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CHOLESTAGEL - CHOLESTAGEL - CT 8427 - English version

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Introduction CHOLESTAGEL 625 mg, film-coated tablet B/180 (CIP code: 353 608-9) Posted on Jun 18 2012 Active substance (DCI) colesevelam Cardiologie - Nouveau médicament Pas d’avantage clinique démontré dans la prise en charge de l’hypercholestérolémie primaire CHOLESTAGEL est un chélateur de sels biliaires indiqué dans l’hypercholestérolémie primaire de l’adulte :en association aux statines, comme traitement d’appoint afin d’obtenir une diminution supplémentaire du taux de LDL-c chez les patients insuffisamment contrôlés par une statine seule ;en monothérapie, pour diminuer les taux de cholestérol total et de LDL-c, si un traitement par statine est inapproprié ou mal toléré ;en association à l’ézétimibe, avec ou sans statine, notamment en cas d’hypercholestérolémie familiale.Son intérêt en termes de réduction de la morbi-mortalité n’a pas été démontré. Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous ATC Code C10AC04 Laboratory / Manufacturer GENZYME SAS CHOLESTAGEL 625 mg, film-coated tablet B/180 (CIP code: 353 608-9) Posted on Jun 18 2012
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 The legally binding text is the original French version  TRANSPARENCY COMMITTEE
OPINION  22 September 2010   CHOLESTAGEL 625 mg, film-coated tablet B/180 (CIP code: 353 608-9)   Applicant: GENZYME SAS  colesevelam ATC code: C10AC04  List I  Date of Marketing Authorisation (centralised): Initialstatins” and as “in monotherapy when a: 10 March 2004, indications “in combination with statin is considered inappropriate or is not well tolerated” Extension of indication:with ezetimibe with or without statin”23 March 2010 “in combination  Reason for request: Inclusion on the list of medicines refundable 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 Colesevelam   1.2. Indications “CHOLESTAGEL co-administered with a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) is indicated as adjunctive therapy to diet to provide an additive reduction in low-density lipoprotein cholesterol (LDL-C) levels in adult patients with primary hypercholesterolaemia who are not adequately controlled with a statin alone.  CHOLESTAGEL as monotherapy is indicated as adjunctive therapy to diet for reduction of elevated total-cholesterol and LDL-C in adult patients with primary hypercholesterolaemia, in whom a statin is considered inappropriate or is not well-tolerated.  CHOLESTAGEL can also be used in combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia (see section 5.1 of the SPC)”   1.3. Dosage “Combination therapy:of CHOLESTAGEL for combination with a statinThe recommended dose with or without ezetimibe is 4 to 6 tablets per day. The maximum recommended dose is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets taken once per day with a meal.  Clinical trials have shown that CHOLESTAGEL and statins can be co-administered or dosed apart, and that CHOLESTAGEL and ezetimibe can be co-administered or dosed apart.  Monotherapy: The recommended starting dose of CHOLESTAGEL is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets once per day with a meal. The maximum recommended dose is 7 tablets per day.  During therapy, the cholesterol-lowering diet should be continued, and serum total-C, LDL-C and triglyceride levels should be determined periodically during treatment to confirm favourable initial and adequate long-term responses.  When a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, or where no clinical data are available on co-administration, CHOLESTAGEL should be administered at least four hours before or at least four hours after the concomitant medication in order to minimize the risk of reduced absorption of the concomitant medication (see section 4.5 of the SPC).  Elderly population:There is no need for dose adjustment when CHOLESTAGEL is administered to elderly patients.  Paediatric population:described in section 5.1 of the SPC but noCurrently available data are recommendation on a posology can be made.”
 
 
 
 
 
 
 
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 2. SIMILAR MEDICINAL PRODUCTS  2.1. ATC classification (2009) C : Cardiovascular system C10 : Lipid modifying agents C10A : Lipid modifying agents, plain C10AC : Bile acid sequestrants C10AC04 : Colesevelam   2.2. Medicines in the same therapeutic category Other representative of bile salt chelating agents indicated in essential hypercholesterolaemia: QUESTRAN (cholestyramine).   2.3. Medicines with a similar therapeutic aim These are other dyslipidaemia treatments that are indicated in combination with statins or if statins cannot be used or are poorly tolerated: EZETROL (ezetimibe), NIASPAN (nicotinic acid), fibrates.   
 
 
 
 
 
 
 
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3.
ANALYSIS OF AVAILABLE DATA
 3.1. Efficacy  The evaluation of the LDL-C lowering efficacy and the tolerance of CHOLESTAGEL is based on 13 randomised, double-blind controlled studies: 4 phase II studies, 2 phase III studies and 6 phase IV studies and pooled data from three studies.  In view of the very short follow-up period (4 to 6 weeks) of the phase II studies and the small number of patients included in each treatment group (about 30 patients), details of these studies will not be given in this Opinion.   studies: 2 phase II studies (GTC-37-201 and GTC-37-202) and 2 phase III4 monotherapy studies (GTC-48-301 and GTC-48-302). Study GTC-48-301, the objective of which was to evaluate the efficacy and tolerance of CHOLESTAGEL versus placebo in patients with primary hypercholesterolaemia followed for 6 months. Study GTC-48-302 the objective of which was to compare the efficacy and tolerance of CHOLESTAGEL 3.8 g/day with placebo in 3 dosing regimens (one dose in the morning, one dose in the evening or 2 doses per day). This study, from which conclusions were drawn about the methods of administration, will not be discussed in this Opinion.   5 studies in combination with a statin alone: two phase II studies (GTC-48-204 and GTC-37-205) and three phase IV studies (WEL-405, WEL-406 and WEL-407), the objective of which was to evaluate the efficacy and tolerance of CHOLESTAGEL in combination with a statin versus the statin alone or in combination with a placebo in patients with primary hypercholesterolaemia followed for 4 to 6 weeks. The company also submitted the pooled analysis of studies 405, 406 and 407, performeda posteriori; since this pooling was not specified in the study protocols, that analysis will not be presented in this Opinion.   2 studies in combination with ezetimibe: o the phase III study WEL-408, the objective of which was to evaluate the efficacy and tolerance of the combination CHOLESTAGEL + ezetimibe versus ezetimibe alone in patients with primary hypercholesterolaemia followed for 10 weeks. o the phase IV study CHOL00107, the objective of which was to evaluate the efficacy and tolerance of the combination CHOLESTAGEL + ezetimibe + statin versus ezetimibe + statin in patients with familial hypercholesterolaemia uncontrolled by primary bitherapy who were followed for 12 weeks.   A 12-month study (Moore et al. 20071) : The objective of this study was to evaluate the efficacy and tolerance of CHOLESTAGEL in combination with atorvastatin and nicotinic acid versus the statin alone and versus bitherapy with nicotinic acid + atorvastatin in patients with atheromatous disease. Since this triple combination has not been validated by the MA, this study will not be discussed in this Opinion.    
                                            1 Moore et al. “Effects of adding extended-release niacin and colesavelam to statin therapy on lipid levels in subjects with atherosclerotic disease” Journal of clinicalilpidology.2007;1:620-5.
 
 
 
 
 
 
 
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3.1.1. Studies of monotherapy:103-84G-CT  Method: Comparative randomised, double-blind, parallel-group phase III study of CHOLESTAGEL versus placebo in 467 patients with primary hypercholesterolaemia followed for 6 months.  Inclusion criteria: Adult patients over 18 years of age with primary hypercholesterolaemia, an LDL-C level between 1.3 and 2.2 g/l and a triglyceride level3 g/l.  Notethe CHOLESTAGEL groups are not in accordance with the: The patients in these studies included in MA indication which stipulates that “CHOLESTAGEL can be used alone in patients in whom a statin is considered inappropriate or is not well-tolerated” .  Treatments: All patients followed a diet for 8 weeks before inclusion in the study; this diet was maintained throughout the study. Patients were randomised to the following treatment groups: - CHOLESTAGEL 2.3 g/day, n 99 = - CHOLESTAGEL 3 g/day, n = 91    CHOLESTAGEL 3.8 g/day, n = 95 -- CHOLESTAGEL 4.5 g/day, n = 94 - Placebo, n = 88. Only the results for the dosage validated by the MA (3.8 g/day) will be presented in this Opinion.  Primary endpoint: Mean variation (reduction) in the LDL-C level after 6 months of treatment.  ESULTS: ITT analysis (cf. Table 1). R  The baseline characteristics of the patients were comparable except for the mean BMI which was significantly higher in the CHOLESTAGEL 3.8 g/l group (30.2 kg/m2) than in the placebo group (27.9 kg/m2).  Table 1: Mean variation in the LDL-C level (mg/dl) after 6 months of treatment.  CHOLESTAGELPlacebo 3.8 g/day n = 94 n = 88 Mean level (mg/dl) at baseline (SD) 158.6 (21.5) 155.1 (19.3) Mean level (mg/dl) after 6 months (SD) 134.6 (23) 154.8 (22.4) Mean variation (SD) -24 (21.6) -0.2 (18.7) p versus placebo <0.0001  After 6 months of treatment, a reduction in LDL-C levels was observed with CHOLESTAGEL 3.8 g/day compared with placebo: -24 mg/dl (21.6) versus -0.2 mg/dl (18.7), difference -23.8 mg/dl (SD not available) p < 0.0001.  3.1.2. Studies in combination with a statin:Studies WEL-405, 406 and 407   Method: Randomised, double-blind, parallel-group comparative phase IV studies of CHOLESTAGEL + simvastatin (study 405) or atorvastatin (study 406) or pravastatin (study 407) versus the statin studied + placebo, in patients treated with the statin studied at a stable dose for 4 weeks, with a follow up of 6 weeks.  Inclusion criteria: Adult patients over 18 years of age treated with a stable dose of the statin studied for 4 weeks and: - an LDL-C level between 1 and 2.5 g/l, - a triglyceride level3 g/l.  
 
 
 
 
 
 
 
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Treatments: Study 405: n = 69 Patients were randomised to the following treatment groups: - CHOLESTAGEL 3.75 g/day (6 tablets/day) + simvastatin, n 44 = - placebo + simvastatin, n = 25.  Study 406: n = 61 Patients were randomised to the following treatment groups: - CHOLESTAGEL 3.75 g/day (6 tablets/day) + atorvastatin, n = 38 - placebo + atorvastatin, n = 23.  Study 407: n = 64 Patients were randomised to the following treatment groups: - CHOLESTAGEL 3.75 g/day (6 tablets/day) + pravastatin, n = 45 - placebo + pravastatin, n = 19.  Note:The dosage of the statin was the one established in the 4 weeks before randomisation.  Primary endpoint: Mean (percentage) variation in the LDL-C level after 6 weeks of treatment compared to the level at baseline.  RESULTS: ITT analysis (cf. Table 2). At baseline,characteristics of the patients were comparable.  Table 2: Mean variation in the LDL-C level (percentage) after 6 weeks of treatment.  Mean level level Mean % Mean p % Difference (mg/dl) (mg/dl) variation (SD) on inclusion at the end (SD) 95% CI (SD) of the study (SD) Studies 405:       Cholestagel + simvastatin 132.1 (23.1) 107.6 (34.2) -18.8% (19.8) (n = 44) -17.5 (4.6)% <0.001 Placebo + simvastatin (n = 25) 126.1 (22.4) 123.3 (17.9) -0.8% (14.4) [-26.7; -8.3] Studies 406:       Cholestagel + atorvastatin 133.2 (27) 109.9 (30.3) -17.3% (16.6) (n = 38) -3.7 (4.1)% NS Placebo + atorvastatin (n = 23) 131.7 (24.2) 112.9 (22.8) -13.4% (13.6) [-12; 4.5] Studies 407:       Cholestagel + pravastatin 132.7 (24.5) 116.0 (24.7) -11.8% (15.1) (n = 45) -7.1 (3.9)% NS Placebo + pravastatin (n = 19) 132.6 (15) 125.0 (17.5) -4.9% (15.2) [-14.9; 0.6]  In study WEL-405, after 6 weeks of treatment, a reduction in LDL-C levels was observed with CHOLESTAGEL + simvastatin compared with placebo + simvastatin: -18.8% versus 0.8%, -difference -17.5%, 95% CI [-26.7 ; -8.3], p < 0.001.  In study WEL-406, after 6 weeks of treatment, no significant difference in LDL-C reduction was observed between CHOLESTAGEL + atorvastatin and placebo + atorvastatin: -17.3% versus -13.4%, difference -3.7%, 95% CI [-12 ; 4.5].  In study WEL-407, after 6 weeks of treatment, no significant difference in LDL-C reduction was observed between CHOLESTAGEL + pravastatin and placebo + pravastatin: -11.8% versus -4.9%, difference -7.1%, 95% CI [-14.9; 0.6].  According to the results of these three studies, the efficacy of CHOLESTAGEL in combination with a statin was demonstrated only with simvastatin.
 
 
 
 
 
 
 
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 3.1.3. Studies in combination with ezetimibe with or without statin  · Study WEL-4082: in combination with ezetimibe alone Method: Comparative randomised, double-blind, parallel-group phase IV study of CHOLESTAGEL 3.8 g/day + ezetimibe 10 mg/day versus ezetimibe 10 mg/day alone in 85 patients with primary hypercholesterolaemia followed for 6 weeks.  Inclusion criteria: adult patients 18-80 years of age with primary hypercholesterolaemia, LDL-C 1.3 g/l and triglycerides4 g/l.  Treatments: All patients followed a diet throughout the study. Patients were randomised to the following treatment groups: - CHOLESTAGEL 3.8 g/day + ezetimibe 10 mg/day, n = 42 - Ezetimibe 10 mg/day + placebo, n = 43.  Primary endpoint: mean variation in the LDL-C level after 6 weeks of treatment.  RESULTS: ITT analysis (cf. Table 3). The baseline characteristics of the patients were comparable in the two groups except for the sex ratio: 51% males in the CHOLESTAGEL + ezetimibe group versus 35% in the ezetimibe alone group.  Table 3: Mean (percentage) variation in the LDL-C level (mg/dl) after 6 weeks of treatment.  CHOLESTAGELEzetimibe 10 mg/day 3.8 g/day + ezetimibe 10 mg/dayn = 43 n = 42  
Mean level (mg/dl) at baseline (SD) 176.6 (30.32) 175 (33.46) Mean level (mg/dl) after 6 weeks (SD) 117.8 (25.09) 137 (28.48) Mean % variation (SD) -32.4% (14.10) -21.3% (10.49) Difference versus ezetimibe % [95% CI] -11% [-16.1; -5.8] p versus ezetimibe <0.001  After 6 weeks of treatment, LDL-C levels decreased by 32.4% (14.10) with CHOLESTAGEL 3.8 g/day + ezetimibe 10 mg/day and by 21.3% (10.49) with ezetimibe 10 mg/day with a difference between the 2 groups of -11%, 95% CI [-16;1; -5.8], p < 0.001. In absolute terms, a reduction in LDL-C levels of 58.8 mg/dl was observed in the CHOLESTAGEL 3.8 g/day + ezetimibe 10 mg/day group versus 38 mg/dl in the group with ezetimibe 10 mg/dl alone, a difference of 20.8 mg/dl (SD not available).  · Study CHOL001073: in combination with ezetimibe and with a statin:  Method: Comparative randomised, double-blind, parallel-group phase IV study of CHOLESTAGEL 3.75 g/day + statin + ezetimibe at an optimal dose versus optimized bitherapy * with statin + ezetimibe in 82 patients with familial hypercholesterolaemia uncontrolled by bitherapy who were followed for 6 weeks.*maximally tolerated dose of statin. effective  
                                            2 Bays et al. Lipid-lowering effects of colesavelam HCL in combination with ezetimibe. Current Medical Research and Opinion, 2006; 22: 2191-2200. 3 Hujgen et al. Colesavelam added to combination therapy with a statin and ezetimibe with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clinical Therapeutics 2010; 32(4): 615-25.
 
 
 
 
 
 
 
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Inclusion criteria: Adult patients aged 18 to 75 years with familial hypercholesterolaemia uncontrolled despite treatment with statin + ezetimibe at an optimal dose administered for at least 3 months.  Treatments: Patients were randomised to the following treatment groups: - CHOLESTAGEL 3.75 g/day + statin + ezetimibe, n = 43 - statin + ezetimibe, n = 39. Patients received ezetimibe 10 mg/day, except for one patient, in combination with the following statin: - atorvastatin: 49% of patients in the CHOLESTAGEL 3.75 g/day + statin + ezetimibe group versus 54% in the statin + ezetimibe group, - simvastatin: 7% versus 22%, - rosuvastatin: 44% versus 22%,  - pravastatin: 0 versus 2%  Primary endpoint: mean variation in the LDL-C level (mmol/l) after 6 weeks of treatment.  RESULTS: ITT analysis (cf. Table 4). The baseline characteristics of the patients were comparable in the two groups except for: - the sex ratio: 51% males in the CHOLESTAGEL + statin + ezetimibe group versus 68% in the statin + ezetimibe group. - history of MI: 29% versus 15%,  presence of hypertension: 31% versus 22%. - Table 4: Mean (percentage) variation in the LDL-C level (mmol/l) after 6 weeks of treatment.  CHOLESTAGELStatin + ezetimibe 3.75 g/day + stat n + i ezetimiben = 39 n = 43
Mean level (mmol/l) at baseline (SD) 3.9* (0.98) 3.8*** (0.98) Mean level (mmol/l) after 6 weeks (SD) 3.3** (0.78) 4**** (1.10) Mean % variation (SD) -11.3% +7% Difference versus ezetimibe % [95% CI] -18.7% [-25.6; -11.8] p versus ezetimibe <0.0001 NA: not available / * 152 mg/dl **129 mg/dl ***148 mg/dl ****156 mg/dl  After 6 weeks of treatment, LDL-C decreased by 11.3% in the CHOLESTAGEL 3.75 g/day + statin + ezetimibe group versus 7% in the statin + ezetimibe group with a difference of -18.7%, 95% CI [-25.6; -11.8] between the 2 groups, p < 0.0001. In absolute terms, a reduction in LDL-C levels of -0.6 mmol/l (-23 mg/dl) was observed in the CHOLESTAGEL 3.75 g/day + statin + ezetimibe group versus +0.2 mmol/l (+8 mg/dl) in the statin + ezetimibe bitherapy group, difference 0.8 mmol/l (-31 mg/dl).   3.2. Adverse effects According to the SPC, the most common adverse events (> 1%) are: serum triglycerides increased, headache, flatulence, constipation, vomiting, diarrhoea, dyspepsia, abdominal pain, abnormal stools, nausea. The adverse events observed in the above-mentioned studies are those described in the SPC.
 
 
 
 
 
 
 
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 3.3. Conclusion  The evaluation of the LDL-C lowering efficacy and the tolerance of CHOLESTAGEL is based on 6 controlled, randomised, double-blind studies in patients with primary hypercholesterolaemia (5 studies) or familial hypercholesterolaemia (1 study).  Studies with monotherapy in patients with primary hypercholesterolaemia (1 study): In study GTC-48-301, after 6 months of treatment, the mean LDL-C reduction was larger with CHOLESTAGEL 3.8 g/day than with placebo: -24 mg/dl (± 21.6) versus -0.2 mg/dl (± 18.7), difference -23.8 mg/dl (SD not available) p < 0.0001.  Studies in combination with a statin in patients with primary hypercholesterolaemia (3 studies): In study WEL-405, after 6 weeks of treatment, the mean decrease in LDL-C from baseline was greater with CHOLESTAGEL + simvastatin than with placebo + simvastatin: -18.8% versus -0.8%, difference -17.5%, 95% CI [-26.7; -8.3], p < 0.001. In study WEL-406, after 6 weeks of treatment, the mean decrease in LDL-C from baseline was not significantly different between CHOLESTAGEL + atorvastatin and placebo + atorvastatin: -17.3% versus -13.4%, difference -3.7%, 95% CI [-12; 4.5]. In study WEL-407, after 6 weeks of treatment, the mean decrease in LDL-C from baseline was not significantly different between CHOLESTAGEL + pravastatin and placebo + pravastatin: - 11.8% versus -4.9%, difference -7.1%, 95% CI [-14.9; 0.6]. In these three studies, the efficacy of CHOLESTAGEL in combination with a statin was demonstrated only with simvastatin.  Studies in combination with ezetimibe (2 studies): In study WEL-408 in patients with primary hypercholesterolaemia, after 6 weeks of treatment, the mean decrease in LDL-C from baseline was greater with CHOLESTAGEL 3.8 g/day + ezetimibe 10 mg/day (32%±14,%) than with ezetimibe 10 mg/day (21.3%±10.5) with a difference of -11%, 95% CI [-16;1; -5.8], p < 0.001. The mean reduction in LDL-C was greater with CHOLESTAGEL 3.8 g/day + ezetimibe 10 mg/day than with ezetimibe 10 mg/dl alone (58.8 mg/dl vs. 38 mg/dl, a difference of 20.8 mg/dl, SD not available). In study CHOL00107 in patients with familial hypercholesterolaemia, after 6 weeks of treatment, the mean decrease in LDC-C from baseline was greater with CHOLESTAGEL 3.75 g/day +  statin + ezetimibe (11.3%) than with statin + ezetimibe (7%) with a difference of -18.7%, 95% CI [-25.6; -11.8], p < 0.0001. The mean LDL-C reduction was -0.6 mmol/l (-23 mg/dl) in the CHOLESTAGEL 3.75 g/day + statin + ezetimibe group versus +0.2 mmol/l (+8 mg/dl) in the statin + ezetimibe group, difference 0.8 mmol/l (-31 mg/dl).  The benefit of CHOLESTAGEL for morbidity and mortality has not been established.  No study comparing CHOLESTAGEL with the other representative of bile salt chelating agents (QUESTRAN) and other lipid-lowering agents is available.  According to the SPC, the adverse effects most commonly associated with CHOLESTAGEL (frequency >1%) are: serum triglycerides increased, headache, flatulence, constipation,  vomiting, diarrhoea, dyspepsia, abdominal pain, abnormal stools, nausea.
 
 
 
 
 
 
 
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4.
TRANSPARENCY COMMITTEE CONCLUSIONS
 4.1. Actual benefit: The cardiovascular disorders associated with hypercholesterolaemia can be life-threatening.  Given the absence of long-term clinical data and potential interactions with ion exchange resins (change in the absorption of many medicines), the efficacy/adverse effect ratio of this medicinal product in its indications is moderate.  In the absence of any data on morbidity and mortality, this medicinal product is considered a symptomatic treatment of hypercholesterolaemia.  In most patients with dyslipidaemia, the therapeutic needs are theoretically covered by the use of statins. In patients who are insufficiently controlled by or intolerant to a statin, there are alternative therapies: NIASPAN (nicotinic acid), ezetimibe, cholestyramine, fibrates.  Public health benefit: Cardiovascular diseases are a major public health burden. A reduction in mortality associated with cardiovascular diseases is a public health need (Law of 9 August 2004 on Public Health Policy). To date, on the basis of available clinical data, the medicinal product CHOLESTAGEL does lower LDL-C levels, but in the absence of data on morbidity and mortality, the impact of the medicinal product CHOLESTAGEL cannot be evaluated. Consequently, the medicinal product CHOLESTAGEL is not expected to offer any public health benefit in the indications of the MA.   Thus: - In the absence of demonstrated efficacy with all of the statins, the actual benefit of
CHOLESTAGEL “co-administered with a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as adjunctive therapy to diet to provide an additive reduction in low-density lipoprotein cholesterol (LDL-C) levels in adult patients with primary hypercholesterolaemia who are not adequately controlled with a statin alone” is moderate. - “As monotherapy as an adjunct to diet for reduction of elevated total cholesterol and LDL-C in adult patients with primary hypercholesterolaemia, in whom a statin is considered inappropriate or is not well-tolerated”the actual benefit of CHOLESTAGEL is substantial. - In view of the possible consequences on the absorption of other medicinal products potentially used in combination, particularly those with a narrow therapeutic margin, “in combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia”, the actual benefit of CHOLESTAGEL is moderate.  4.2. Improvement in actual benefit “Co-administered with a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as adjunctive therapy to diet to provide an additive reduction in low-density lipoprotein cholesterol (LDL-C) levels in adult patients with primary hypercholesterolaemia who are not adequately controlled with a statin alone”, CHOLESTAGEL does not provide any improvement in actual benefit (IAB V) in the treatment strategy for these patients.  
 
 
 
 
 
 
 
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“As monotherapy as an adjunct to diet for reduction of elevated total-cholesterol and LDL-C in adult patients with primary hypercholesterolaemia, in whom a statin is considered inappropriate or is not well-tolerated”, CHOLESTAGEL does not provide any improvement in actual benefit (IAB V) in the treatment strategy for these patients.  “In combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia”, CHOLESTAGEL does not provide any improvement in actual benefit (IAB V) by comparison with QUESTRAN.  4.3. Therapeutic use In dyslipidaemic patients, a reduction in fat consumption, physical exercise and the management of other risk factors, particularly smoking, are the first strategy to implement and maintain throughout treatment.  The treatment algorithm is then guided by LDL-C thresholds, which differ according to the patient’s level of cardiovascular risk and tolerance of the treatments.  In patients who are not controlled with a statin alone, it is necessary to ensure that the information about their cardiovascular risk is correct and understood and that the treatment is taken regularly. Poor compliance is in fact the main reason for not achieving treatment goals. It is also necessary to ensure that the statin is prescribed in the dosages that have demonstrated a clinical benefit in the various studies of morbidity and mortality.  When the dyslipidaemia is still not controlled despite treatment with a statin taken regularly in an appropriate dosage, cholestyramine or ezetimibe can be used in combination. Combined with a statin when the cholesterol-lowering effect is not sufficient, nicotinic acid is an alternative to cholestyramine or ezetimibe.  Reduction of LDL-C levels is a surrogate endpoint for the efficacy of cardiovascular prevention by lipid-lowering agents. When a combination of lipid-lowering agents can be considered, the choice made depends on the residual lipid abnormality under monotherapy: - to lower LDL-C, the combination statin+ezetimibe and statin+resin can be considered, -on triglycerides and HDL-C, the combination statin+nicotinic acid is possible. to act  For dyslipidaemic patients in whom statin treatment is poorly tolerated, the prescriber currently has the choice of three medicines: fibrates, cholestyramine and ezetimibe. Fibrates are preferably used in mixed dyslipidaemia with elevation of LDL-C and triglycerides and reduced HDL-C, whereas cholestyramine and ezetimibe would preferably be used in pure hypercholesterolaemia.   On the basis of the studies included in the dossier, CHOLESTAGEL has demonstrated its efficacy on the reduction of LDL-C levels in the following situations: - in combination with simvastatin, in patients with primary hypercholesterolaemia insufficiently controlled by a statin alone; in this indication CHOLESTAGEL could represent an alternative to ezetimibe or cholestyramine. - monotherapy in combination with diet, in adult patients with primary in hypercholesterolaemia in whom statin treatment is inappropriate or poorly tolerated; in this indication CHOLESTAGEL could represent an alternative to ezetimibe or cholestyramine.   
 
 
 
 
 
 
 
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