The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 17 October 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 17 October 2012 Examination of the dossier for proprietary medicinal products included for a 5-year period starting on 25 July 2006 (Official Gazette of 23 December 2008) OPTRUMA 60 mg, film-coated tablet B/28 (CIP code: ) B/84 (CIP code: ) Applicant: PIERRE FABRE MEDICAMENT Raloxifene hydrochloride ATC code: G03XC01 (SERM, antiosteoporotic) List I Date of Marketing Authorisation: 5 October 1998, amended on 11 August 2008 (centralised procedure) Reason for request: Renewal of inclusion on the list of medicines refundable by National Health Insurance. Medical, Economic and Public Health Assessment Division 1/15

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Raloxifene hydrochloride 1.2. Indications OPTRUMA is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated. When determining the choice of OPTRUMA or other therapies, including oestrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits Dosage The recommended dose is one tablet daily by oral administration, which may be taken at any time of the day without regard to meals. No dose adjustment is necessary for elderly women. Due to the nature of this disease process, OPTRUMA is intended for long term use. Generally calcium and vitamin D supplements are advised in women with a low dietary intake. Use in renal impairment: OPTRUMA should not be used in patients with severe renal impairment. In patients with moderate and mild renal impairment, OPTRUMA should be used with caution. Use in hepatic impairment: OPTRUMA should not be used in patients with hepatic impairment Contraindications - Hypersensitivity to the active substance or to any of the excipients. - Must not be used in women with child bearing potential. - Active or past history of venous thromboembolic events, including deep vein thrombosis, Hepatic impairment including cholestasis. - Severe renal impairment. - Unexplained uterine bleeding. - OPTRUMA should not be used in patients with signs or symptoms of endometrial cancer as safety in this patient group has not been adequately studied. 2/15

3 2 REMINDER OF THE COMMITTEE S OPINION AND CONDITIONS OF INCLUSION The opinion concerning the inclusion of OPTRUMA in 2001 referred to the opinions concerning the inclusion of EVISTA, hence these opinions are cited in the history of the assessment of OPTRUMA by the Transparency Committee. Opinion of the Committee of 10 May 2000 Inclusion of EVISTA In menopausal women, as the primary aim is overall management of menopause, EVISTA does not provide an improvement in actual benefit compared with hormone replacement therapy. During this time of life, prevention of osteoporosis by raloxifene is recommended in cases where there are a high risk of vertebral fractures and certain contraindications for HRT. The principal contraindications for EVISTA, breast cancer and thromboembolic events, are comparable to those for HRT. In light of current data, the role of EVISTA during menopause is therefore limited. In women who are well past the age of menopause, who are not receiving HRT, prevention of fractures is important and, in this context, EVISTA, as an alternative to hormone replacement therapy, represents a level III improvement in actual benefit in the prevention of vertebral fractures. The Committee requests that the company establish monitoring of the prescription and use of EVISTA. Opinion of the Committee of 24 January Modification of the wording of indications The indication: prevention of non-traumatic vertebral fractures in postmenopausal women at increased risk of osteoporosis has been replaced by the following wording: treatment and prevention of osteoporosis in postmenopausal women. A decrease in vertebral fractures, but not in femoral neck fractures, has been demonstrated. Opinion of the Committee of 4 April 2001 Inclusion of OPTRUMA The actual benefit of OPTRUMA is substantial. Refer to the opinion concerning EVISTA Opinion of the Committee of 1 February Inclusion of B/84 The Transparency Committee recommends inclusion in the list of medicines refundable by National Health Insurance of B/84 in addition to the B/28 packaging. Opinion of the Committee of 5 July Renewal and amendment of the scope of reimbursable indications The Transparency Committee recommends continued inclusion on the list of medicines refundable by National Health Insurance: Scope of reimbursement Treatment of postmenopausal osteoporosis to reduce the risk of vertebral fractures: - in patients with a fracture caused by bone fragility, - in the absence of a fracture, in women with substantially decreased bone density (T-score < -3) or with a T-score -2.5 associated with other risk factors for fractures, in particular, age > 60 years, current or past systemic corticosteroid therapy at a dosage 7.5 mg/day prednisone equivalent, a body mass index < 19 kg/m², a history of femoral neck extremity fracture in a first-degree relative (mother), early menopause (before the age of 40 years). 3/15

4 3 SIMILAR MEDICINAL PRODUCTS 3.1. ATC Classification (2011) G G03 G03X G03XC G03XC01 : Genitourinary system and sex hormones : Sex hormones and modulators of the genital system : Other sex hormones and modulators of the genital system : Selective estrogen receptor modulators : Raloxifene 3.2. Medicines in the same therapeutic category Another proprietary medicinal product containing raloxifene, with the same indications: EVISTA 60 mg is co-marketed with OPTRUMA. NB: Another proprietary medicinal product belonging to the class of selective estrogen receptor modulators (SERM): CONBRIZA (bazedoxifène) is not rembursable. These medicinal products have only demonstrated efficacy against vertebral fractures Medicines with a similar therapeutic aim Medicines which have demonstrated their efficacy in the prevention of vertebral and peripheral fractures, including femoral neck fractures: - the following bisphosphonates with a significant AB: o ACLASTA 5 mg (zoledronic acid), once yearly intravenous perfusion, o ACTONEL (risedronic acid) 5 mg tablet (every day), 35 mg tablet (every week), 75 mg tablet (2 consecutive days per month), ACTONELCOMBI tablet (risedronate 35 mg + calcium 1000 mg + vitamin D 880 IU) (every week), o FOSAMAX (alendronic acid) 10 mg tablet (every day), 70 mg tablet (every week) and the other products containing alendronic acid 10 mg and 70 mg, FOSAVANCE and ADROVANCE (alendronate or alendronate + vitamin D combination) tablet every week. - PROTELOS (strontium ranelate) granules for oral suspension (daily), due to concern raised by the risk of occurrence of serious hypersensitivity reactions of DRESS type and venous thromboembolic events, the AB of PROTELOS is moderate in the population limited to: o o patients with a contraindication to or intolerance to bisphosphonates, patients with no risk factors for venous thromboembolic events, including in particular history of a venous thromboembolic event, age over 80 years, immobility (opinion of 11 May 2011). - PROLIA (denosumab) subcutaneous injection once every six months, vertebral and non-vertebral efficacy including femoral neck (significant AB, IAB level IV as second-line treatment following bisphosphonates) 4/15

5 Other medicines indicated in the treatment of postmenopausal osteoporosis but which do not have demonstrated efficacy in the prevention of femoral neck fractures - FORSTEO (teriparatide), subcutaneous injection every day, refundable in cases of severe osteoporosis (at least two vertebral fractures), efficacy demonstrated in peripheral fractures but not those of the hip. Note: The Committee points out the AB of the following bisphosphonates was judged to be insufficient in December 2010: - DIDRONEL 400 mg tablet (etidronic acid), 1 tablet/14 days/3 months - BONVIVA 150 mg/1 month tablet and 3 mg/3 months solution for injection (ibandronic acid) Hormonal treatments for menopause are indicated in the prevention of osteoporosis if there are also menopausal problems or if other treatments are contraindicated or not tolerated. They are the subject of a re-assessment by the Transparency Committee. Calcium and vitamin D are generally used for adjuvant treatment. 5/15

6 4 UPDATE OF AVAILABLE DATA 4.1. Efficacy Only those studies which were conducted within the indications and at the dosage of the MA and took place after the previous opinion of the Transparency Committee issued on 5 December 2007 have been considered: - a comparative study versus alendronate concerning fractures - two studies on BMD or bone quality, - a combined analysis of mortality in studies that had already been evaluated by the Transparency Committee. Anti-fracture effect of raloxifene versus alendronate 1 The aim of this study was to demonstrate the non-inferiority of raloxifene (RLX, 60 mg per day) compared to alendronate (10 mg per day) with respect to reducing the incidence of osteoporotic fractures (vertebral or non-vertebral) in patients with postmenopausal osteoporosis, no history of vertebral fracture and no previous treatment for osteoporosis. The protocol planned the enrolment of 1750 patients per group in order to attain a power of 90% and to establish non-inferiority with a margin set at 30%. Due to difficulties in recruiting patients who had not received any previous treatment, the study was terminated prematurely. The mean duration of treatment was 312 days and the analysis was performed on 1412 out of 1423 randomised patients. At the time the study was terminated, 22/713 (3.1%) of patients in the alendronate group versus 20/699 (2.9%) of patients in the RLX group had experienced a new fracture. In the absence of statistical power, it is not possible to reach a conclusion concerning the non-inferiority of raloxifene versus alendronate. Densitometric effect of raloxifene versus placebo after treatment with parathormone (PTH) 2 In this study, 380 patients aged from 50 to 80 years with postmenopausal osteoporosis were treated for 1 year with teriparatide 20 µg per day. At the end of this year of treatment, 329 of these 380 patients were randomised to a year of treatment with RLX 60 mg/day (n = 157) or placebo (n = 172). At the end of this second year of treatment, 300 of the 380 patients received 60 mg RLX in an open-label phase. The primary objective was to evaluate the percentage variation of lumbar BMD between RLX and placebo during the course of the second year of the study. During the second year, a decrease in lumbar BMD was observed in both groups, compared to the increase in BMD observed during the first year of treatment with teriparatide. This decrease was however smaller in the RLX group than in the placebo group: -1 +/- 0.3% with RLX and -4 +/- 0.3% with placebo (p < 0.001). Effect on bone microstructure 3 The company also cited the computed tomography results in 15 patients treated with RLX for 15 months, which showed an improvement in bone microstructure parameters. 1 Recker et al. Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone. 2007; 40(4): Adami et al. Effect of raloxifene after recombinant teriparatide [hpth (1-34)] treatment in postmenopausal women with osteoporosis. Osteoporos Int Jan; 19 (1): Radspieler H. Individualized treatment of osteoporosis with medication: preventing fractures by increasing bone mineralization and quality. Int. J. Clin. Rheumatol 2010; 5: 4. 6/15

7 Indirect comparison: The company submitted a publication 4 comparing the decreases in absolute risks of fractures and the number needed to treat (NNT) in order to avoid a fracture for various antiosteoporosis medicines. This was derived from the phase III studies which had formed the basis for the respective MAs. The results of these comparisons, which were performed without the use of validated statistical methods for indirect comparisons, cannot be taken into consideration. Effect of RLX on BMD after treatment with alendronate 5,6 A total of 99 patients with postmenopausal osteoporosis were treated with alendronate 10 mg per day for a mean period of 43 months and were then randomised into three groups to receive placebo, RLX 60 mg/day or to continue with alendronate on an open-label basis for 1 year. The primary endpoints were BMD and bone markers. The patients were not uniform with respect to the numbers having non-vertebral fractures at baseline: 9 in the alendronate group (27.3%), 18 in the placebo group (54.5%) and 16 in the raloxifene group (48.5%). Compared with placebo, alendronate and raloxifene had prevented lumbar bone loss after 1 year (-0.75% with RLX, -0.54% with alendronate and -2.66% with placebo, p < 0.05). The significance of the results of this study is limited (low numbers, intermediate primary endpoint) Safety Pharmacovigilance data (PSUR): As a reminder, the PSUR is common for RLX (EVISTA and the co-marketed product OPTRUMA). Raloxifene obtained authorisation for the first time on 9 December 1997 (USA). It has MAs in 102 countries and is marketed in 71 countries. Outside the European Union, raloxifene is also prescribed to reduce the risk of invasive breast cancer (MA obtained in the USA for this extension of indication on 13 September 2007). The pharmacovigilance data reported for OPTRUM are for the period from December 2005 to November During this period, the following serious adverse effects were reported in France with respect to OPTRUMA: - venous and arterial thromboembolic events (21 cases) Of these 21 cases: o 9 cases of pulmonary embolism, of which 4 resulted from misuse: 2 patients with a personal history of pulmonary embolism/phlebitis, which is a contraindication for the use of RLX, and 2 with a family history, who therefore should not have been treated with RLX. In 6/9 cases, a delayed occurrence of the pulmonary embolism was reported; it occurred within 3 to 6 months after the start of treatment. o 6 cases of deep vein thrombosis/phlebitis occurred. In addition, 2 patients reported deep vein thrombosis/phlebitis associated with pulmonary embolism. o 4 cases of retinal venous thrombosis were reported in patients with risk factors (hypertension, hypercholesterolaemia, concomitant treatment with MTX). o 2 cases of ischaemic stroke and one case of haemorrhagic stroke were reported. The causal relationship with OPTRUMA was judged to be doubtful. This adverse effect was not mentioned in the OPTRUMA SPC. 4 Ringe et al. Absolute risk reduction in osteoporosis: assessing treatment efficacy by number needed to treat. Rheumatol Int. 2010; 30: This study preceded the previous opinion of the Committee concerning EVISTA but will be described in the opinion for OPTRUMA. 6 Michalska D, Stepan J.J, Basson R, Pavo I. The Effect of Raloxifene after Discontinuation of Long- Term Alendronate Treatment of Postmenopausal Osteoporosis, J Clin Endocrinol Metab 2006; 91: /15

8 - cancer: 13 cases of cancer were reported, of which 11 affected the reproductive system (5 breast, 3 uterine, 2 endometrial and 1 ovarian). The causality of these reproductive system cancers, which are not mentioned in the OPTRUMA SPC, was considered to be doubtful in 6/11 cases and could not be evaluated due to insufficient information in 5/11 cases. Other reported cancers, for which the causal relationship with OPTRUMA was judged to be doubtful were: one meningioma and one basocellular carcinoma of the eyelid. - three serious eye disorders were reported during this period, these being two cases of macular degeneration and one of intraocular hypertension, with causality being judged doubtful. Amendments were introduced into the SPC on 12 July 2006, 27 March 2007, 19 November 2007 and 11 August 2008, particularly with respect to the addition of new adverse effects: - thrombocytopenia (very rare <0.01%); - peripheral oedema (rare <0.1%); - venous thromboembolic reaction (rare <0.1%); - arterial thromboembolic reaction (very rare <0.01%). A warning concerning the prescription of OPTRUMA to women with a history of stroke or significant risk factors was added: In a study 7 of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, raloxifene did not affect the incidence of myocardial infarction, hospitalized acute coronary syndrome, overall mortality, including overall cardiovascular mortality, or stroke, compared to placebo. However, there was an increase in death due to stroke in women assigned to raloxifene. The incidence of stroke mortality was 1.5 per 1000 women per year for placebo versus 2.2 per 1000 women per year for raloxifene. This finding should be considered when prescribing raloxifene for postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischaemic attack or atrial fibrillation. In addition, other safety information for RLX obtained from the RUTH study was added to the SPC: - update of the incidence of hot flushes, venous thromboembolic events, leg cramps, peripheral oedema: Across all placebo-controlled clinical trials of raloxifene in osteoporosis, venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis occurred at a frequency of approximately 0.8% or 3.22 cases per 1000 patient-years. A relative risk of 1.60 (CI: ) was observed in patients treated with EVISTA compared to placebo. The risk of a thromboembolic event was greatest in the first four months of therapy. Superficial vein thrombophlebitis occurred in a frequency of less than 1%. In the RUTH study, venous thromboembolic events occurred at a frequency of approximately 2.0% or 3.88 cases per 1000 patient-years in the raloxifene group and 1.4% or 2.70 cases per 1000 patient-years in the placebo group. The hazard ratio for all VTE events in the RUTH study was HR = 1.44 ( ). Superficial vein thrombophlebitis occurred in a frequency of 1% in the raloxifene group and 0.6% in the placebo group. In the RUTH study, the occurrence of vasodilatation (hot flushes) was 7.8% in the raloxifene-treated patients and 4.7% in the placebo-treated patients. In the RUTH study, leg cramps were observed in 12.1% of raloxifene-treated patients and 8.3% of placebo-treated patients. 7 This is the RUTH study included in the combined analysis of the effect of RLX on mortality. 8/15

9 In the RUTH study, peripheral oedema occurred in 14.1% of the raloxifene-treated patients and 11.7% of the placebo-treated patients, which was statistically significant. - addition of the adverse effect cholelithiasis and additional specification of the rate of cholecystectomy. In the RUTH study, cholelithiasis was diagnosed in 3.3% of raloxifene-treated patients and 2.6% of placebo-treated patients. Cholecystectomy rates for raloxifene (2.3%) were not statistically significantly different from placebo (2.0%). Combined analysis of the effect of RLX on mortality 8 The company supplied the results of an analysis of the effect of RLX on all-cause mortality, based on the combined data of three studies (MORE, CORE and RUTH), which had already been reviewed by the Transparency Committee. To recapitulate, the MORE study, which lasted 4 years, evaluated the anti-fracture efficacy of RLX versus placebo in more than 7700 patients and was followed by the CORE study, which lasted 4 years. The RUTH study was conducted in more than 10,000 postmenopausal women with known coronary disease or an increased risk of coronary events. In this study, no change in the incidence of myocardial infarction, hospital admissions for acute coronary syndrome or stroke, nor in overall mortality, including mortality of cardiovascular origin, was observed in the group treated with RLX. However, an increase in the incidence of mortality due to stroke was observed in patients treated with RLX (1.5 per 1000 woman-years for placebo versus 2.2 per 1000 woman-years for RLX). In the MORE and CORE studies, mortality was not evaluated as a primary endpoint, which limits the level of evidence of the results of these studies for this endpoint. The combined analysis of these three studies shows a decrease in overall mortality in favour of RLX (7.88%) compared to placebo (8.65%), p=0.05. There is no statistical difference for deaths of cardiovascular origin (4.93% with placebo vs. 4.97% with RLX). The reduction in all-cause mortality is essentially due to the reduction in non-cardiovascular and non-cancerrelated mortality, in particular mortality of infectious origin. (28 deaths with RLX vs. 51 with placebo, p = 0.01). This decrease remains unexplained. Conclusion concerning safety data: The updated safety data for OPTRUMA, which are based on the study results available and on pharmacovigilance data, show that there is a risk of fatal stroke (which was not included in the SPC during the last opinion of the Committee on the renewed inclusion of OPTRUMA). Otherwise, the safety profile is unchanged (vasomotor symptoms more frequent than in the placebo group in the RUTH study, venous thromboembolic events, leg cramps). 8 Grady et al. Effect of Raloxifene on all-cause mortality. Am J Med 2010; 123: /15

10 5 USAGE DATA FOR THE MEDICINE IMS DOREMA data According to IMS-EPPM data (mobile annual total to February 2012), a total of 132,000 prescriptions were issued for this proprietary medicinal product. The mean daily dosage was 1 tablet and the mean duration of prescription was 142 days. AGIR monitoring An observational study in community practices (GPs, gynaecologists and rheumatologists) has been set up by Daiichi Sankyo France and is currently under way in France (4 th quarter 2010 to 3 rd quarter 2011). The inclusion phase for patients took place between 4 March 2011 and 31 July The protocol planned for the enrolment of 3000 osteoporotic female patients aged 50 years or more receiving a first prescription for osteoporosis medication or a change in such medication. The main objective of the study was to evaluate compliance with official instructions and guidelines concerning the management of postmenopausal osteoporosis in current community medical practice in France with respect to this disease. The secondary objectives are to describe and evaluate: - The population of women affected by postmenopausal osteoporosis - Compliance with medical treatment and dietary and lifestyle advice three months after the consultation - Fears and beliefs concerning osteoporosis and its management among patients and physicians in order to determine their impacts. Results of VISION post-marketing study In response to the request made by the Transparency Committee in its opinions of 10 May 2000 and 24 January 2001, Lilly (new local representative Daiichi Sankyo France) and Pierre Fabre conducted a joint observational follow-up study of the prescription and use of EVISTA and OPTRUMA from 2005 to A population of 2628 patients presenting with a prescription for raloxifene were included, by means of a random sample from 551 pharmacies. The baseline data were integrated into the opinion concerning renewal of inclusion of 5 July The additional data received subsequently correspond to observational data (over 12 months). Main results The mean age of the enrolled patients was 65 years, 98% of them stated they were postmenopausal and 4% were currently receiving hormonal treatment for menopause. In 30% of cases, the patients said they had experienced at least one fracture since menopause: vertebral fracture (13%), fracture of the wrist (12%), femoral neck fracture (2%). A diagnosis of osteoporosis had been established for 50% of patients prior to treatment with raloxifene and, of these, 62% stated that they had received anti-osteoporotic treatment previously. In total, 92% of patients had received prophylaxis or treatment for osteoporosis: non-fracture osteoporosis (36%), fracture osteoporosis (26%), prophylaxis of osteoporosis in postmenopausal women (28%). One or several risk factors for osteoporosis were found in 64% of patients: age 65 years (50%), family history of fractures (19%), history of fractures during minimal trauma (17%), age at menopause < 40 years (11%) and BMI < 19 kg/m 2 (9%). In 76% of cases, bone densitometry was performed before the start of raloxifene treatment and, in 51% of documented cases, osteoporosis was demonstrated (T-score -2.5). 9 9 The WHO has proposed a classification scale of four levels for decreased bone mass: Level 1: normal, bone mass bone mineral density (BMD) shows less than one standard deviation difference from the reference value (T-score greater than -1) Level 2: low bone mass (osteopenia) T-score between -1 and /15

11 In 40% of cases, a second treatment was co-prescribed on the same prescription (calcium-vitamin D in 85% of these cases). At 12 months follow-up, data was available for 1213 patients (i.e. 46.2% of the total of 2,628 enrolled patients). Patients lost to view at 12 months differed from patients not lost to view with respect to educational level (lower in those lost to view) and occurrence of a fracture after menopause (higher incidence in those lost to view). At 12 months, 82.0% of women about whom information was available stated that they were continuing their treatment. The main reasons for discontinuing treatment were the physician s decision (48.2% of cases of discontinuation) and adverse effects (29.2%). Of the 890 patients who had continued treatment, 92.9% forgot less than five doses during the previous four weeks. Forgetting was the main reason the patients gave for non-compliance. The mean duration of treatment was estimated using the Kaplan-Meier method and was 52 +/- 0.5 months, i.e. 4.3 years. However, the large quantity of censored data makes it impossible to estimate the median duration of treatment and its 95% confidence interval. The additional survey that was set up in order to evaluate the outcomes for patients lost to view showed that 64% of these continued with treatment. The rate for continuation of treatment at one year can therefore be extrapolated as being 73.3% for all participants. Conclusion The prescription of raloxifene in this study complied with the indications in the MA in 90% of cases. The ordinance of 10 July 2001, amending the list of medicines refundable by National Health Insurance and the list of medicines approved for use by hospitals and various public services indicated that OPTRUMA only qualifies for use and for reimbursement by National Health Insurance in the following therapeutic indication: "treatment of confirmed postmenopausal osteoporosis with at least one osteoporotic fracture. In this context, the results of this study showed that only 30% of the women had stated that they had experienced at least one fracture since menopause and thus complied with the scope of refundable indications of raloxifene, as defined in In 2006, the Transparency Committee, in its opinion of 5 July 2006 concerning the renewal of inclusion of OPTRUMA, wished to change the scope of the reimbursable indications to the following: Treatment of postmenopausal osteoporosis to reduce the risk of vertebral fractures: - in patients with a fracture caused by bone fragility and, - in the absence of fracture, in women with a substantial decrease bone density (T-score < -3) or with a T-score -2.5 associated with other risk factors for fractures, in particular: age > 60 years, current of past systemic corticosteroid therapy at a dosage 7.5 mg/day prednisone equivalent, a body mass index < 19 kg/m², a history of femoral neck extremity fracture in a first-degree relative (mother), early menopause (before the age of 40 years). (Official Gazette of 11 October 2006). In this study, the results as presented do not enable an analysis of all the criteria involved in the definition of this scope of reimbursement, which came into force during the course of the study. This study does however enable it to be documented that compliance with the criteria for the scope of reimbursement, as defined in 2006, appears to be infrequent. In fact, bone densitometry was only performed in 76% of cases and osteoporosis was present in 51% of cases (osteoporosis defined by a T-score less than or equal to -2.5). Level 3: osteoporosis, T-score below -2.5 Level 4: severe osteoporosis, the severity of the osteoporosis and the risk of fracture become greater the more the T-score falls below /15

12 Finally, due to the large number of patients lost to view, the follow-up of the patients does not enable a precise determination of the rate of treatment continuation nor of the therapeutic compliance with raloxifene. Among patients not lost to view, the rate of persistence with treatment at 12 months is 82%. Following an additional study, the rate among those lost to view was estimated at 64%. 12/15

13 6 TRANSPARENCY COMMITTEE CONCLUSIONS 6.1. Re-assessment of actual benefit Osteoporosis is a serious disorder because of the risk of fractures. In particular, fractures of the femoral neck can be life-threatening. OPTRUMA is a treatment for the prophylaxis of osteoporotic fractures and their recurrence. Its efficacy has been demonstrated solely in the prevention of vertebral fractures. Its efficacy/adverse effects ratio is high. This proprietary medicinal product is a first-line treatment as an alternative to bisphosphonates, but should be limited to patients with spinal osteoporosis and a low risk of femoral neck fractures, aged < 70 years, with no risk factors for venous thromboembolic events (lack of personal or family history of venous thromboembolic events) and who are receiving supplementation for calcium deficiency. Alternative medicinal products exist. The actual benefit provided by this proprietary medicinal product is substantial in the treatment and prevention of spinal osteoporosis, solely in patients at low risk of femoral neck fracture, aged less than 70 years and with no risk factors for venous thromboembolic events (lack of personal or family history of venous thromboembolic events) Therapeutic use Osteoporosis is defined by a T-score -2.5 in the absence of any other cause of an osteopathy characterized by demineralization or bone fragility. The purpose of treatment of osteoporosis is to prevent fractures. Prior to initiation of any anti-osteoporotic treatment, deficiencies in calcium and vitamin D should be investigated and corrected. The vitamin and calcium supplementation should be continued if required during the anti-osteoporotic treatment. Treatment of postmenopausal osteoporosis is routinely recommended in cases of osteoporosis complicated by fracture. In the absence of fractures in post-menopausal women, the indication for treatment should be considered on a case by case basis, depending on the individual risk of fracture. This risk is evaluated on the basis of the T-score value and the potential presence of other risk factors for fractures. Treatment must therefore be considered in women with: - a substantial reduction in bone mineral density (T-score < - 3) or - a T-score associated with other risk factors for fractures, in particular: age > 60 years, current or past systemic corticosteroid therapy at a dosage 7.5 mg/day prednisone equivalent, a body mass index < 19 kg/m², a history of femoral neck extremity fracture in a first-degree relative (mother), early menopause (before the age of 40 years). In the absence of a direct comparison between different anti-osteoporosis medicines (bisphosphonates, raloxifene, teriparatide and strontium ranelate), the choice of treatment will depend on the risk of vertebral and/or non-vertebral fractures, age, number and location of fractures, as well as on predisposing factors and any contraindications to any of these medicinal products, on product safety and on the potential duration of the treatment. If a fracture occurs after the first year of treatment and despite satisfactory compliance, the treatment should be reappraised. Another medicinal product may be suggested, including one from the same pharmacological class. 13/15

14 Therapeutic use of raloxifene Raloxifene is a selective oestrogen receptor modulator. It acts both as an agonist and/or as an antagonist of oestrogen receptors, depending on the cell and tissue type and the target genes. The available data suggest that raloxifene has an agonist activity on bone (decreasing bone resorption and lowering levels of biochemical markers) and on lipid metabolism, and an antagonistic activity on breast and endometrial tissue. Taking into account that its anti-fracture efficacy has solely been demonstrated with respect to vertebrae, it should be reserved for patients aged less than 70 years, with spinal osteoporosis, at low risk of femoral neck fractures and with no contraindications to its use, in particular venous thromboembolic events (family or personal history), severe renal impairment, hepatic impairment including cholestasis, or signs or symptoms of endometrial cancer. According to expert opinion, it is essential to have different therapeutic classes with different modes of action and pharmacological properties available for use in the management of osteoporosis, in order to be able to offer personalised treatment to each patient. The extra-osseous effect of raloxifene (in particular the reduction in risk of breast cancer) should be taken into account when prescribing Target population The target population for OPTRUMA consists of women with postmenopausal osteoporosis, who have had a fracture due to fragility and, where no fracture due to bone fragility is present, postmenopausal women with a substantially decreased bone density (T-score < -3) or a T-score of -2.5 associated with several risk factors for fracture and with a low risk of femoral neck fracture, aged less than 70 years and with no risk factors for venous thromboembolic events (absence of personal or family history of venous thromboembolic events). The population of postmenopausal women with osteoporosis may be estimated from the following data: - approximately 25% to 40% of women aged 65 years and 50% to 70% of women aged 80 years have osteoporosis i,ii - applied to the female population as updated for 1 January 2012, and taking into account the linear progression in prevalence between 65 years and 80 years. These data lead to an estimated population with postmenopausal osteoporosis consisting of between 2.5 and 3.6 million women. Pharmacological treatment with OPTRUMA is only justified in patients with spinal osteoporosis, at low risk of femoral neck fracture, aged less than 70 years and with no risk factors for venous thromboembolic events (absence of personal or family history of venous thromboembolic events). The available data, in particular the fact that bone densitometry has only recently become a reimbursable procedure in France, do not enable a precise estimate to be made of this subpopulation of patients. 14/15

15 6.4. Transparency Committee recommendations The Transparency Committee recommends continued inclusion on the list of medicines refundable by National Insurance within the scope of reimbursement described below Scope of reimbursement Prophylaxis and treatment of postmenopausal osteoporosis to reduce the risk of vertebral fractures in patients with spinal osteoporosis and a low risk of femoral neck fractures, aged < 70 years, with no risk factors for venous thromboembolic events (lack of personal or family history of thromboembolic events) and who are receiving supplementation for calcium deficiency Packaging: Not appropriate for the prescription conditions. The Committee points out that in accordance with its decisions on 20 July 2005, it recommends harmonisation of the size of packaging to 30 days for treatments lasting one month and consequently of the 90-day packaging for treatments lasting three months Reimbursement rate: 65% i Société Française de rhumatologie [French Rheumatology Society] Dossier Ostéoropose Pourquoi dit-on que l ostéoporose est un problème de santé publique? [Osteoporosis File Why is osteoporosis said to be a public health problem?] ( ii Ministère de la Santé, de la Famille et des Personnes handicapées [Ministry of Health, Families and Disabled People]. Direction générale de la santé [Directorate General for Health] Report of the Groupe Technique National de Définition des Objectifs de Santé Publique (GTNDO) [National Technical Objective Definition Group for Public Health] Analyse des connaissances disponibles sur des problems de santé sélectionnés, leurs determinants, et les strategies de santé publique. Définition d objectifs [Analysis of knowledge available on selected health problems, their influencing factors, and public health strategies: Definition of objectives.] March ( 15/15