Resolution by the Federal Joint Committee on an amendment to the Pharmaceutical Directive (AM-RL): Appendix XII Resolutions on the benefit assessment of pharmaceuticals with new active ingredients, in accordance with the German Social Code, Book Five (SGB V), section 35a from 5 February 2015 In its session on 5 February 2015, the Federal Joint Committee resolved to amend the Pharmaceutical Directive (AM-RL), version published 18 December 2008/22 January 2009 (Federal Gazette, number 49a of 31 March 2009), last amended on 22 January 2015 (Federal Gazette, AT 18.02.2015 B2) as follows: I. Appendix XII shall be amended in alphabetical order to include the active ingredient empagliflozin: Therapeutic indication: Jardiance is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as: Monotherapy When diet and exercise alone do not provide adequate glycaemic control in s for whom use of metformin is considered inappropriate due to intolerance. Add-on combination therapy In combination with other glucose lowering pharmaceuticals including insulin, when these, together with diet and (see sections 4.4, 4.5, and 5.1 for data currently available on various combinations). 1. Additional benefit of the pharmaceutical over appropriate comparator a) In monotherapy, when diet and exercise alone do not provide adequate glycaemic control in s for whom the use of metformin is considered inappropriate due to intolerance Appropriate comparator: a sulfonylurea (glibenclamide or ) Extent and probability of additional benefit of empagliflozin over a sulfonylurea (glibenclamide or ) An additional benefit has not been proved. b) In combination with other glucose-lowering medicinal products (except insulin), when these, together with diet and b1) In dual combination with metformin Appropriate comparator: metformin + a sulfonylurea (glibenclamide or ) (Please note: if metformin is inappropriate when used according to product information, human insulin is to be used as a treatment option)
Extent and probability of additional benefit of empagliflozin in combination with metformin over metformin and a sulfonylurea (glibenclamide or ): An additional benefit has not been proved. Study results according to endpoints (study 1245.28) 1 Symptomatic hypoglycaemia (PG 54 mg/dl) Symptomatic hypoglycaemia (54 mg/dl PG 70 mg/dl) Severe hypoglycaemia Intervention empagliflozin + metformin N = 765 s with events n (%) Control + metformin N = 780 s with events n (%) 5 (0.7) 62 (7.9) 0.08 [0.03; 0.20] < 0.001 a 8 (1.0) 104 (13.3) 0.08 [0.04; 0.16] < 0.001 a No relevant evaluation was available for this endpoint Renal and urinary disorders d 112 (14.6) 55 (7.1) 2.02 [1.50; 2.73] < 0.001 a Diseases of the sexual organs and 91 (11.9) 46 (5.9) 1.95 mammary gland d [1.40; 2.73] < 0.001 a Genital infections e 90 (11.8) 17 (2.2) 5.40 [3.25; 8.98] < 0.001 Overall rate AE 661 (86.4) 673 (86.3) Intervention vs. control RR or Peto-OR [95% CI] p-value Mortality All-cause mortality 5 (0.7) 5 (0.6) POR 1.02 [0.29; 3.54] > 0.999 a Morbidity MACE 12 (1.6) 16 (2.1) 0.76 [0.36; 1.61] 0.569 a Cardiovascular death 1 (0.1) 4 (0.5) 0.25 [0.03; 2.28] 0.375 a Non-fatal myocardial infarction 3 (0.4) 7 (0.9) POR 0.46 [0.13; 1.58] 0.342 a Non-fatal stroke 9 (1.2) 7 (0.9) POR 1.31 [0.49; 3.51] 0.624 a Change in MV at study end b in kg (SE) DM b [95% CI] p-value Body weight 3.12 (0.13) 1.34 (0.13) 4.46 [ 4.81; 4.10] < 0.001 Medical condition (EQ-5D VAS) Health-related quality of life No applicable data Side effects No applicable data available c 1 Data from IQWiG benefit assessment A 14-26 from 13 November 2014; study 1245.28: RCT, direct comparison: 25 mg + metformin vs. + metformin (104 weeks).
Intervention empagliflozin + metformin N = 765 s with events n (%) Control + metformin N = 780 s with events n (%) Intervention vs. control RR or Peto-OR [95% CI] p-value Overall rate SAE 119 (15.6) 89 (11.4) 1.36 [1.06; 1.76] 0.017 a Termination of treatment due to AE 39 (5.1) 34 (4.4) 1.17 [0.75; 1.83]; 0.494 a IQWiG calculation, exact Fisher test. b Adjusted for baseline scores, HbA1c, kidney function (egfr), and geographical region. c Only analysis without replacement of missing scores available. Because the percentage of s not considered in the analysis was > 30%, the data are not shown. d Evaluation according to system organ class (MedDRA-SOC). e Evaluation (planned in advance) in accordance with MedDRA query developed by the pharmaceutical company. Abbreviations: egfr: estimated glomerular filtration rate; EQ-5D VAS: Euro-Qol-5D visual analog scale; CI: confidence interval; MACE: major adverse cardiovascular events; MedDRA: Medical Dictionary for Regulatory Activities; MV: mean value, DM: difference of means; N: number of s evaluated; n: number of s with events; PG: plasma glucose; POR: Peto odds ratio; RCT: randomized controlled trial; RR: relative risk; SE: standard error; SAE: serious adverse event; AE: adverse event; vs: versus b2) In dual combination with another glucose-lowering pharmaceutical other than metformin and insulin Appropriate comparator: + a sulfonylurea (glibenclamide or ) (Please note: if metformin is inappropriate when used according to product information, human insulin is to be used as a treatment option) Extent and probability of additional benefit of empagliflozin in combination with another glucose-lowering pharmaceutical (other than metformin and insulin) over metformin and a sulfonylurea (glibenclamide or ): An additional benefit has not been proved. c) In combination with at least two other glucose-lowering medicinal products when these, together with diet and Appropriate comparator: metformin + human insulin (Please note: therapy only with human insulin if metformin as used according to product information is insufficiently effective or not tolerated.) Extent and probability of additional benefit of empagliflozin in combination with at least two other glucoselowering pharmaceuticals over metformin and human insulin: An additional benefit has not been proved. d) In combination with insulin (with or without an oral anti-diabetic medication) Appropriate comparator: metformin + human insulin (Please note: therapy only with human insulin if metformin as used according to product information is insufficiently effective or not tolerated.) Extent and probability of additional benefit of empagliflozin in combination with insulin (with or without an oral anti-diabetic medication) over metformin and human insulin: An additional benefit has not been proved. 2. s and criteria for defining s eligible for treatment a) In monotherapy, when diet and exercise alone do not provide adequate glycaemic control in s for whom the use of metformin is considered inappropriate due to intolerance Number: approx. 221,400 s b) In combination with other glucose-lowering medicinal products (except insulin), when these, together with diet and b1) In dual combination with metformin Number: approx. 468,700 s
b2) In dual combination with another glucose-lowering pharmaceutical other than metformin and insulin Number: approx. 35,900 s (dual combination with a sulfonylurea) c) In combination with at least two other glucose-lowering medicinal products when these, together with diet and Number: approx. 77,400 s d) In combination with insulin (with or without an oral anti-diabetic medication) Number: approx. 450,000 650,000 s 3. Requirements for quality-assured administration The specifications outlined in the product information are to be followed. The European Medicines Agency (EMA), the European regulatory authority, provides the product information for Jardiance (active ingredient: empagliflozin) at the following public link (last accessed: 13 January 2014): http://www.ema.europa.eu/docs/en_gb/document_library/epar_- _Product_Information/human/002677/WC500168592.pdf 4. Costs of treatment a) In monotherapy, when diet and exercise alone do not provide adequate glycaemic control in s for whom the use of metformin is considered inappropriate due to intolerance Duration of treatment: Pharmaceutical evaluated (empagliflozin) treatment days per per year ongoing Appropriate comparator (sulfonylurea [glibenclamide or ]) Glibenclamide or ongoing ongoing Consumption: Strength Quantity per pack (tablets) 2 Average annual consumption (tablets) Pharmaceutical evaluated (empagliflozin) 10 mg 25 mg Appropriate comparator (sulfonylurea [glibenclamide or ]) Glibenclamide 3 or 3.5 mg 1 6 mg 182.5 1,095 Costs: Cost of pharmaceutical: Pharmaceutical evaluated (empagliflozin) 10 mg or empagliflozin 25 mg 191.78 224.65.00 [ 1.77 4 ; 10.01 5 ] 211.05 [ 1.77 4 ; 11.83 5 ] 2 3 4 5 Largest pack. Calculation is based on a strength of 3.5 mg. Dosage according to product information 1.75 10.5 mg. Rebate in accordance with SGB V, section 130. Rebate in accordance with SGB V, section 130a.
Appropriate comparator (sulfonylurea [glibenclamide or ]) Glibenclamide 6 or 14.93 12.85 [ 1.77 4 ; 0.31 5 ] 6 16.87 82.53 14.63 75.10 [ 1.77 4 ; 0.47 5.66 5 ] Lauer-Taxe, effective: 1 January 2015 Costs for additional, necessary SHI benefits: none Annual treatment costs: Pharmaceutical evaluated (empagliflozin) Annual treatment costs per 657.00 770.33 Appropriate comparator (sulfonylurea [glibenclamide or ]) Glibenclamide or 13.03 78.17 29.67 152.29 b) In combination with other glucose-lowering medicinal products (except insulin), when these, together with diet and b1) In dual combination with metformin Duration of treatment: per year Pharmaceutical evaluated (empagliflozin in combination with metformin) treatment days per per year ongoing ongoing Glibenclamide or ongoing ongoing ongoing Consumption: Strength Quantity per pack (tablets) 2 Pharmaceutical evaluated (empagliflozin in combination with metformin) 10 mg 25 mg Average annual consumption (tablets) 7 1,000 mg 1,095 Glibenclamide 3 or 3.5 mg 1 6 mg 182.5 1,095 7 1,000 mg 1,095 6 7 Reference price. Calculation is based on a strength of 1,000 mg. Dosage according to product information 1,000 to 3,000 mg.
Costs: Cost of pharmaceutical: Pharmaceutical evaluated (empagliflozin in combination with metformin) 10 mg or 191.78.00 [ 1.77 4 ; 10.01 5 ] empagliflozin 25 mg 224.65 211.05 [ 1.77 4 ; 11.83 5 ] 6 18.78 16.39 Glibenclamide 6 or 6 14.93 16.87 82.53 12.85 [ 1.77 4 ; 0.31 5 ] 14.63 75.10 [ 1.77 4 ; 0.47 5.66 5 ] 6 18.78 16.39 Lauer-Taxe, effective: 1 January 2015 Costs for additional, necessary SHI benefits: none Annual treatment costs: Annual treatment costs per Pharmaceutical evaluated (empagliflozin in combination with metformin) + metformin 690.24 870.04 Glibenclamide + metformin or + metformin 46.27 177.88 62.91 252.00 b2) In dual combination with another glucose-lowering pharmaceutical other than metformin and insulin Duration of treatment: treatment days per per year Pharmaceutical evaluated (empagliflozin in combination with another glucose-lowering pharmaceutical besides metformin and insulin) 8 1 daily ongoing Glibenclamide or ongoing Glimepiride ongoing Glibenclamide or ongoing ongoing ongoing 8 The combination with a sulfonylurea is shown as an example of a combination therapy with another glucose-lowering pharmaceutical besides metformin and insulin.
Consumption: Strength Quantity per pack (tablets) 2 Average annual consumption (tablets) Pharmaceutical evaluated (empagliflozin in combination with another glucose-lowering pharmaceutical besides metformin and insulin) 8 10 mg 25 mg Glibenclamide 3 or 3.5 mg 1 6 mg 182.5 1,095 Glibenclamide 3 or 3.5 mg 1 6 mg 182.5 1,095 7 1,000 mg 1,095 Costs: Cost of pharmaceutical: Pharmaceutical evaluated (empagliflozin in combination with another glucose-lowering pharmaceutical besides metformin and insulin) 8 10 mg or 191.78.00 [ 1.77 4 ; 10.01 5 ] empagliflozin 25 mg 224.65 211.05 [ 1.77 4 ; 11.83 5 ] Glibenclamide 6 or 14.93 12.85 [ 1.77 4 ; 0.31 5 ] 6 16.87 82.53 14.63 75.10 [ 1.77 4 ; 0.47 5.66 5 ] Glibenclamide 6 or 6 14.93 16.87 82.53 12.85 [ 1.77 4 ; 0.31 5 ] 14.63 75.10 [ 1.77 4 ; 0.47 5.66 5 ] 6 18.78 16.39 Lauer-Taxe, effective: 1 January 2015 Costs for additional, necessary SHI benefits: none Annual treatment costs: Annual treatment costs per Pharmaceutical evaluated (empagliflozin in combination with another glucose-lowering pharmaceutical besides metformin and insulin) 8 + glibenclamide or empagliflozin + 670.03 848.50 686.67 922.62 Glibenclamide + metformin or + metformin 46.27 177.88 62.91 252.00
c) In combination with at least two other glucose-lowering medicinal products when these, together with diet and Duration of treatment: treatment days per per year Pharmaceutical evaluated (empagliflozin as a combination therapy with at least two other glucose-lowering pharmaceuticals) 9 ongoing Glibenclamide or ongoing Glimepiride ongoing ongoing Appropriate comparator (metformin + human insulin; therapy only with human insulin if metformin is Human insulin (NPH insulin) ongoing ongoing Conventional insulin therapy (combination insulin) ongoing Consumption: Strength Quantity per pack (tablets) 2 Average annual consumption (tablets) Pharmaceutical evaluated (empagliflozin as a combination therapy with at least two other glucose-lowering pharmaceuticals) 9 10 mg 25 mg Glibenclamide 3 or 3.5 mg 182.5 1,095 1 6 mg 7 1,000 mg 1,095 Appropriate comparator (metformin + human insulin; therapy only with human insulin if metformin is insufficiently effective or not tolerated) Human insulin (NPH insulin) 10 IU/ml 3,000 IU 13,797 27,594 IU 1,000 mg 1,095 Conventional insulin therapy (combination insulin) 10 IU/ml 3,000 IU 13,797 27,594 IU Costs: Cost of pharmaceutical: Pharmaceutical evaluated (empagliflozin as a combination therapy with at least two other glucose-lowering pharmaceuticals) 9 10 mg oder empagliflozin 25 mg 191.78 224.65.00 [ 1.77 4 ; 10.01 5 ] 211.05 [ 1.77 4 ; 11.83 5 ] 9 10 The combination with a sulfonylurea and metformin is shown as an example of combination therapy with at least two other glucose-lowering medicinal products. Average insulin need: 0.5 1 IU/kg BW/day; reference body weight: 75.6 kg BW ("microcensus 2009").
Glibenclamide 6 or 14.93 12.85 [ 1.77 4 ; 0.31 5 ] 6 16.87 82.53 14.63 75.10 [ 1.77 4 ; 0.47 5.66 5 ] 6 18.78 16.39 Appropriate comparator (metformin + human insulin; therapy only with human insulin if metformin is Human insulin (NPH insulin) 6 89.64 81.65 [ 1.77 4 ; 6.22 5 ] 6 18.78 16.39 Conventional insulin therapy (combination insulin) 6 89.64 81.65 [ 1.77 4 ; 6.22 5 ] Lauer-Taxe, effective: 1 January 2015 Costs for additional, necessary statutory health insurance (SHI) benefits: Additional necessary SHI benefits Cost/pack 11 Consumption/ Designation Number/day year Cost/year Appropriate comparator human Blood sugar strips 12.00 1 3 1,095 87.60 262.80 insulin plus metformin Lancets 3.80 1 3 1,095 6.94 20.80 (or therapy only with human insulin) Single-use needles 22.80 1 2 730 83.22 166.44 Annual treatment costs: Annual treatment costs per Pharmaceutical evaluated (empagliflozin as a combination therapy with at least two other glucose-lowering pharmaceuticals) 9 + metformin + glibenclamide or empagliflozin + metformin + 703.27 948.21 719.91 1,022.33 Appropriate comparator (metformin + human insulin; therapy only with human insulin if metformin is Human insulin (NPH insulin) + metformin 408.75 850.73 Conventional insulin therapy (combination insulin) 375.51 751.02 Costs for additional, necessary SHI benefits: Blood sugar test strips Lancets Single-use needles d) In combination with insulin (with or without an oral anti-diabetic medication) Duration of treatment: 87.60 262.80 6.94 20.80 83.22 166.44 treatment days per per year Pharmaceutical evaluated (empagliflozin as a combination therapy with insulin [with or without an oral anti-diabetic medication]) 12 ongoing 11 12 test strips/pack = 50; lancets/pack = 200; single-use needles/pack = ; least expensive pack according to "Lauer- Taxe"; effective: 1 January 2015. is named as an example of an additional anti-diabetic medication.
Human insulin (NPH insulin) ongoing ongoing Appropriate comparator (human insulin with metformin; therapy only with human insulin if metformin is Human insulin (NPH insulin) ongoing ongoing Conventional insulin therapy ongoing (combination insulin) 10 Consumption: Strength Quantity per pack (tablets) 2 treatment days per per Average annual consumption (tablets) Pharmaceutical evaluated (empagliflozin as a combination therapy with insulin [with or without an oral anti-diabetic medication]) 12 10 mg 25 mg Human insulin (NPH insulin) 10 IU/ml 3,000 IU 13,797 27,594 IU 7 1,000 mg 1,095 Appropriate comparator (human insulin with metformin; therapy only with human insulin if metformin is Human insulin (NPH insulin) 10 IU/ml 3,000 IU 13,797 27,594 IU 1,000 mg 1,095 Conventional insulin therapy IU/ml 3,000 IU 13,797 27,594 IU (combination insulin) 10 Costs: Cost of pharmaceutical: Pharmaceutical evaluated (empagliflozin as a combination therapy with insulin [with or without an oral anti-diabetic medication]) 12 10 mg or 191.78.00 [ 1.77 4 ; 10.01 5 ] 25 mg 224.65 211.05 [ 1.77 4 ; 11.83 5 ] Human insulin (NPH insulin) 6 89.64 81.65 [ 1.77 4 ; 6.22 5 ] 6 18.78 16.39 Appropriate comparator (human insulin with metformin; therapy only with human insulin if metformin is Human insulin (NPH insulin) 6 89.64 81.65 [ 1.77 4 ; 6.22 5 ]
6 18.78 16.39 Conventional insulin therapy (combination 89.64 insulin) 6 [ 1.77 4 ; 6.22 5 ] Lauer-Taxe, effective: 1 January 2015 Costs for additional, necessary SHI benefits: none Annual treatment costs: Annual treatment costs per Pharmaceutical evaluated empagliflozin as a combination therapy with insulin (with or without an oral anti-diabetic medication) 12 + human insulin (NPH insulin) or empagliflozin + human insulin (NPH insulin) + metformin 1,032.51 1,521.35 1,065.75 1,621.06 Appropriate comparator human insulin with metformin; therapy only with human insulin if metformin is insufficiently effective or not tolerated Human insulin (NPH insulin) + metformin 408.75 850.73 Conventional insulin therapy (combination insulin) 375.51 751.02 II. This resolution takes effect on the day of its publication in the internet on the website of the Federal Joint Committee on 5 February 2015. The justification for this resolution will be published on the websites of the Federal Joint Committee at www.g-ba.de. Berlin, 5 February 2015 The Federal Joint Committee in accordance with SGB V, section 91 The Chair Hecken