JANUVIA - JANUVIA - CT 12239 - Version anglaise
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JANUVIA - JANUVIA - CT 12239 - Version anglaise

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25 Pages
English

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Présentation JANUVIA 25 mg, comprimé pelliculé B/28 - Code CIP : 3792467 B/50- Code CIP : 5707081 JANUVIA 50 mg, comprimé pelliculé B/28 - Code CIP : 3792496 B/50- Code CIP : 5707106 Mis en ligne le 11 avr. 2013 Substance active (DCI) sitagliptine (phosphate de) monohydraté Diabétologie - Nouvelles présentations Pas d’avantage clinique démontré en monothérapie ni en bithérapie en association à un sulfamide ou à l’insulineAvis défavorable au remboursement en association à la metformine Les spécialités JANUVIA/XELEVIA existent désormais sous deux nouveaux dosages destinés aux diabétiques de type 2 avec insuffisance rénale modérée (50 mg), sévère ou terminale (25 mg).Leur intérêt clinique est faible en monothérapie et modéré en association à un sulfamide ou à l’insuline.En association à la metformine, leur intérêt clinique est insuffisant pour une prise en charge par la solidarité nationale.Le risque de réaction grave d'hypersensibilité, de syndrome de Stevens-Johnson et de pancréatite doit être pris en compte. Code ATC A10BH01 Laboratoire / fabricant MSD - CHIBRET JANUVIA 25 mg, comprimé pelliculé B/28 - Code CIP : 3792467 B/50- Code CIP : 5707081 JANUVIA 50 mg, comprimé pelliculé B/28 - Code CIP : 3792496 B/50- Code CIP : 5707106 Mis en ligne le 11 avr. 2013

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Published 19 September 2012
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 The legally binding text is the original French version  TRANSPARENCY COMMITTEE
 OPINION  19 September 2012   JANUVIA 25 mg, film-coated tablets B/28 (CIP code:379 246-7) B/50 (CIP code:570 708-1)  JANUVIA 50 mg, film-coated tablets B/28 (CIP code:379 249-6) B/50 (CIP code:570 710-6)  Applicant: MERCK SHARP & DOHME-CHIBRET  Sitagliptin ATC code: A10BH01 (DPP-4 inhibitor or gliptin)  List I  Date of the initial Marketing Authorisation (centralised procedure): 21 March 2007 Amendment to the Marketing Authorisation of 22 December 2011 (deletion from the SPC of the precautions for use for sitagliptin in patients with renal impairment)   Reason for request: Inclusion on the list of medicines refundable by National Health Insurance (B/28) and approved for hospital use (B/28 and B/50).   The applicant requests the inclusion of JANUVIA 25 mg on the list for use in patients with type 2 diabetes with severe renal impairment or end-stage renal disease treated by dialysis and of JANUVIA 50 mg for use in patients with type 2 diabetes with moderate renal impairment in the following indications:  as monotherapy, ·  in combination with a sulfonylurea or insulin.1 ·       Medical, Economic and Public Health Assessment Division
                                            1 The company has excluded from its request the indications in combination with metformin. The reason for this is that metformin is contraindicated in patients with renal impairment, whatever the level of severity.   1/25 
BACKGROUND: Development of sitagliptin in diabetic patients with renal impairment 
  During the initial Marketing Authorisation request for JANUVIA, a clinical study (study P028) was appended to the dossier examined by CHMP. This study evaluated the safety and efficacy of appropriate doses of sitagliptin (25 mg and 50 mg) in 65 patients with type 2 diabetes and moderate to severe renal impairment or end-stage renal disease treated by dialysis. In view of the small size of the patient population, the CHMP requested the implementation of supplementary studies in patients with diabetes and moderate, severe or end-stage renal disease within the framework of the Risk Management Plan (RMP). The SPC, in the “precautions for use” section, staet s that: “Clinical study experience with JANUVIA in patients with moderate or severe renal impairment is limited. Therefore, use of JANUVIA is not recommended in this population.”   Because the 25 and 50 mg dosages of JANUVIA are appropriate for patients with renal impairment and bearing in mind the restriction on use in patients with renal impairment, the inclusion of these dosages on the list of medicines refundable by National Health Insurance and the approval for hospital use was not requested in the initial request for inclusion of JANUVIA 100 mg on the list (dossier examined by the Transparency Committee [TC] in June 2007).  MSD has carried out the studies requested in the Marketing Authorisation: studies P063 (study to evaluate doses of 25 mg and 50 mg of sitagliptin in diabetic patients with moderate to severe renal impairment) and P073 (study to evaluate the 25 mg dose of sitagliptin in diabetic patients with end-stage renal disease treated by dialysis). These two studies permitted the removal, on 22 December 2011, of the restriction on the use of sitagliptin in diabetic patients with moderate to severe or end-stage renal disease.  JANUVIA, at dosages of 25 mg and 50 mg, has been granted Marketing Authorisation in the United States, in Australia, and in Japan. In Europe, these proprietary medicinal products are currently covered by the national health insurance systems in Germany and the United Kingdom.  
 
 
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1.
CHARACTERISTICS OF THE MEDICINAL PRODUCT
  1.1. Active ingredient  Sitagliptin   1.2. Indications  “For adult patients with type 2 diabetes mellitus, JANUVIA is indicated to improve glycaemic control:  as monotherapy: · in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindication or intolerance.  as dual oral therapy in combination with: · when diet and exercise plus metformin  metformin,alone do not provide adequate glycaemic control. · a sulfonylurea when diet and exercise plus maximal tolerated dose of a sulfonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance. · a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e. a thiazolidinedione) when use of a PPARγagonist is appropriate and when diet and exercise plus the PPARγalone do not provide adequate glycaemic control. (Obsolete  agonist indication not requiring evaluation by the TC, as glitazones are no longer available in France).  as triple oral therapy in combination with: · a sulfonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. · PPAR aγagonist and metformin when use of a PPARγagonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. (Obsolete indication not requiring evaluation by the TC, as glitazones are no longer available in France).  JANUVIA is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.”
 
 
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 To recap, the TC has concluded that, for JANUVIA 100 mg:  - as monotherapy: AB insufficient (see Opinion of 18 July 2012) - as dual oral therapy in combination with:  • metformin: substantial AB, IAB IV (see Opinion of 6 June 2007)  • a sulfonylurea: low AB, IAB V (see Opinion of 24 June 2009) - as triple oral therapy in combination with:  • a sulfonylurea and metformin: substantial AB, IAB V (see Opinion of 24 June 2009) - in combination with insulin: AB insufficient (see opinion of 18 July 2012) - in combination with insulin and metformin: substantial AB, IAB V (see Opinion of 18 July 2012).   1.3. Dosage  “The dose of JANUVIA is 100 mg once daily. When JANUVIA is used in combination with metformin, the dose of metformin should be maintained and JANUVIA administered concomitantly.   When JANUVIA is used in combination with a sulfonylurea or with insulin, a lower dose of the sulfonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4 of the SPC).  If a dose of JANUVIA is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day. JANUVIA may be taken with or without food.  Patients with renal impairment When considering the use of sitagliptin in combination with another anti-diabetic product, its precautions for use in patients with renal impairment should be checked. For patients with mild renal impairment (creatinine clearance [CrCl] ml/min), no dose 50 adjustment for JANUVIA is required. For patients with moderate renal impairment (CrCl30 to < 50 ml/min), the dose of JANUVIA is 50 mg once daily. For patients with severe renal impairment (CrCl < 30 ml/min) or with end-stage renal disease requiring haemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of dialysis. Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.  Patients with hepatic impairment No dose adjustment is necessary for patients with mild to moderate hepatic impairment. JANUVIA has not been studied in patients with severe hepatic impairment.  Elderly patients No dose adjustment is necessary based on age. Limited safety data is available in patients 75 years of age and care should be exercised.  Paediatric population JANUVIA is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy.”   
 
 
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1.4. Special warnings and precautions for use (see SPC)  “Hypoglycaemia when used in combination with other anti-hyperglycaemic agents In clinical trials of JANUVIA as monotherapy and as part of combination therapy with agents that do not normally lead to hypoglycaemia (for example metformin), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulfonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo.of hypoglycaemia, a lower dose of sulfonylurea orTherefore, to reduce the risk insulin may be considered.   Renal impairment JANUVIA is renally excreted. To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate to severe renal impairment as well as in patients with end-stage renal disease requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2). When considering the use of sitagliptin in combination with another antidiabetic product, its precautions for use in patients with renal impairment should be checked.  Hypersensitivity reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA.These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some cases occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes of the event, and institute alternative treatment for diabetes.  Pancreatitis In postmarketing experience, there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, JANUVIA and other potentially suspect medicinal products should be discontinued.”   
 
 
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2.
SIMILAR MEDICINAL PRODUCTS
  2.1. ATC Classification (2012)  A: Alimentary tract and metabolism A10: Drugs used in diabetes A10B:  Blood glucose lowering drugs, excluding insulins A10BH: Dipeptidyl peptidase-4 (DPP-4) inhibitors A10BH01:  gliptiniSat   2.2. Medicines in the same therapeutic category  JANUVIA 25 mg and JANUVIA 50 mg are two new dosages intended for dose adjustment in patients with type 2 diabetes and moderate to severe renal impairment or end-stage renal disease. According to their SPCs, the indications for the use of other gliptins in cases of renal impairment (RI) are as follows:  - ONGLYZA 2.5 mg (saxagliptin), indicated in combination with metformin or a sulfonylurea,  may be used in patients with type 2 diabetes who have moderate RI, with caution in patients with severe RI, and is not recommended in patients with end-stage renal disease requiring haemodialysis. (Request for inclusion of this proprietary medicinal product examined by the TC on 7 September 2011; following the issuing of a draft Opinion on 21 September 2011, the request was withdrawn by the company. The TC classified the AB as insufficient)  - TRAJENTA (linagliptin), indicated in monotherapy, particularly where metformin is contraindicated because of renal impairment, in combination with metformin ± a sulfonylurea, may be used in patients with type 2 diabetes who have RI without dose adjustment. (See TC Opinion of 20 June 2012 – AB insufficient in monotherapy, particularly where metformin is contraindicated because of RI, substantial AB and IAB V in dual therapy and triple therapy)  - GALVUS and JALRA (vildagliptin), indicated in monotherapy, in combination with metformin or a sulfonylurea, may be used in patients with moderate or severe RI and with caution in those with end-stage renal disease requiring dialysis. Under evaluation by the TC, dossier submitted on 30 July 2012.  
 
 
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2.3. Medicines with a similar therapeutic aim  Table 1: Medicinal products with a similar therapeutic aim to JANUVIA 25 mg and 50 mg as a function of the degree of renal impairment (RI) in patients with type 2 diabetes  
 
CI
authorised 
authorised 
† CI
authorised 
authorised 
Moderate RI (Creatinine clearance 30 to 50 ml/min) Severe RI CreatinineCI CI clearance) 30 ml/min <  CI: Contraindicated in the SPC. NR: Not recommended in the “precautions for use” section of the SPC. **: Administered by injection. †if the creatinine clearance is < 25 ml/min/1.73 m: Contraindicated 2.                               
 
 
Exenatide: authorised Liraglutide:  NR
NR
authorised 
authorised 
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3.
ANALYSIS OF AVAILABLE DATA
  The proprietary medicinal product JANUVIA already exists in the form of a different presentation with a dose of 100 mg. When its Marketing Authorisation was granted, it was accompanied by a European Risk Management Plan that included, among other things, the implementation of clinical studies in patients with type 2 diabetes and moderate, severe or end-stage renal disease, studies P063 and P073, which are the subject of this evaluation.   3.1. Efficacy results   3.1.1. Study P063  Aim and method: Randomised, double-blind, phase III study, to demonstrate, in monotherapy, the non-inferiority of sitagliptin to glipizide, in patients with type 2 diabetes inadequately 2 controlled by diet and exercise alone and moderate to severe renal impairment, after 54 weeks of treatment.  Inclusion in the study and randomisation were preceded by a washout phase during which the antidiabetic medication was discontinued and diet and physical activity were optimised (for 14 weeks), followed by 2 weeks of single-blind placebo treatment.3   The randomisation was stratified according to the severity of renal impairment (moderate/severe), cardiovascular disease history (with/without a history of cardiovascular, cerebrovascular, or peripheral vascular disease), and history of cardiac failure (with/without).  Inclusion criteria: Patients with type 2 diabetes, at least 30 years of age, with moderate to severe renal impairment, inadequately controlled by diet and exercise alone (HbA1c level7% and9%) who have not received antidiabetic treatment for at least 3 months, or who are under treatment with antidiabetic monotherapy or low-dose dual therapy (dose50% of the maximum recommended dose of each antidiabetic4) and with an HbA1c level6.5% and9%.  Principal exclusion criteria: -Patients on dialysis -Known cardiovascular disease (myocardial infarction or unstable angina) or angioplasty during the preceding 3 months -signs of cardiac failure or aggravation of cardiac failure in the 3 monthsRecent preceding inclusion -Severe peripheral vascular disease -Recent episode or diagnosis of cerebrovascular accident, transient ischaemic attack, or neurological complaints, or recent changes of treatment for these complaints -Treatment with a GLP-1 analogue or gliptin in the preceding 3 months.  Dosing regimen: Four hundred and twenty-six (426) patients were randomised to receive: - in case of severe renal impairment or mg/day sitagliptin at a dosage of 25 either 50 mg/day in case of moderate renal impairment (n = 211)
                                            2Assessment of the glomerular filtration rate is based on the MDRD (Modification of the Diet in Renal Disease) foof rbmeutlwa eaennd  t etsho/ 1. 7fg/amsien 0lm3 evesr2ity are as follows: moderate renal impairment is defined by a glomerular filtration rate < 50 ml/min/1.73m2 a b, severe renal rate ration < 30 ml/min/1.73m2 ,adaenbd  3fmen iocru yero dise tis. alysyt enrmaimp itlif raluremolg 3ebit crtaemtne twere able to stat trs ehlgnilb-ed inacplo ebeatrneitaP r ton stngvieieciaidnt agstree d and-en esad si laneside aspht entm immediately. 4These drugs were discontinued during the pre-inclusion phase.   8/25 
- mg/day glipizide at an initial dose of 2.5 mg/day, which could be increased up to 20 or (n = 212).   One centre did not follow good clinical practice, and its three patients were excluded from the analysis. Patients with inadequate glycaemic control could be given insulin. To avoid an increase in the risk of hypoglycaemia, patients on glipizide discontinued their treatment once insulin treatment was initiated.  Primary efficacy endpoint: Average change in HbA1c level after 54 weeks of treatment compared with the baseline value.  Sitagliptin could be considered non-inferior to glipizide if the upper limit of the 95% confidence interval of the difference between the two treatments (sitagliptin – glipizide) in respect of the criterion “change in the HbA1c level” was less than0.4%.5 The protocol envisaged the inclusion of 162 patients in theper protocolanalysis.  Secondary endpoints after 54 weeks of treatment: - change in the fasting blood glucose level mean - change in weight - of patients with an HbA1c level < 7% percentage  The analyses of the subgroups specified in the protocol were carried out (age, body mass index, severity of renal impairment, HbA1c at inclusion, previous antidiabetic treatments and duration of diabetes). As no adjustment method was applied to take account of multiple comparisons, the possibility of an overestimation of the effect cannot be ruled out. Consequently, no conclusions can be drawn on the basis of these exploratory analyses, and they are therefore not presented.  Results: At inclusion, the characteristics of the patients in the two treatment groups were similar. On average, the patients were 64.6 years old (48.7% of the patients were aged 65 or over), and they were overweight (mean BMI 26.7 kg/m2). They had had diabetes for 10 years on average. Among the patients randomised, 78.2% of those in the sitagliptin group and 77.4% of those in the glipizide group had previously received antidiabetic treatment (a sulfonylurea for 90% of patients on sitagliptin and 93% of those on glipizide, metformin for 35.1% of patients on sitagliptin and 38.4% of those on glipizide, and an insulin for 5.5% of patients on sitagliptin and 3.7% of those on glipizide). At inclusion, the mean HbA1c level was 7.8%, and 58.5% of the patients had a HbA1c level between 7 and 8%. The median level was 7.6%. About 74% of the patients had moderate renal impairment and 26% had severe renal impairment. The renal impairment was due to diabetic nephropathy in 83% of cases.  27.4% of the patients on sitagliptin and 23.9% of the patients on glipizide had a history of cardiovascular disease. The mean dose given to patients treated with glipizide was 7.5 mg. 27.4% of the patients in the glipizide group were given the maximum authorised dose of 20 mg/day. 
                                            5Sdosage recommended in their Marketing Authorisations.itagliptin and glipizide were used at the optimal The threshold of non-inferiority used is that normally used in the evaluation of antidiabetics.    9/25 
Table 2: Characteristics of the patients included (per-protocol population)   Sitagliptin group Glipizide group N = 135 N = 142 Age Mean (years) 64.8 64.3 < 55 years old n (%)  (12.0)26 (19.3) 17 Between 55 and 64 years old n (%) 37 (27.4) (43.7) 62 Between 65 and 74 years old n (%) 50 (37.0) 42 (29.6) 75 years old n (%)  (14.8) 2122 (16.3) Mean weight (kg) 68.0 70.2 Mean body mass index (kg/m²) 26.5 27.0 renal i airment Severity of mp  Moderate n (%)  (74.6) 10698 (72.6) Severe n (%) 37 (27.4) 36 (25.4) Mean HbA1c level (%) 7.8 7.8 Number (%) of patients with HbA1c levels at  inclus o i n < 7% 7 (5.2) 6 (4.2) 7% and 8%  (57.7) 8280 (59.3) < 8% and < 9%  48 (33.8)42 (31.1)  6 (4.4) (4.2)9% 6 Mean fasting blood glucose level (mg/dl) 148.1 143.9 Mean duration of diabetes (years) 10.7 10.1 Oral antidiabetic treatment before inclusion   yes n (%)  (65.5) 9394 (69.6) No n (%)  49 (34.5)41 (30.4)   Primary efficacy endpoint:  Table 3: Change in HbA1c levels after 54 weeks in the per-protocol population:  Mean baseline Change by week 54 compared with baseline Treatment group ev l1cbA el H(SD)NeMnai  newke5  4 Mean (SD) L (SD) S mean (95% CI) Sitagliptin 135 7.76 (0.65) 7.05 (0.74) -0.70 (0.80) -0.76 (-0.89. -0.62) Glipizide 142 7.79 (0.70) 7.17 (0.80) -0.62 (0.91) -0.64 (-0.78. -0.51)
Estimated difference Sitagliptinversusglipizide 
Difference between the LS means (95% CI) -0.11 (-0.29, 0.06)
 After 54 weeks of treatment, the difference between sitagliptin and glipizide in the per-protocol population in terms of the reduction in the HbA1c level was -0.11%, 95% CI [-0.29; 0.06]. As the u er limit of the confidence interval of this difference is less than the fixed threshold (0.4%), the non-inferiority of sitagliptin with respect to glipizide has been demonstrated. This result was confirmed in the ITT population. The 54 week data were missing for about 32% of the patients included (33.2%, 70/211 of the patients in the sitagliptin group and 30.2%, 64/212 of the patients in the glipizide group). It should be noted that sitagliptin was most effective up to the 42nd week of treatment. HbA1c levels rose after that point. For glipizide, the effect reached a maximum in the 18th and week was maintained after that.  
 
 
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Secondary endpoints:  - change in the fasting blood glucose level: Mean After 54 weeks of treatment, no difference was observed between the two treatment groups.  - in weight: Change
 
In the per-protocol population, after 54 weeks of treatment, the average body weight had fallen by -0.6 kg 95% CI [-1.2; -0.0] in the sitagliptin group (n = 143) and increased by 1.2 kg 95% CI [0.6; 1.8] in the glipizide group (n = 148), which is a difference of -1.8 kg; 95% CI [-2.6; -1.0];p< 0.001).
- Percentage of patients with an HbA1c level < 7%: The clinical target was achieved by 47.4% of the patients on sitagliptin (64/135) and 41.5% of the patients on glipizide (59/142).
  3.1.2. Study P073  Aim and method: Randomised, double-blind, phase III study to evaluate the efficacy and safety of sitagliptin monotherapy at a dosage of 25 mg in patients with type 2 diabetes inadequately controlled by diet and exercise alone and end-stage renal disease treated by dialysis after 54 weeks of treatment. There was also of group treated with glipizide in this study.  Inclusion in the study and randomisation was preceded by a washout phase during which the antidiabetic medication was discontinued diet and physical activity were optimised (for 14 weeks) followed by 2 weeks of single-blind placebo treatment.6   The protocol envisaged randomisation according to age (< 65 or years old), 65 cardiovascular disease history (with/without a history of cardiovascular, cerebrovascular, or peripheral vascular disease), history of cardiac failure (with/without).  Inclusion criteria: Patients with type 2 diabetes, at least 30 years of age, with end-stage renal disease treated by haemodialysis or peritoneal dialysis for at least 6 months, inadequately controlled by diet and exercise alone (HbA1c level7% andwho have not received antidiabetic treatment for9%) at least 3 months, or who are under treatment with antidiabetic monotherapy or low-dose dual therapy (dose50% of the maximum recommended dose of each antidiabetic7) and with an HbA1c level6.5% and9%.  Principal exclusion criteria: Identical to those in study P063, except treatment by dialysis.  Dosing regimen: One hundred and twenty-nine (129) patients were randomised to receive: - sitagliptin at a dosage of 25 mg/day (n = 64) either - glipizide at an initial dosage of 2.5 mg/day, which could be increased up to 20 mg/day or (n = 65).8  
                                            6 not receiving antidiabetic treatment were able to start the single-blind placebo treatment phase Patients immediately. continued during the pre-inclusion . 87rease in the ris kfo nt gicieemiclycartloc nodlb c uon vegie n.lisuiniova oT cni na dh insuffents wit aPitp ahes diswereugs e drhTse hypoglycaemia, patients on glipizide discontinued their treatment once insulin treatment was initiated. Two patients on sitagliptin and four on glipizide had recourse to insulin.   11/25