4.2% 2.1% 3.1% Hypothyroidism 2.1% 4.1% 0% *: safety population: patients who received at least one dose of the treatment during the study; : the clinical study report states that most patients affected had thyroid disease or a TSH result outside of the normal limits at inclusion. No serious adverse events were deemed to be related to the study medicinal product. 2 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_ _ _ port/human/002041/WC500124088.pdf Public assessment re 8/17
Endometrial thickness was measured by MRI at inclusion and at the end-of-treatment visit (week 13). The results of these measurements are shown intable 8. Table 8: endometrial thickness Placebo ESMYA 5 mg ESMYA 10 mg ean endometrial thickness M - at inclusionn=47 n=92 n=88 8.3 ± 3.5 6.8 ± 3.1 7.9 ± 3.3 n=47 n=89 n=88 - at W13 8.2 ± 3.5 8.7 ± 6.1 8.5 ± 5.0 Patients with endometrium >16 mm - at inclusion n (%)* 0 1 (1.1) 2 (2.0) - at W13 n (%)* 1 (2.1)* 10 (10.5) 7 (7.1) *: percentage calculated from population which received at least one treatment dose during the study. An endometrial biopsy was performed at patient selection and at the end of treatment (week 13). Results (a consensus of three independent pathologists) are shown intable 9. Table 9: results of endometrial biopsies ESMYA 10 mgPlacebo ESMYA 5 mg n=48 n=95 n=98 Interpretable biopsies - at inclusion n patients (%) 48 (100.0) 88 (92.6) 95 (96.9) - at W13 n patients (%) 39 (81.3) 78 (82.1) 78 (79.6) Biopsy abnormality - at inclusion 0 1* 0 - at W13 0 1 1 Endometrium "physiological" in appearance§ - at inclusion (%)|| 71.6 73.5 77.1 - at W13 (%)|| 58.3 15.3 12.6 *: atypical hyperplasia, patient excluded from the study; : benign polyp; : hyperplastic polyp; §: "Non-physiological" appearance: epithelial changes and/or large cystic structure in endometrial glands and/or unusual vascular changes: percentage calculated from the population which received at least one treatment dose during the study; The presence of ovarian cysts of diameter≥4 cm by MRI was investigated at inclusion and at the end of treatment (week 13). - one patient had a cyst at the end of treatment in the placebo group, - four patients had a cyst only at the start of the study, two patients had a cyst at the start and the end of the study and five only at the end of the study in the 5 mg group. - two patients had a cyst only at the start of the study, two patients had a cyst at the start and end of the study and two only at the end of the study in the 10 mg group. Study PGL07-021 - extension phase: follow-up without treatment This extension phase included two follow-up visits at the end of treatment: weeks 26 and 38 of the study. During this phase only adverse events related to the intervention stipulated in the protocol, follow-up for ongoing adverse events at the end of treatment and uterine bleeds were to be recorded. Iron could continue to be administered on the investigator's decision. A total of 224 patients took part, 45 in the placebo group, 89 in the 5 mg group and 90 in the 10 mg group. The most common adverse event was anaemia: three cases in the placebo group, four in the 5 mg group and one in the 10 mg group. Metrorrhagia/uterine bleeds were seen in three cases in the placebo group, one case in the 5 mg group and four cases in the 10 mg group.
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One case of endometrial hyperplasia and one polyp were diagnosed in the placebo group. Endometrial thickness was measured by MRI at weeks 26 and 38 in patients who had not undergone hysterectomy or myomectomy. The results of these measurements are shown in table 10. Table 10: endometrial thickness 10 mg ESMYA 5 mgPlacebo ESMYA Mean endometrial thickness - at W26 n=28 n=56 n=55 7.6 ± 3.3 7.1 ± 4.0 7.1 ± 5.0 - at W38 n=28 n=49 n=53 7.8 ± 4.2 6.8 ± 3.8 7.2 ± 3.2 Patients with endometrium >16 mm n (%) - at W26 0 3 (5.0) 3 (5.3) - at W38 1 (3.3) 2 (3.3) 1 (1.8) An endometrial biopsy was performed at week 38 in patients who had not undergone a hysterectomy or endometrial resection. Results (a consensus of three independent pathologists) are shown intable 11. Table 11: results of endometrial biopsies ESMYA 5 mgPlacebo ESMYA 10 mg n=38 n=77 n=78 Interpretable biopsies n patients (%)* 30 (78.9) 60 (77.9) 61 (78.2) Biopsy abnormality - complex atypical hyperplasia 1 (2.6) 0 0 - benign polyp 0 1 (1.3) 0 Endometrium “physiological in appearance (%)* 58.4 60.3 68.4 *: percentage calculated from the number of women who had not undergone a hysterectomy or endometrial resection; : “non-physiological appearance; endometrial changes and/or large cystic structure in endometrial glands and/or unusual vascular changes: The presence of ovarian cysts of diameter≥of MRI was investigated in weeks 26 and4 cm 38: - no patients had a cyst in the placebo group - one patient had one cyst at week 26, two at week 26 and 38 (one of whom had a cyst since inclusion and the other since week 13) and four at week 38 in the 5 mg group - three patients had one cyst at week 26 alone and one at the end of the study in the 10 mg group.
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Study PGL07-022 Main safety criteria: results are shown intable 12. Table 12: results of main safety criteria*: ESMYA 10 m rorelin ESMYA5 mg g Leup n=97 n=103 3.75 mg - n=101 Mean serum E2 concentration (log10) 1.9 ± 0.04 1.8 ± 0.04 1.4 ± 0.04 W13 Proportion of patients who developed moderate or severe hot flushes on 11.3 9.7 39.6 treatment (%) *safety population: patients who received at least one treatment dose during the study; : least squares: methods; Adverse events which occurred from treatment start until week 17 (i.e. 4 weeks after the end of treatment) were included. The most common adverse events which occurred during the study are shown intable 13. Table 13: adverse events which occurred during the study Adverse events (% of patients ESMYA 5 mg ESMYA 10 mg Leuprorelin affected*) n=97 n=103 3.75 mg - n=101 At least 1 AE 77.3 76.7 84.2 At least 1 serious AE related to 0 1.9 (n=2) 0 treatment AE leading to treatment being stopped 1.0 1.9 5.9 The most common adverse events (% of patients affected) Hot flushing 25.8 24.3 65.3 Headache 25.8 18.4 28.7 Abdominal pain 6.2 11.6 13.9 Dysmenorrhoea 4.1 4.9 2.0 Pelvic pain 3.1 4.9 3.0 Ovarian cyst 1.0 4.9 2.0 Mastodynia 4.1 1.0 2.0 Migraine 2.1 2.3 3.0 *: percentage calculated from the population which received at least one treatment dose during the study; : one aggravation of uterine bleeding and one pedunculated fibroid which required hospital admission for removal; Endometrial thickness was measured on ultrasound at inclusion and at the end-of-treatment visit (week 13). The results of these measurements are shown intable 14. Table 14: endometrial thickness measured by ultrasound ESMYA 5 mg ESMYA 10 mg Leuprorelin 3.75 mg Mean endometrial thickness - at inclusion n=96 n=100 n=100 8.9 ± 4.2 8.9 ± 4.3 9.0 ± 3,9 - at W13 n=93 n=98 n=95 9.4 ± 5.7 10.7 ± 5,9 5.1 ± 3,5 patients with endometrium >16 mm - at inclusion n (%)* 5 (5.2) 5 (4.9) 4 (4.0) - at W13 n (%)* 11 (11.3) 15 (14.6) 1 (1.0) *:received at least one treatment dose during the study;percentage calculated from the population which An endometrial biopsy was performed at patient selection and at the end of treatment (week 13). Results (a consensus of three independent pathologists) are shown intable 15.
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