TRANSPARENCY COMMITTEE OPINION. 15 October 2008

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 15 October 2008 TANDEMACT 30 mg/20 mg tablets Box of 30 (CIP: ) Box of 90 (CIP: ) TANDEMACT 30 mg/4 mg tablets Box of 30 (CIP: ) Box of 90 (CIP: ) Applicant : TAKEDA pioglitazone / glimepiride List I ATC Code: A10BD06 Date of MA (centralised procedure): January 8, 2007 for TANDEMACT 30 mg/4 mg March 31, 2008 for TANDEMACT 30 mg/2 mg Reason for request: Inclusion on the list of medicines reimbursed by National Health Insurance and approved for use by hospitals. Medical, Economic and Public Health Assessment Division 1

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient pioglitazone / glimepiride 1.2. Indications TANDEMACT is indicated in the treatment of type 2 diabetes in patients already treated with a combination of pioglitazone and glimepiride and who show intolerance or a contraindication to metformin Dosage Oral route. The tablets should be taken once daily just before or during the first main meal of the day. The tablets should be swallowed whole with a glass of water. In the event of hypoglycaemia, the dosage of TANDELACT should be reduced or a flexible combination treatment should be considered. For patients previously treated with pioglitazone and a sulphonylurea other than glimepiride, glycaemic control must be achieved before switching to TANDEMACT. Elderly: No dose adjustment is required for elderly patients. Patients suffering from renal impairment: TANDEMACT must not be used by patients suffering from severe renal impairment (creatinine clearance < 30 ml/min). Patients suffering from hepatic impairment: TANDEMACT must not be used by patients suffering from hepatic impairment. Children and adolescents: As there is no data available, TANDEMACT is not recommended for patients under the age of Contraindications TANDEMACT is contraindicated in patients presenting with: - known hypersensitivity to pioglitazone, glimepiride or any of the excipients of the tablet or to other sulphonylureas - heart failure or a history of heart failure (NYHA class I to IV) - hepatic impairment - type I diabetes mellitus - a diabetic coma - diabetic ketoacidosis - severe renal impairment - during pregnancy - when breastfeeding. 2

3 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2008) A: Alimentary tract and metabolism A10: Drugs used in diabetes A10B: Oral antidiabetics A10BD: Combinations of oral antidiabetics A10BD06: pioglitazone / glimepiride 2.2. Medicines in the same therapeutic category Comparator medicines: - pioglitazone: ACTOS 15 mg, 30 mg, 45 mg, indicated particularly in oral dual therapy in combination with a sulphonylurea, only in patients who show intolerance or a contraindication to metformin, with insufficient glycaemic control despite a maximum tolerated dose of oral single sulphonylurea therapy. - products containing glimepiride and their generics: AMAREL 1 mg, 2 mg, 3 mg, 4 mg indicated in non-insulin-dependent diabetes, in combination with an appropriate diet, when this diet does not control glycaemia sufficiently Medicines with a similar therapeutic aim dual oral therapy: - in type 2 diabetic patients not achieving adequate glycaemic control despite maximum tolerated doses of oral single metformin therapy: other sulphonylureas intestinal alpha-glucosidase inhibitors glinides other glitazone (rosiglitazone) dipeptidyl peptidase-4 inhibitors (DPP-4) parenteral incretin mimetics - in type 2 diabetic patients with inadequate glycaemic control despite maximum tolerated doses of oral single sulphonylurea therapy and who show intolerance or a contraindication to metformin: intestinal alpha-glucosidase inhibitors parenteral incretin mimetics (in combination with a sulphonylurea) 3

4 3 ANALYSIS OF AVAILABLE DATA The clinical development of the fixed combination of pioglitazone/glimepiride (TANDEMACT) is based on 5 pharmacokinetic studies: two studies aiming to demonstrate the bioequivalence of the fixed pioglitazone + glimepiride (30 mg/2 mg) combination and the flexible combination of each active ingredient at the same doses. Only one of these studies has been validated and is considered acceptable by the EMEA one study demonstrating the bioequivalence of the fixed pioglitazone + glimepiride (30 mg/4 mg) combination and the flexible combination of each active ingredient at the same doses two studies evaluating the effects of meals on the pharmacokinetics of the fixed combination. No clinical study has been conducted specifically with the fixed combination. The clinical efficacy data submitted by the firm relates to the flexible pioglitazone sulphonylurea combination. This data has already been evaluated by the Transparency Committee 1. Below is a reiteration of the data from these studies: 1. TC opinion of March 28, 2001: listing of ACTOS products among dual therapy indications. Results of the study in combination with a sulphonylurea (Study PNFP-10) The sulphonylurea given to the majority of patients (around 85%) in the study was glimepiride. The main adverse effects observed were: dose-dependent oedemas (more frequent in patients aged over 65), weight gain of around 5 kg after 72 weeks, anaemia, increase (usually transient) of around 10% in HDL cholesterol and of around 15% in protein kinase C. The incidence of adverse hepatobiliary effects was low, similar to the patients in the comparator groups. Conclusion: the pioglitazone + sulphonylurea combination evaluated causes a greater decrease in HbA1c than a sulphonylurea alone. However, given the indications of pioglitazone, it would have been useful to compare with a metformin + sulphonylurea combination (in patients with no contraindication to metformin) to determine the advantages of this new oral antidiabetic. There is not enough current data to exclude a long-term deleterious effect on the cardiac function of patients suffering from mild to moderate heart failure (stage I or II according to NYHA classification). The studies did not include patients with stage III or IV heart failure. 2. TC opinion of March 24, 2004: reevaluation of improvement in actual clinical benefit of ACTOS products in dual therapy indications. Results of study EC 409 of combination with a sulphonylurea (multicentre, randomised, double-blind study over 2 years, evaluating the pioglitazone mg + sulphonylurea combination (n=315) compared to the metformin mg + sulphonylurea combination (n=313). In this study, no difference was observed in the effect of the different treatments, on HbA1c or on the percentage of responsive patients. It must be stressed that only 19% of the patients included in this study were given glimepiride. More patients treated with pioglitazone gained weight and experienced oedemas. These effects were dose-dependent. The hypoglycaemia was more frequent in patients treated with sulphonylurea. These studies did not specifically evaluate the pioglitazone/glimepiride combination. The efficacy and safety data concerning this combination are therefore limited. 1 Opinion on ACTOS of March 28, 2001 and March 24,

5 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Type 2 diabetes is a chronic disease with potentially serious complications, particularly on the cardiovascular system. TANDEMACT products are designed to be used for the treatment of hyperglycaemia. Efficacy/adverse effects ratio: No clinical study has been conducted specifically on the fixed combination. Only pharmacokinetic studies have been submitted. Although the bioequivalence of the fixed combination and separate administration of the active ingredients has been demonstrated, there is no clinical study comparing the two active ingredients taken separately to other reference dual therapies to ascertain the efficacy and safety of the fixed combination. It must be stressed that the evaluation data on the flexible combination is limited. Glimepiride is a sulphonylurea carrying a high risk of serious and severe hypoglycaemia, particularly at a dose of 4 mg. It is absolutely essential to take the sulphonylurea with a meal. As glimepiride is taken once daily, contrary to other sulphonylureas, there is a significant risk of hypoglycaemia when the patient misses a meal or does not eat enough during the meal. The merits of choosing this sulphonylurea are therefore open to debate. Furthermore, the adverse effects of pioglitazone are peripheral oedemas, macular oedemas, heart failure, with no increase in mortality, weight gain, and risk of fractures in women. Consequently, it has not been established whether the fixed combination provides any clinical benefit to patients. The use of glimepiride requires maintaining single therapy, with the possibility of increasing the doses to 1, 2, 3 or 4 mg in cases of poor glycaemic control and good tolerance. In this context, dual therapy is not necessary. The dosage of 2 mg glimepiride in the fixed combination is therefore unsuitable. The efficacy/ adverse effects ratio cannot be established. Therapeutic use: According to the Treatment of type 2 diabetes recommendation published by the Afssaps and HAS in November 2006, at the oral dual therapy stage (when patient is refractory to single therapy): HbA1C > 6.5% after 6 months of one of the single therapies at maximum dose), one of the following dual therapies may be proposed: - metformin + insulin secretor (sulphonylurea or glinide) - metformin + glitazone - metformin + alphaglucosidase inhibitor - insulin secretor + glitazone, in the event of known and persistent intolerance to metformin or a contraindication to metformin. - or insulin secretor + alphaglucosidase inhibitors (if there is major postprandial hyperglycaemia although this combination is less effective on HbA1c than the other combinations). The choice of combination must take into account the safety and contraindications of each drug class, the patient s age, the risk and degree of hypoglycaemia and the specific clinical and biological profile of each patient (professional consensus). No data exists to demonstrate that the sulphonylurea + glitazone combination is superior to the sulphonylurea + metformin combination. It is therefore difficult to position this fixed combination in terms of therapeutic use or to judge the advantage it offers over taking the two active ingredients separately. 5

6 One of the benefits of the fixed combination, in theory, is better patient compliance. TANDEMACT is a combination of pioglitazone and glimepiride, which are administered separately one tablet daily. The decrease in the number of tablets taken each day would therefore be limited with the fixed combination (decrease of one tablet compared to flexible combination). For the reasons explained in the above paragraphs on the efficacy / adverse effects ratio and therapeutic use, this fixed combination is in danger of leading to use that is non-ma approved and outside the scope of Good Practice Guidelines. The primary risk of misuse is the prescription of this fixed combination for first-line treatment, which does not comply with current recommendations. Indeed, recommendations are in favour of administering metformin, the only oral antidiabetic to reduce angiopathic complications, in first-line treatment, as a single therapy or in dual therapy. In practice, it is preferable to have each separate active ingredient to adapt the doses of each class of antidiabetic individually to the current glycaemic control. Sulphonylureas are particularly contraindicated among the elderly, and patients with renal or hepatic impairment. The same contraindications are reported for metformin. Therefore, patients likely to benefit from treatment with TANDEMACT should show intolerance only to metformin, which, in practice, is difficult to assess and not widely documented (in addition, within this group, the percentage of patients able to take glitazone is unknown). The need is therefore very minor and this fixed combination is thought to concern a limited number of patients. It is therefore difficult to determine the therapeutic relevance of TANDEMACT. There are therapeutic alternatives to these products. Public health benefit: The public health burden of type 2 diabetes is substantial. The sub-population of patients given ACTOS + sulphonylurea dual therapy in the event of intolerance or a contraindication to metformin represents a moderate burden. Improved therapeutic management of type 2 diabetics is a public health need 2. However, existing dual therapies (including the flexible combination of pioglitazone and glimepiride) already help to cover this need. There is no data to demonstrate the benefit of treatment with this fixed combination compared to the flexible combination of these two active ingredients. TANDEMACT is therefore not expected to have any effect on morbidity and mortality or quality of life. In addition, as the safety profile of pioglitazone is uncertain, and as this fixed combination carries a possible risk of misuse and a probable heightened risk of hypoglycaemia associated with glimepiride, it is not possible to exclude a negative effect from TANDEMACT on morbidity and mortality in real treatment situations. For this reason, TANDEMACT is not expected to benefit public health. In light of all these factors, the Committee feels that the actual benefit of TANDEMACT is not great enough for it to be covered by national solidarity, compared to existing treatments Improvement in actual clinical benefit not relevant 4.3. Therapeutic use not relevant 2 according to the priorities established by the French Public Health objectives group (GTNDO) 6

7 4.4. Target population not relevant 4.5. Transparency Committee recommendation The Transparency Committee does not recommend inclusion on the list of medicines reimbursed by National Insurance and on the list of medicines approved for use by hospitals and various public services. 7

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