COMPETACT - COMPETACT - CT 10278 - English version
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2011
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06 juillet 2011
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Introduction COMPETACT 15 mg/850 mg, film-coated tablets B/60 (CIP code: 377 383-7) B/180 (CIP code: 377 388-9) Posted on Jul 06 2011 Active substance (DCI) pioglitazone hydrochloride / metformin hydrochloride Avis défavorable au maintien du remboursement en raison de son absence d’intérêt clinique et de son profil de tolérance COMPETACT est une association fixe pioglitazone + metformine indiquée dans le traitement du patient diabétique de type 2, en particulier en surcharge pondérale, insuffisamment équilibré par la metformine seule à dose maximale tolérée.Outre ses effets indésirables déjà connus, des données récentes établissent un lien potentiel entre le traitement par pioglitazone et la survenue d’un cancer de la vessie.Ce profil de tolérance a conduit à la suspension de l’AMM de la pioglitazone en France depuis le 9 juin 2011.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous. ATC Code A10BD05 Laboratory / Manufacturer TAKEDA COMPETACT 15 mg/850 mg, film-coated tablets B/60 (CIP code: 377 383-7) B/180 (CIP code: 377 388-9) Posted on Jul 06 2011
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Publié le
06 juillet 2011
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The legally binding text is the original French version TRANSPARENCY COMMITTEE
ompliance with article R 163-21
OPINION 6 July 2011 COMPETACT 15 mg/850 mg, film-coated tablets B/60 (CIP code: 377 383-7) B/180 (CIP code: 377 388-9) Applicant: TAKEDA pioglitazone hydrochloride / metformin hydrochloride ATC code: A10BD05 List I Date of the initial Marketing Authorisation (centralised procedure): 28 July 2006 Reason for examination:Re-assessment of actual benefit in c of the French Social Security Code. Medical, Economic and Public Health Assessment Division
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1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient pioglitazone hydrochloride / metformin hydrochloride 1.2. Indication "COMPETACT is indicated as treatment of type 2 diabetes mellitus adult patients, particularly overweight patients, who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone." 1.3. Dosage1 "Administration in adults The usual dose of COMPETACT is 30 mg/day pioglitazone plus 1700 mg/day of metformin hydrochloride (this dose is achievable with one tablet of COMPETACT 15 mg/850 mg, taken twice a day). Dose titration with pioglitazone (added to the optimal dose of metformin) should be considered before the patient is switched to COMPETACT. When clinically appropriate, direct change from metformin monotherapy to COMPETACT may be considered. Taking COMPETACT with or just after food may reduce gastrointestinal symptoms associated with metformin. Elderly As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking COMPETACT should have their renal function monitored regularly. Renal impairment COMPETACT should not be used in patients with renal failure or renal dysfunction (creatinine clearance < 60 ml/min). Hepatic impairment COMPETACT should not be used in patients with hepatic impairment. Children and adolescents As no data are available, the use of COMPETACT is not recommended: in children and adolescents under 18 years of age."
1 dosage of pioglitazone: treatment may be initiated at 15 mg or 30 mg once daily. The dose usual may be increased in increments up to 45 mg once daily. usual dosage of metformin: in combination with other oral antidiabetic agents, the usual initial dosage is one tablet two or three times per day of GLUCOPHAGE 500 mg or 850 mg, taken with or after food. After 10-15 days, the dosage is adjusted according to blood glucose levels. In patients on high doses of metformin (2-3 grams daily) it is possible to replace two tablets of metformin 500 mg with one tablet of metformin 1000 mg. The maximum recommended dose of metformin is 3 g per day. 2/12
1.4. Contraindications " - Hypersensitivity to the active substance or to any of the excipients - Cardiac failure or history of cardiac failure (NYHA stages I to IV) - Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock - Hepatic impairment - Acute alcohol intoxication, alcoholism - Diabetic ketoacidosis or diabetic pre-coma . - Renal failure or renal dysfunction (creatinine clearance <60 ml/min) - Acute conditions with the potential to alter renal function such as dehydration, severe infection, shock, intravascular administration of iodinated contrast agents - Breast-feeding. " 1.5. Special warnings and precautions for use (see SPC) "Fluid retention and cardiac failure Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease), physicians should start with the lowest available dose and increase the dose gradually. There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Since insulin and pioglitazone are associated with fluid retention, concomitant administration of insulin and COMPETACT may increase the risk of oedema. Competact should be discontinued if any deterioration in cardiac status occurs. A cardiovascular morbidity-mortality outcome study of pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study. Caution should be exercised in patients over 75 years because of the limited experience in this patient group in this study. "
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2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2011) A: Alimentary tract and metabolism A10: Drugs used in diabetes A10B: Blood glucose lowering drugs, excluding insulin A10BD: Combinations of oral blood glucose lowering drugs A10BD05: metformin and pioglitazone 2.2. Medicines in the same therapeutic category Comparator medicines: medicinal products based on metformin, and generics: proprietary GLUCOPHAGE 500 mg, 850 mg, 1000 mg, tablets, indicated in the treatment of type 2 diabetes particularly in overweight patients, if diet and exercise are not sufficient to restore blood sugar control in adults (as a monotherapy or in combination with other oral antidiabetics), in children aged 10 and over and in adolescents (as a monotherapy or in combination with insulin). A reduction in the complications of diabetes was observed in overweight adult patients with type 2 diabetes who were treated with metformin hydrochloride as a first-line treatment, after dietary measures had failed. medicinal products based on pioglitazone, and generics: proprietary ACTOS 15 mg, 30 mg, scored tablets, indicated in the treatment of non-insulin-dependent diabetes, in combination with an appropriate diet, if this diet alone is not sufficient to restore blood sugar control. 2.3. Medicines with a similar therapeutic aim Proprietary medicinal products indicated as dual oral therapy, in combination with metformin, for patients with type 2 diabetes patients who have not achieved appropriate blood sugar control despite maximal tolerated dose of oral metformin monotherapy: · Sulfonylureas · ha- lucosidase inhibitors Intestinal al · Glinide · DPP liptins 4 inhibitors · incretin mimetics Injectable
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3 REMINDER OF THE TRANSPARENCY COMMITTEE’S OPINIONS Committee Opinion dated 13 December 2006 Inclusion on the list of medicines refundable by National Insurance and approved for use by hospitals The efficacy/adverse effects ratio is high. This proprietary medicinal product is a second-line treatment for patients with type 2 diabetes, particularly overweight patients, whose disease is inadequately controlled by metformin alone at the maximum tolerated dose. COMPETACT is an additional means of managing patients with type 2 diabetes. The actual benefit of COMPETACT is substantial. COMPETACT, a fixed-dose combination of pioglitazone and metformin, does not provide an improvement in actual benefit (IAB V) in comparison with separate administration of the two active substances.
4 ANALYSIS OF DATA MADE AVAILABLE SINCE PREVIOUS OPINION 4.1. Efficacy data Marketing authorisation for COMPETACT was granted on the basis of two pharmacokinetic studies: - one study that showed that the fixed-dose combination of pioglitazone and metformin (15 mg/850 mg) was bioequivalent to the free combination of the active substances at the same doses - one study that evaluated the influence of meals on pharmacokinetic characteristics of the fixed-dose combination. No clinical study is available that examined the fixed-dose combination, as assessment of efficacy and tolerance was primarily done for pioglitazone (ACTOS). The applicant provided no new clinical studies. No studies of COMPETACT that used acceptable methodology were found in the literature. 4.2. Tolerance data 4.2.1. Data from PSURs and from the SPC From the post-marketing pharmacovigilance data for COMPETACT from the most recent Periodic Safety Update Reports (PSUR 22) covering the period 1 February 2010 to 31 July 2010, 80 adverse effects have been reported, 11 of which can be considered to be serious. There was one death (which is considered to be potentially linked to COMPETACT treatment) following hypoglycaemia. The recorded serious cases were as follows: four cases of cardiac failure, two cases of cardiac ischaemia, two cases of hypoglycaemia, one case of weight gain of more than 30 kg,2one case of rhabdomyolysis (an adverse effect that is not mentioned in the SPC), one case of anaphylactic reaction. 2The weight gain occurred four months after treatment started.Over one year of treatment. 5/12
Of the other reported cases, the following were of note: - eight cases of weight gain of between 1 and 6 kg, two of which were associated with oedema - five cases of macular oedema3 - four cases of anaphylactic reaction and angioedema - one case of hepatobiliary disorder - one life-threatening case of lactic acidosis - one myocardial infarction. 4.2.2. Literature data Pioglitazone, in comparison with sulfonylureas, was associated with an increased risk of congestive heart failure (OR=1.68, 95% CI [0.99; 2.85]).4 A meta-analysis5evaluated the risk of heart failure inincluding 29 placebo-controlled studies patients with type 2 diabetes or who were at high risk of developing type 2 diabetes (n=20,254). Glitazones were associated with an increased risk of heart failure in comparison with placebo (OR=1.59, 95% CI [1.34; 1.89], p<0.00001), and this risk was higher for rosiglitazone (OR=2.73, 95% CI [1.46; 5.10], p<0.00001) than for pioglitazone (OR=1.51, 95% CI [1.26; 1.81], p NS). The risk of occurrence of severe heart failure, in comparison with placebo, was the same for each glitazone (OR=1.47, 95% CI [1.16; 1.87], p=0.002). Glitazones were associated with a risk of oedema (OR=2.04, 95% CI [1.85; 2.26], p<0.00001). Pioglitazone, in comparison with metformin, was associated with an increased risk of fracture (OR=1.57, 95% CI [1.13; 2.17])6. This increased risk of fracture was particularly marked in women aged over 65 after one year of treatment.6 The SPC states that "An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone- and 7400 comparator-treated patients, on treatment for up to 3.5 years. Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator." A new risk (occurrence of pneumonia) has been identified.7 Recent data in the literature highlight increased weight gain, oedema, fracture and the risk of 8,9 congestive heart failure in patients treated with pioglitazone. Recent data have established a potential link between pioglitazone treatment and bladder cancer.10 3 The SPC states that post-marketing reports have been received of new-onset or worsening macular oedema, with decreased visual acuity. Several of these cases occurred concomitantly with peripheral oedema. 4 Oral diabetes medications for adults with type 2 diabetes. An update. Comparative effectiveness review number 27. Effective healthcare. AHRQ Agency for Healthcare Research and Quality. March 2011 5Hernandez AV et al. Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials. Am J Cardiovasc drugs. 2011; 11:115-28 6fractures in patients with type 2 Habib ZA et al. Thiazolidinedione use and the longitudinal risk of diabetes mellitus. J Clin Endocrinol Metab 2010; 95:592-600 7use of thiazolidinediones and the associated risk of pneumonia or lower S et al. Long-term Singh respiratory tract infection: systematic review and meta-analysis. Thorax 2011; 66:383-8 8of hyperglycemia in type 2 diabetes: a consensus algorithmD. M. Nathan et al. Medical management for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2009; 52: 17-30. 9 Patrick J Phillips, Stephen M Twigg. Oral hypoglycaemics: A review of the evidence. Australian family physician, Vol 39, No. 9, Sep 2010: 651-653 6/12
The PROactive study,11,12 prospective randomised study of morbidity and mortality over a 34.5 months, compared pioglitazone with placebo and involved 5,238 patients with type 2 diabetes. This study showed 14 cases of bladder cancer in patients treated with pioglitazone (n=2,605) compared with six cases in the placebo arm (n=2,633). In another study, which was requested by the FDA, comparing pioglitazone with glimepiride and evaluating liver tolerance, two cases of bladder cancer were observed in patients on pioglitazone, compared with zero in patients on glimepiride. The odds ratio of occurrence of bladder cancer on pioglitazone, combining the results of this study with those of the PROactive study, is 2.68 (95% CI [1.05; 6.85]). A further post-marketing study lasting 36 months was requested by the FDA, and this recorded three cases in patients on pioglitazone (n=1,051) versus zero cases on glibenclamide (n=1,046). The results of this study combined with those of PROactive give an odds ratio of occurrence of bladder cancer of 2.87, 95% CI [1.08; 8.9]. Interim results after five years of a cohort study13,14carried out in the United States, the aim of which was to compare the incidence of bladder cancer in patients exposed to pioglitazone versus patients not exposed to pioglitazone, which involved 193,099 patients, 30,173 of whom were treated with pioglitazone, showed a statistically significant increase in the risk of bladder cancer in patients treated for more than 24 months (HR=1.4, 95% CI [1.03; 2.0]). In a study15that aimed to detect notifications of bladder cancer associated with pioglitazone using spontaneous notifications to the FDA between 1 January 2004 and 31 December 2009, 93 cases of bladder cancer were declared, 31 of which were associated wiht pioglitazone (OR=4.30, 95% CI [2.82; 6.52], p<0.001). As of 29 March 2011, 15 cases of bladder cancer had been reported in France, 12 of which had occurred after an exposure of more than 12 months. As of 31 May 2011,16 cases of bladder cancer in patients taking pioglitazone had been 46 reported in France, 42 of which were in 2011 (two cases had been reported before the FDA alert, and two at the end of 2010)17. A cohort study18 wasout using data from the French national inter-regime health carried insurance system (SNIIRAM)19 with data from the programme for clinical combined information systems (PMSI). The cohort included 1,491,060 patients with diabetes who were on the general health insurance regime and who were between 40 and 79 years old in 2006. Patients who had had bladder cancer before entering the cohort or within the six months 10 Philip Home, DM, DPhil. Safety of PPAR Agonists. Diabetes care, May 2011, Volume 34. No. supplement 2, S215-S219 11 Dormandy J 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 12pioglitazone in high-risk patients with type 2 diabetes: anDormandy J et al. Safety and tolerability of overview of data from PROactive. Drug Saf 2009;32:187-202 13Observational cohort study based on American data (KPNC/Kaiser Permanente Northern California) over 10 years, requested in 2005 14bladder cancer among diabetic patients treated with pioglitazone: interim JD and al. Risk of Lewis report of a longitudinal cohort study. Diabetes Care 2011;34:916-22 15 Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes care 2011.34:1369-1371. 1176 dceanile,asabatahp lanogivocamr2es w cas13M a t10 1ya2 ht eanitatf or mrt of da Repo of the e naturetoeh r 5/42 ere identified as being transitional cell carcinomas. The precis cases was not specified. Two cases resulted in death. 18 Risk of bladder cancer in patients with diabetes treated with pioglitazone in France: a cohort study using data from SNIIRAM and the PMSI. CNAM (National Health Insurance Fund), Paris, France. Final report 07/06/2011 19SNIIRAM contains full individualised and anonymised data about all reimbursements for healthcare expenses. This information can be combined with the PMSI database, which provides clinical information about all inpatients, including ICD-10 diagnostic codes (version 10 of the International Classification of Diseases). Data on exposure to pioglitazone was collected using SNIIRAM reimbursement data. Occurrence of bladder cancer was determined using admission data from the PMSI. 7/12
following entry into the cohort were excluded. Exposure to pioglitazone (and to any antidiabetic agent) was defined in SNIIRAM as at least two prescriptions of an active substance within six consecutive months. Follow-up was for four years, from 2006 to 2009. Incidence of bladder cancer was identified using reported hospital admissions in the PMSI with a primary diagnosis of bladder cancer or connected to bladder cancer, and within the same admission a significant surgical procedure and/or instillation into the bladder of a pharmacological agent via urethral catheterisation and/or chemotherapy and/or radiotherapy. These were cases of infiltrating bladder cancer. A sensitivity analysis was carried out. Results 155,535 patients with diabetes were exposed to pioglitazone, and 1,335,525 patients with diabetes were not exposed to pioglitazone. Mean age of those who were exposed was 61.5 years, compared with 63.4 years for those not exposed. There were 175 new cases of bladder cancer in the group of patients exposed to pioglitazone and 1,841 in the group who were not exposed. Use of pioglitazone was significantly associated with incidence of bladder cancer (adjusted HR = 1.22, 95% CI [1.05; -1.43], p=0.01). A dose-response relationship was observed, with a significant risk for those with a cumulative dose of greater than or equal to 28,000 mg (adjusted HR = 1.75, 95% CI [1.22; -2.50]) and for duration of exposure of between 12 and 23 months (adjusted HR = 1.34, 95% CI [1.02; -1.75], p=0.03) and greater than 24 months (adjusted HR = 1.36, 95% CI [1.04; -1.79] p=0.02). For all other types of cancer that were studies (lung, ENT, colorectal, breast cancer in women and kidney cancer), there was no increase in risk associated with exposure to pioglitazone. Conclusion: Analysis of this cohort of patients with diabetes who were followed up in France between 2006 and 2009 confirms the hypothesis of a statistically significant association between exposure to pioglitazone and incidence of bladder cancer. The results observed were similar to the results seen in the KPNC cohort study. 4.2.3. Marketing authorisation committee assessment of risk/benefit ratio On 7 April 2011 the MA Committee re-examined the risk/benefit ratio of pioglitazone, and pharmacovigilance data reported at this meeting showed an increased risk of bladder cancer in patients with diabetes who were treated with pioglitazone (ACTOS, COMPETACT). Following an increase in the number of spontaneous notifications of bladder cancer, AFSSAPS and CNAMTS established a large retrospective cohort study involving more than 200,000 patients treated with pioglitazone in France between 2006 and 2009, the final results of which are presented above. The EMA has initiated a re-assessment of the risk/benefit ratio of proprietary medicinal products that are based on pioglitazone. This re-assessment is currently underway. On 9 June 2011, AFSSAPS decided to suspend the use of products containing pioglitazone in France, as of 11 July 2011. 4.3. Conclusion Since the most recent opinion issued by the Committee, no new studies have become available that compare COMPETACT with its two active substances taken separately, or with other dual therapies. It is therefore difficult to assess the benefit of this fixed-dose combination. This fixed-dose combination leads to problems with dosage adjustment. The metformin dose of 850 mg twice daily is low in comparison with doses evaluated in the available studies, particularly the UKPDS study, in which the mean daily metformin dosage was 2,550 mg (850 mg three times daily).
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Dosage levels of metformin in this fixed-dose combination limits possible treatment adjustments. This fixed-dose combination would only be suitable for patients treated with a maximum metformin dosage of 850 mg twice daily. It is not useful for patients treated with > 2,000 mg of metformin daily, which is often the case in practice . The main risk of misuse is that this fixed-dose combination may be prescribed as a first-line treatment, given that the wording of its indication does not state that it is a substitute for dual therapy with metformin + pioglitazone, but that it should initially be prescribed after metformin monotherapy. It should be remembered that use of metformin requires continuing monotherapy with the possibility of increasing the dose up to 2,000-3,000 mg daily if blood sugar control is insufficient and if the drug is well tolerated, before prescribing in combination with another oral antidiabetic agent. The dosage of 850 mg metformin twice daily in the fixed-dose combination is therefore not appropriate to patient management; any need to increase the metformin dose would risk either exposure to excessively high pioglitazone doses, or the addition of another product containing only metformin. Given that COMPETACT contains a low dose of metformin in comparison with the guidelines and with data from clinical practice, and given that it exposes patients to severe adverse effects linked with pioglitazone, this fixed-dose combination is not useful. Recent reports have suggested a link between prolonged exposure to pioglitazone and an increased risk of bladder cancer (see section 4.2 of this opinion). The Transparency Committee has stated that other fixed-dose combinations containing 850 mg of metformin20provide an insufficient AB, for the following reasons: - of data evaluating this dose of metformin lack - dosage of metformin in comparison to dosage levels assessed in the available low studies, particularly UKPDS, and in comparison with clinical practice, in which prescribed dosages are between 2,000 and 3,000 mg.
5 DRUG USAGE DATA 5.1. Prescribing data According to IMS data (moving cumulative annual total, February 2011), COMPETACT box of 60 tablets was prescribed 266,000 times for the indication given in the MA at a daily dosage level of 2 tablets. The presentation as a box of 180 tablets was never marketed. 5.2. Data from use in practice Between November 2010 and January 2011 the applicant carried out a cross-sectional epidemiological survey of a sample of generalist physicians (n=123) and diabetes specialists (n=80), the aim of which was to describe the population of patients treated with COMPETACT in terms of patient characteristics (e.g. demographics, laboratory test results, cardiovascular diseases, etc.), history and management of diabetes and blood sugar control. Eight hundred and eighteen patients were included in this study. An EGB analysis21 also used (Echantillon Généraliste des Bénéficiaires - a sample of was health insurance recipients) for patients who were prescribed COMPETACT at least once during the first quarter of 2010. The aim of this analysis, which involved 403 patients, was to
20EUCREAS - JANUMET - VELMETIA - fixed-dose gliptin/metformin combinations See Opinion of the Transparency Committee dated 29 April 2009 21 This is a representative sample of 1/97 of those covered by the French national health insurance system, consisting of over 500,000 people with data on the care they have received and been refundable for since 2003, with no hospital data for the moment. 9/12
establish the profile of patients who were treated with COMPETACT using data available in the EGB, and to estimate the size of the population treated with COMPETACT. Comparison of common features of these two studies meant that the validity of the sample used in the cross-sectional study could be verified. If there was a clear imbalance between the populations in the two studies, the scientific review board would correct the analysis of the cross-sectional study. One of the limitations of the cross-sectional study was the representative nature of the sample of doctors. The proportion of generalist physicians was 60.6%, compared with 84.1% in the EGB. In order to take into account this under-representation of generalist physicians in the cross-sectional study (60.6%), the data were corrected in the statistical analysis.22 This was a descriptive statistical analysis. After correction, the data from the cross-sectional study and from the EGB were of the same order of magnitude. According to the data from the cross-sectional study, patients treated with COMPETACT had a mean age of 63.5 years and the majority were overweight (44.2%) or obese (43.2%). At the time of the study, 35.5% had had diabetes for more than ten years, 67.2% for more than five years and 89.4% for at least three years. Since they first had diabetes, 40.2% of patients had had an HbA1c level of≥9% and 75.2% had had a level of≥ 8%. 21.4% of patients were reported to have had macroangiopathy (angina in 10.7%, history of myocardial infarction or known acute coronary syndrome in 8.4%), 20.8% had had microangiopathy (12.2% of whom had diabetic retinopathy). 91% of patients in the cross-sectional study had previously received metformin treatment (88.1% of the patients in the EGB), at a maximum dose of≤ for 13% of patients, mg 1,700 between 2,000 and 2,500 mg for 39.4% of patients and≥ 3,000 mg for 37.9% of patients. 16.4% of patients had previously received pioglitazone treatment. According to data from the EGB, at the time of the first prescription of COMPETACT 200/403 patients had another prescription for an antidiabetic agent. This was metformin for 28 patients, pioglitazone for six patients, and a fixed-dose combination of rosiglitazone and metformin for two. At the most recent prescription of COMPETACT, 235/403 patients had another prescription for an antidiabetic agent. For 35 patients this was metformin and for seven this was pioglitazone. In the cross-sectional study, patients had been receiving their current COMPETACT treatment for a mean period of one year and three months (median 11 months). Before starting COMPETACT treatment, 41.7% had had an HbA1c level of > 8%. Mean HbA1c level at the time of inclusion was 7.9 ± 1.2%. On COMPETACT treatment, mean HbA1c level was 7.0 ± 0.8% (a mean reduction of 0.9% ± 1.0% with a median of 0.8%).
22 correction was calculated on the basis of the percentage of prescribers of the most recent The prescription of COMPETACT in the EGC who were generalist physicians (84.1%). 10/12
6 TRANSPARENCY COMMITTEE CONCLUSIONS 6.1. Re-assessment of actual benefit provided by COMPETACT 15 mg/850 mg Type 2 diabetes is a chronic disease with potentially serious complications, particularly cardiovascular complications. The aim of COMPETACT is to treat hyperglycaemia. Efficacy/adverse effects ratio: In the absence of relevant new data, the level of clinical benefit cannot be assessed. COMPETACT contains inadequate levels of metformin. It has not been shown that a dosage of 850 mg metformin twice daily has a clinical benefit. This dose is not appropriate for clinical practice, as few patients who require dual therapy are treated with 850 mg metformin twice daily, as shown in the EGB data and the epidemiological study carried out by the applicant. As such, it has not been established that COMPETACT has a benefit for patients. In addition, the tolerance profile of pioglitazone is worrying (see section 4.2 of this opinion). For this reason, the efficacy/adverse effects ratio of COMPETACT does not seem to be sufficiently favourable. Therapeutic use The aims of therapeutic management of diabetes are glycaemic control: control of HbA1c and control of associated risk factors. The choice of drug treatment and the aims of treatment must be adjusted for individual patients (age, length of history of diabetes, particular situations, risk of hypoglycaemia, etc.). Patients with type 2 diabetes should first be treated with diet and lifestyle measures, which must continue throughout treatment. The practitioner may resort to using oral antidiabetics when diet and lifestyle measures alone are no longer sufficient to control blood glucose levels. The adoption of an active lifestyle and nutritional planning are essential interventions at all stages of diabetes management. If HbA1c remains > 6.5% despite a maximum dose of monotherapy, one of the following dual therapies can be used: - metformin + insulin secreter - metformin + glitazone - metformin + alphaglucosidase inhibitor -secreter + glitazone, if there is clear and persistent intolerance to metformin or insulin if metformin is contraindicated. - or insulin secreter + alphaglucosidase inhibitors (if there is severe postprandial hyperglycemia, though this combination has a lower efficacy on HbA1c than the other combinations). If HbA1c levels are > 7%, a triple therapy can be used, or insulin in combination with metformin or other oral antidiabetic agents, except pioglitazone. This therapeutic strategy is currently being reviewed. The role of GLP-1 analogues and DPP-4 inhibitors still needs clarification. The most recent recommendations by the EASD (European Association for the Study of Diabetes) and the American Diabetes Association8 that pioglitazone is a therapy with state less of an evidence base than the combination of metformin + a sulfonylurea. Glitazones are only recommended in specific cases:23 if there is a major risk of hypoglycaemia and if there is a need to avoid this. 23Olivia J. Phung et al. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 2010; 303: 1410-1418 11/12
