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ACTOS - ACTOS - CT 3226 - English version

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16 pages
Introduction ACTOS 15 mg, tablets Pack of 28 (CIP: 355 632-4) ACTOS 30 mg, tablets Pack of 28 (CIP: 355 635-3) Posted on Feb 15 2010 Active substance (DCI) Pioglitazone ATC Code A10BG03 Laboratory / Manufacturer TAKEDA ACTOS 15 mg, tablets Pack of 28 (CIP: 355 632-4) ACTOS 30 mg, tablets Pack of 28 (CIP: 355 635-3) Posted on Feb 15 2010
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 The legally binding text is the original French version  TRANSPARENCY COMMITTEE   Opinion  2 April 2008   ACTOS 15 mg, tablets Pack of 28 (CIP: 355 632-4) ACTOS 30 mg, tablets Pack of 28 (CIP: 355 635-3)  Applicant: TAKEDA  Pioglitazone   List I ATC Code: A10BG03  Date of first marketing authorisation: 13/10/2000, last amendment 20/08/2007   Reason for request: - Reassessment of the IAB in the monotherapy and dual oral therapy indications (in combination with metformin or a sulphonylurea) following the submission of new data. The extensions of indication and variations to the SPC since the last assessment of this proprietary medicine are discussed in two complementary opinions.     After hearing the company, the opinion was changed as follows:      Medical, Economic and Public Health Assessment Division        
 
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1. CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient Pioglitazone 
1.2. Indication “Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:  as monotherapy: - in patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance. as dual oral therapy in combination with: - metformin, in patients (particularly overweight patients) with insufficient glycaemic control des ite maximal tolerated dose of monothera with metformin: - a sul hon lurea, onl in atients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of oral monotherapy with a sulphonylurea:  as triple oral therapy in combination with - metformin and a sulphonylurea, in patients, particularly overweight patients, with insufficient glycaemic control despite the above dual oral therapy combinations.  Pioglitazone is also indicated in combination with insulin in type 2 diabetes mellitus patients with insufficient glycaemic control on insulin for whom metformin is contraindicated or poorly tolerated (see section 4.4)”  
1.3. Dosage (see SPC) Pioglitazone is administered orally once daily during or between meals. Pioglitazone may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg once daily. In combination with insulin, the insulin dose can be continued upon initiation of pioglitazone therapy. If patients report hypoglycaemia, the dose of insulin should be decreased.  Elderly subjects: No dose adjustment is necessary (see section 5.2).  Renal impairment: No dose adjustment is necessary in patients with impaired renal function (creatinine clearance > 4 ml/min) (see section 5.2). As no information is available in dialysed patients, pioglitazone should not be used in this population. Hepatic impairment: Pioglitazone should not be used in patients with hepatic impairment (see section 4.4.) Children and adolescents: As there are no data available on the use of pioglitazone in patients under 18 years of age, its use is not recommended in this age group.
1.1. Contraindications:  Pioglitazone is contra-indicated in patients with: - to the active ingredient or to one of the excipients, hypersensitivity - heart failure or a history of heart failure (NYHA), - impairment, hepatic - diabetic ketoacidosis.  
 
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2. SIMILAR MEDICINAL PRODUCTS
2.1. ATC Classification  A : DIGESTIVE TRACT AND METABOLISM A10 : DRUGS USED IN DIABETES A10B : ORAL ANTIDIABETICS A10BG : THIAZOLIDINEDIONES A10BG03 : PIOGLITAZONE
2.2. Medicines in the same therapeutic category  Other proprietary glitazones on the list of reimbursable products:  · As monotherapy, in type 2 diabetic patients who show intolerance to metformin or for whom metformin is contraindicated and who are inadequately controlled by diet and lifestyle measures: AVANDIA (rosiglitazone) · dual oral therapy: As - in combination with metformin, in type 2 diabetic patients (particularly overweight patients), inadequately controlled despite maximum tolerated dose of metformin: AVANDIA (rosiglitazone), AVANDAMET (fixed-dose combination of rosiglitazone and metformin), COMPETACT (fixed-dose combination of pioglitazone and metformin)  - incombination with a sulphonylurea only in the case of contraindication or intolerance to metformin in patients inadequately controlled despite maximum tolerated dose of a sulphonylurea: AVANDIA (rosiglitazone)   
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2.3. Medicines with a similar therapeutic aim As oral monotherapy, in the case of contraindication or intolerance to metformin in type 2 diabetic patients, inadequately controlled by diet and lifestyle measures:  intestinal alphaglucosidase inhibitors,  sulphonylureas,  glinides.
· As dual oral therapy:  - In type 2 diabetic patients not achieving adequate glycaemic control despite maximal tolerated dose of oral monotherapy with metformin:   sulphonylureas  inhibitors ha- lucosidase al intestinal  glinides  l peptidase-4 inhibitors DPP 4 dipeptid - incretin mimetics parenteral  - In type 2 diabetic patients with inadequate glycaemic control despite maximal tolerated dose of monotherapy who show intolerance to metformin or for whom metformin is contraindicated:  intestinal alpha-glucosidase inhibitors parenteral incretin mimetics (in combination with a sulphonylurea)       
 
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3. SUMMARY OF PREVIOUS TRANSPARENCY COMMISSION OPINIONS
 Opinion of 28 March 2001 ACTOS 15 mg and 30 mg tablet (packs of 28 and 50): First inscription - combination with metformin, only in obese patientsIn - in combination with a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is contraindicated (pack of 28 reimbursed by National Insurance and approved for Hospital use; Hospital pack of 50)
Actual benefit: Type 2 diabetes is a chronic disease with potentially serious complications. The action mechanism of ACTOS is the same as AVANDIA and different from that of other oral antidiabetics. The marketing of a new pharmacological class presents a real interest. In combination with an oral antidiabetic, the efficacy/safety ratio of this medicinal product is positive and seems to be high according to current data. ACTOS is for third-line therapy. This product may be used when dual oral therapy with metformin + sulphonylurea is contra-indicated. Alternative medicinal products exist. The actual benefit of ACTOS in these indications is high.
Improvement in actual benefit: According to current data and in particular in the absence of a comparative study with the usual antidiabetic combinations, the Transparency Committee is unable to fix a level of improvement in actual benefit compared to currently available treatments for the sub-groups of diabetics covered by the marketing authorisation.   Opinion of 7 May 2003 ACTOS 15 mg and 30 mg tablets (packs of 28 and 50): - Lifting of the restriction of prescription to specialists.   Opinion of 24 March 2004 ACTOS 15 mg and 30 mg tablet (packs of 28): - Reassessment of IAB in the combination therapy indication - the conditions of inscription following the variation of the SCP:Change in extension of indication as monotherapy + possible increase in the dosage to 45 mg/day + variation of the indication in combination with metformin ACTOS 45 mg (packs of 28): Inclusion on the list of medicines reimbursed by National Insurance and approved for hospital use. 
 
Actual benefit Type 2 diabetes is a chronic disease with potentially serious complications. ACTOS is used for the treatment for hyperglycaemia. The efficacy/safety ratio of this product is high according to current data. Alternative medicinal products exist. ACTOS represents an additional means of therapy for the management of type 2 diabetic patients. The expected public health benefit is high on the basis of the fall in HbA1c, provided that positive results are obtained in terms of morbidity and mortality. The actual benefit of ACTOS is high.
Improvement in actual benefit  As monotherapy, ACTOS provides a level IV (minor) improvement in Actual Benefit compared to gliclazide.
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In combination with metformin, ACTOS provides a level IV (minor) improvement in Actual Benefit compared to dual oral therapy with gliclazide + metformin.  In combination with a sulphonylurea, ACTOS provides no improvement in Actual Benefit (level V) compared to dual oral therapy with metformin + a sulphonylurea.
Transparency Committee Recommendations The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Insurance and on the list of medicinal products approved for hospital use and various public services in the extension of indication for ACTOS 15 and 30 mg and in all the indications of the MA for ACTOS 45 mg.  The Committee would like to give a favourable opinion for lifting ACTOS’s status as a medicinal product for exceptional use.  The Committee requests the setting up of an observational study on a double cohort of patients receiving monotherapy and dual oral therapy with prolonged follow-up for not less than 2 years. This study should make it possible to describe treated patients under real life conditions: observed efficacy in terms of HbA1c, number of responders, treatment escape as well as safety and compliance.  The Committee would like to be informed about the results of the morbidity and mortality study requested by EMEA.  NB: ACTOS 45 mg not listed  
4. ANALYSIS OF AVAILABLE DATA
 In support of its request, Takeda submitted: - placebo-controlled, morbidity and mortality study, PROACTIVE A - Cumulative data for the first 15 PSURs and PSUR16 - Meta-analyses on cardiac safety (Lago 2007, Lincoff 2007) The GLAI1 CHICAGO and2 studies (off-label use) which are not discussed in this evaluation, were also submitted.  4.1. Efficacy · Takeda submitted a study, PROACTIVE, which studied patients who at baseline were treated by diet alone, oral antidiabetics, monotherapy, dual oral therapy, or insulin. · observational study required by the French Transparency Commission The in order to describe patients treated under real life conditions (observed efficacy in terms of HbA1c, number of responders, treatment escape, safety and compliance) is on-going. The results are not yet available and could not therefore be provided.       4.1.1.ProActive morbidity and mortality study (PROspective PioglitAzone Clinical Trial in MacroVascular Events EC 444)3,4,5 
                                            1 Goldberg RB, Kendall DM, Deeg MA, et al. GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidaemia. Diabetes Care 2005 ; 28(7):1547-54 2 Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomised trial. JAMA 2006;296:2572-2581 3 Study report 4Charbonnel B, et al; PROactive Study Group. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care 2004;27:1647-1653  5
  Primary objective: to show that pioglitazone reduces all-cause mortality and macrovascular morbidity in a population of type 2 diabetics with a past history of macrovascular disease. Design: randomised, double-blind, placebo-controlled comparison.  Inclusion criteria: the study enrolled type 2 diabetics (HbA1c > 6.5% despite a diet alone or associated with oral antidiabetics (OAD), with or without insulin), aged from 35 to 75 years, with a history of macrovascular disease defined by the presence of at least one of the following criteria: MI6, stroke7intervention or coronary artery bypass graft more, percutaneous coronary than 6 months before entry in the trial, acute coronary syndrome8 than three months more before entry or objective signs of coronary artery disease, or peripheral9 or lower limb occlusive arterial disease (PAOD)10. The exclusion criteria included heart failure (stage>II NYHA classification). The planned total duration of the study was 4 years with follow-up once monthly during the first two months, every two months during the first year and then every three months. Study treatments: randomisedpioglitazone (15 mg, 30 mg or 45 mg patients received either once daily)11at maximum tolerated dose or a placebo as adjunct to their on-going treatment. Primary endpoint: time to first occurrence of an event of the following composite endpoint (7 items): death, nonfatal MI (including silent MI), stroke, acute coronary syndrome, cardiac intervention including percutaneous coronary dilatation or coronary artery bypass graft, amputation of a limb (above the ankle) or arterial revascularisation of a lower limb. Secondary endpoint: cardiovascular mortality  Results:  Population: five thousand two hundred and thirty eight (N=5,238) patients (mean age:62 years, 66% male subjects) were included (2,605 in the pioglitazone group, 2,633 in the placebo group) with mean baseline HbA1c levels of approximately 8%, mean BMI of 30.9 kg/m2 and documented diabetes for 9.5 years. The mean duration of the study was 34.5 months. The results were obtained by analysing all randomised patients and those who had received at least one dose of treatment.  The most frequent macrovascular history was: ischaemic heart disease 48%, myocardial infarction 47%, coronary artery revascularisation 31%. A history of at least two macrovascular events was found in 48% of the patients.  At baseline, 4% of the patients were receiving a diet without hypoglycaemic treatment, 9% were treated by metformin monotherapy, 19% by a sulphonylurea monotherapy, 25% by dual oral metformin + sulphonylurea therapy and 34% of the patients were receiving insulin (on average 46.6 units/day). Most of the patients (89%) received pioglitazone at the dose of 45 mg/day and continued it at this dose (93%). Most patients (95%) were taking cardiovascular drugs (beta-blockers, ACEi, angiotensin II receptor antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).   Primary efficacy endpoint: There was no difference in the time to occurrence of one of the events of the primary composite endpoint between the two treatment groups: 514 (19.7%) patientsin thepioglitazone group versus 572 (21.7%) in the placebo group, HR 0.90 95% CI [0.80-1.02], NS (p=0.095). Secondary endpoint: Cardiovascular mortality: 127 (4.9%) in the pioglitazone group versus 136 (5.2%) in the placebo group, HR 0.94 95% CI [0.74,1.20-], NS.                                                                                                                                             5 Dormandy JA et al. PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial, Lancet 2005;366:1279-1289 6 Myocardial infarction documented in the medical records or a hospital discharge report 7 Stroke documented by imaging or the clinical history 8 Defined by at least one symptomatic episode at rest associated with ECG changes and/or with biochemical markers 9 Documented by at least one of the following findings: positive stress test, angiography showing stenosis > 50%, or positive scintigraphy 10 Symptoms confirmed by an ankle/arm or toe/arm blood pressure index <0.90, or amputation due to occlusive arterial disease of the lower limbs 11 Forced titration during the first 3 months of the study, then dosage adjustment according to safety.  6
Conclusion: In this morbidity and mortality study conducted in type 2 diabetics with a history of macrovascular disease and insufficiently controlled (mean HbA1c 8.1%) by diet alone or combined with oral antidiabetics (OAD) with or without insulin, the effect of pioglitazone was not different from that of placebo for the time to first occurrence of an event of the composite primary endpoint: death, nonfatal MI (including silent MI), stroke, acute coronary syndrome, cardiac intervention including percutaneous coronary dilatation or coronary artery bypass graft, amputation or arterial revascularisation of a lower limb.    Literature data 4.1.2.  A literature search found a Cochrane review published in 200612which included twenty-two controlled studies versus placebo or versus OAD (metformin, glibenclamide, glicazide, repaglinide, acarbose, rosiglitazone) combined or not with insulin, for a duration of at least 24 weeks13studying 6,200 type 2 diabetics treated by pioglitazone (morbidity and mortality criteria evaluated in a single study, PROACTIVE). Pioglitazone was not shown to have any benefit on morbidity and mortality, metabolic control measured from Hba1c levels, or safety and quality of life.  4.2. Safety  Safety data were derived from the ProActive study, PSURs and two meta-analyses of cardiac safety published in 2007.  4.2.1. ProActive  At least one adverse event was observed in 81.7% of the patients in the pioglitazone group (N=2,605) and in 80.6% of those in the placebo group (N=2,633) (mean exposure time 30.3 months). Treatment discontinuation was noted in 9.4% of the patients on pioglitazone and 7.7% of patients on placebo. A serious adverse event (SAE) was observed in 46.2% of patients in the pioglitazone group versus 48.4% of those in the placebo group.  Death:6.8% of the patients in the pioglitazone group (N=177/2,605) and 7.1% (N=186/2,633) of those in the placebo group with MI or HF14 first causes declared by investigators. SAE as causing death included two heart failures in the pioglitazone group and one heart failure and a stroke in the placebo group which were considered to be related to treatment by the investigator.   The most frequently reported adverse events were hypoglycaemia15, œdema16, heart failure17, with a higher incidence in the pioglitazone group than in the placebo group:  gopyHiaemcaly:non-fatal hypoglycaemic coma in each of the 227.2% versus 18.8% with 1 groups.  Oedema:26.4% versus 15.1%, causing treatment discontinuation in 2.7% versus 0.8%.  Heart failure (HF):a higher percentage was observed in the pioglitazone group: 417 reports in 11% of the pioglitazone group patients versus 302 in 8% of placebo group patients i.e. a difference of 115 events. (p<0.0001) Fatal HF rates18similar in the 2 groups (0.96% versus 0.84%). HF requiring were hospitalisation was more frequent in the pioglitazone group (6% versus 4%, p=0.007). In the case of hospitalisation, the mean length of stay in cardiology intensive care was 8.9 days in the pioglitazone group and 5.7 days in the placebo group, with a mean total duration of hospitalisation of 16.1 days versus 14.2 days.
                                            12 Richter et al. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006060. DOI: 10.1002/14651858.C D006060.pub2 2007. 13 16 studies as monotherapy 14 Heart failure, acute heart failure, congestive heart failure 15 Symptomatic or blood glucose levels < 2 mmol/l 16 If no other sign of heart failure 17 New-onset or worsening 18 Considered as first cause of death validated by a committee  7
The percentage of severe HF was 5.7% versus 4.1% (causing treatment discontinuation: 0.7% versus 0.4%).  Weight gainwas observed in 3.6% of patients in the pioglitazone group versus 1.3% of those in the placebo group (mean weight gain +3.8 kg (±6.4) and -0.6 kg (±5.3).  Conclusion: history of macrovascular disease, the previously describedin these patients with a safety profile of pioglitazone and in particular the risk of hypoglycaemias and oedema was confirmed. A higher incidence of heart failure was also noted with pioglitazone, with no increase in mortality. Weight gain was observed in patients in the pioglitazone group (mean weight gain +3.8 kg versus -0.6 kg in the placebo group).   4.2.2. Meta-analyses concerning cardiac safety  Two meta-analyses on the cardiac safety of pioglitazone were submitted by the laboratory.  19 Lincoff et al. The authors evaluated the incidence of ischaemic cardiovascular (CV) complications using a composite endpoint (time to first event of a composite endpoint including: all-cause mortality/non fatal MI/non-fatal stroke) on the basis of individual data from 19 randomised, double blind, placebo- or active comparator-controlled (metformin, sulphonylurea, rosiglitazone, insulin) studies of monotherapy or combination therapy including ProActive (study durations 4 months to 3.5 years).  For a total of 16,390 patients (8,554 in the pioglitazone group versus 7,836 in the OAD comparator ± insulin group), a significant difference for the principal composite endpoint was observed in favour of the pioglitazone group: HR=0.82 [0.72 ; 0.94], p=0.005. This significant difference was not found if the ProActive study was excluded from the meta-analysis. Severe heart failures (HF) were more often reported in the pioglitazone group than in the control group, HR=1.41 [1.14; 1.76] p=0.002). However, no difference between groups was observed for the composite endpoint of severe heart failure or death. This meta-analysis has several limitations: non-exhaustiveness of the studies analysed most of which were not designed to evaluate CV events and outcome variables that were not systematically validated by an independent scientific committee.  Lago et al.20  The authors evaluated the risk of occurrence of congestive heart failure (CHF) and CV death, in pre-diabetic patients or type 2 diabetics treated by glitazones, on the basis of an analysis of randomised, double-blind studies on glitazones and reporting an estimated risk or an incidence of CHF and CV death. This meta-analysis confirmed the risk of CHF related to glitazones, with no associated excess mortality. On the basis of the 7 studies found to comply with the selection criteria, (5 rosiglitazone studies with 14,491 patients and 2 pioglitazone studies with 5,700 patients including ProActive), grouping together 20,191 pre-diabetic and diabetic patients, the risk of onset of HF was higher with glitazones than with comparators: A total of 360 CHF were reported in the 20,191 pre-diabetic and diabetic patients, 214 in the glitazone group (9,360), and 146 in the comparator group (10,931); RR=1.72 [1.21; 2.42], p =0.002; in the pioglitazone subgroup 256 CHF, RR=1.32 [1.04; 1.68], p =0.02. On the contrary, the risk of cardiovascular death was not significantly increased with either of the glitazones RR=0.93 95% CI [0.67 ; 1.29], p = 0.68. The results should be viewed with caution taking into account, in particular, the lack of exhaustiveness of the studies analysed, the variable definition of HF with no systematic                                             19 Lincoff M et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. A meta-analysis of randomised trials. JAMA 2007;298:1180-8 20 Lago RM et al, Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007;370:1129-1136   8
validation by an independent scientific committee and the non-homogeneous population concerned (pre-diabetic, diabetic, metabolic syndrome patients).   4.2.3. Cochrane 2007  
In this review of 22 randomised controlled studies integrating ProActive including 6200 patients on pioglitazone, the incidence of oedema was increased. The exclusion of ProActive did not modify the relative risk. The percentage of SAE was similar between the pioglitazone group and the control group. A higher percentage of treatment discontinuations was noted in the pioglitazone group in particular receiving monotherapy. Weight gain was reported in the pioglitazone group (up to 3.9 kg) and an increase in BMI (up to 1.5 kg/m2) was described in 7 studies. In the pioglitazone group, hypoglycaemias were less frequently reported with monotherapy and more frequently noted in combination with insulin. Severe hypoglycaemias were rarely reported.  The authors underlined the difficulty in distinguishing between the initial publications and publications derived from them and this may have introduced bias in the presented results.   4.2.4. Changes to the safety information in the SPC  
According to the company, the estimated number of patients exposed to pioglitazone since it was first marketed is 8.1 million patient-years including 1.1 million patient-years in Europe (cumulative data of the first 15 Periodic Safety Update Reports21up to 31 January 2007).  Since the last assessment by the Transparency Committee in March 2004, the SPC of ACTOS has been modified with bolstering of the “Warnings and Precaution for Use” section of the SPC (Cf. opinion). The main changes concerned: and heart failure: Institution of pioglitazone at of information about fluid retention  Bolstering low dose and gradual uptitration in patients at risk of developing HF (e.g. history of myocardial infarction, symptomatic coronary heart disease), examination for signs of HF, weight gain and oedema more particularly in patients with a low cardiac reserve or in combination with insulin, increase in HF in patients with major macrovascular disease, with no increase in mortality; limited evidence in patients aged over 75 years;  Bolstering of weight gain section. This weight gain is dose-dependent and may be due to fat accumulation and in some cases associated with fluid retention which may be a symptom of cardiac failure in certain cases.  of a specific sentence about the onset of hypoglycaemia: As a consequence of Addition increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.  Moreover, post marketing reports of new-onset or worsening of macular oedema with decreased visual acuity, have been reported with thiazolidinediones including pioglitazone. Several of these patients reported concomitant peripheral oedema. It is unclear whether or not there is a direct association between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity; an appropriate ophtalmological referral should be considered (cf. SPC).  A fracture risk was identified in women treated by pioglitazone during studies and pharmacovigilance follow-up and was drawn to the attention of prescribers (letter to prescribers April 2007). The fracture risk must be taken into consideration during long-term management of women treated by pioglitazone (cf. SPC).  
                                            21 collected as monotherapy or in combination (including with insulin), as well as data for the new fixed-dose combination (pioglitazone-metformin) marketed in the USA from August 2005.    9
Data obtained from randomised, placebo- or active comparator-controlled, double-blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, followed-up for up to 3.5 years were analysed. A higher fracture rate was observed in women treated by pioglitazone (2.6%) compared to those treated by a comparator (1.7%). No increase in fracture rates was observed in men treated by pioglitazone (1.3%) versus a comparator (1.5%). In the ProActive study, a cardiovascular morbidity and mortality study performed over 3.5 years, 44/870 (5.1%) of the women treated by pioglitazone had fractures versus 23/905 (2.5%) of women receiving a comparator. No increase in fracture rates was observed in men treated by pioglitazone (1.7%) versus a comparator (2.1 %).
 4.2.5. Reassessment by EMEA  The reassessment of the benefit/risk ratio of glitazones by EMEA (October 2007) confirmed a positive benefit-risk ratio (pioglitazone and rosiglitazone) in the treatment of type 2 diabetes.22   4.3. Conclusion  Since the last examination of ACTOS in March 2004,theFrench Transparency Committee has reviewed:   - results of the morbidity and mortality study of pioglitazone versus placebo, ProActive, The that included 5,238 type 2 diabetics with a history of macrovascular disease inadequately controlled (mean HbA1c 8.1%) by diet alone (4%) or combined with oral antidiabetics (including 9% on metformin monotherapy and 19% on sulphonylurea monotherapy), with or without insulin; - Cochrane review published in 2007; A -Variations to the SCP (on 20/08/2007);  - on cardiac safety (Lago 2007, Lincoff 2007) the methods of which had Meta-analyses limitations so that no formal conclusions may be drawn.   To conclude: in terms of efficacy, in ProActive, the clinical benefit of pioglitazone for secondary prevention of death and macrovascular events including non-fatal MI (including silent MI), stroke, acute coronary syndrome, cardiac interventions including percutaneous coronary dilatation or aorto-coronary artery bypass grafting, amputation, arterial revascularisation of a lower limb, was not clearly shown.   According to a Cochrane review published in 2007, integrating the ProActive study, the benefit of pioglitazone in terms of morbidity and mortality, safety and quality of life was not established. The metabolic control, measured from the Hba1c levels, an indirect endpoint, showed no difference with the other oral antidiabetics (metformin, glibenclamide, glicazide, glimrepiride).    · In terms of safety, a higher percentage of hypoglycaemia, oedema and heart failure without an increase in mortality was observed in pioglitazone-treated patients in the studies. Weight gain was also confirmed in patients receiving pioglitazone (mean +3.8 kg).  New risks were identified. A fracture risk was noted during the studies and drug safety monitoring of women treated by pioglitazone and this was drawn to the attention of prescribers (class effect). Some cases of macular oedema were also reported (class effect).  · European risk management plan includes in particular monitoring of heart failure, The weight gain, peripheral oedema, macular oedema, hepatic disorders, bone disorders and neoplastic diseases.                                              22www.emea.europa.eu/pdfs/human/press/pr/48427707en.pdf - 2007-10-18    10
 
5.TRANSPARENCY COMMITTEE CONCLUSIONS 
  5.1. Actual benefit
5.1.1. As oral monotherapy, in patients (particularly overweight patients) for whom metformin is inappropriate because of contraindications or intolerance 
 -diabetes is a chronic disease with potentially serious complications. 2  Type - is used for the treatment of hyperglycaemia. ACTOS  - The efficacy/safety ratio of the proprietary medicine ACTOS is moderate, in the absence of any demonstrated benefit in terms of morbidity and mortality and a relatively poor safety profile confirmed by recent data (peripheral oedema, macular oedema, heart failure with no increase in mortality, weight gain, fracture risk in women) - Alternative medicinal products exist (AGIs, sulphonylureas, glinides). - ACTOS is used for second-line treatment  Public Health Benefit: The public health burden of type 2 diabetes mellitus is high. The subpopulation of patients unable to receive metformin and who receive ACTOS monotherapy, represents a low burden because of its smaller size. Improved therapeutic management of type 2 diabetics is a public health need23. There is no evidence that the proprietary medicine ACTOS as monotherapy has a beneficial effect on morbidity, mortality and quality of life. Taking into account new data on the risks of this treatment and the existence of better alternatives as monotherapy, the proprietary medicine ACTOS is not expected to have any impact on morbidity, mortality or quality of life.  Consequently, ACTOS is not expected to benefit public health in this indication.  In its indication as oral monotherapy, in patients who show intolerance to metformin or for whom metformin is contraindicated, the Committee  ofconsiders that the Actual benefit ACTOS monotherapy remains high according to current knowledge.  As dual oral therapy, in combination with metformin, in particular in overweight patients or in combination with a sulphonylurea in patients who show intolerance to metformin or for whom metformin is contraindicated:    -mellitus is a chronic disease with potentially serious complications. ACTOS 2 diabetes  Type is used for the treatment of hyperglycaemia.  -proprietary medicine ACTOS is moderate, in the absence ofThe efficacy/safety ratio of the  a proven benefit in terms of morbidity and mortality and a relatively poor safety profile confirmed by recent data (peripheral oedema, macular oedema, heart failure with no increase in mortality, weight gain, fracture risk in women) - medicinal products exist in combination with metformin (metformin + Alternative   sulphonylurea or glinide, metformin + AGI), or combination with a sulphonylurea in the case of contraindication or intolerance to metformin (sulphonylurea + AGI). No study has clearly demonstrated a clinical benefit in terms of morbidity and mortality. - used in its indications as dual oral therapy remains a means of therapeutic ACTOS management of type 2 diabetics.  Public health benefit
                                            23 within the scope of identified public health priorities (GTNDO priorities: National Technical Group for Definition of Public Health Goals (DGS-2003)   11