from 5 September 2013

(1)

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 Lixisenatide

from 5 September 2013

In its session on 5 September 2013, the Federal Joint Committee resolved to amend the Pharmaceutical Directive (AM-RL), version published 18 December 2008/22 January 2009 (Federal Gazette, number 49 a of 31 March 2009), last amended on 15 August 2013 (Federal Gazette, AT 28 August 2013 B3), as follows:

I.

Appendix XII shall be amended in alphabetical order to include the active ingredient lixisenatide: Lixisenatide

Therapeutic indication:

Lyxumia® is used for the treatment of adults with type 2 diabetes mellitus to achieve glycaemic control in combination with oral glucose lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control.

1. Additional benefit of the pharmaceutical over appropriate comparator

a) Add-on combination therapy in combination with metformin, when metformin, together with diet and exercise, do not provide adequate glycaemic control:

Appropriate comparator: sulfonylurea (glibenclamide or glimepiride) + metformin

Extent and probability of additional benefit over sulfonylurea (glibenclamide or glimepiride) + metformin: An additional benefit has not been proved.

b) Add-on dual combination with an oral anti-diabetic medication (except metformin), when it, together with diet and exercise, does not provide adequate glycaemic control:

Appropriate comparator: metformin + sulfonylurea (glibenclamide or glimepiride)

(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 over metformin + sulfonylurea (glibenclamide or glimepiride): An additional benefit has not been proved.

c) Add-on triple combination with an oral anti-diabetic medication when it, together with diet and exercise, does not provide adequate glycaemic control:

Appropriate comparator: metformin + human insulin

(Note: if applicable therapy only with human insulin if metformin is ineffective) Extent and probability of additional benefit over metformin + human insulin:

An additional benefit is not considered proved.

d) Add-on combination with a basal insulin (with or without metformin when basal insulin (with or without metformin), together with diet and exercise, does not provide adequate glycaemic control:

Appropriate comparator: metformin + human insulin

(Note: if applicable therapy only with human insulin if metformin is not tolerated or ineffective when used according to product information)

Extent and probability of additional benefit over metformin + human insulin: An additional benefit has not been proved.

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2. Number of patients and criteria for defining patients eligible for treatment

a) Add-on combination therapy with metformin when metformin, together with diet and exercise, does not provide adequate glycaemic control:

Number: approx. 634,600 patients

c) Add-on triple combination with an oral anti-diabetic medication when it, together with diet and exercise, does not provide adequate glycaemic control:

d) Add-on combination with a basal insulin (with or without metformin) when basal insulin (with or without metformin), together with diet and exercise, does not provide adequate glycaemic control:

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 contents of the product information for Lyxumia® (active ingredient: lixisenatide) at the following public link (last accessed: 1 July 2013):

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002445/WC500140401.pdf

So far no studies are available on the combination therapy of lixisenatide with dipeptidyl peptidase-4 (DPP4) inhibitors. The use of GLP1 receptor antagonists (including lixisenatide) is associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis.

According to a current EMA statement on pancreatic cancer in the context of a GLP1-based therapy (including lixisenatide), although clinical data do not indicate an increased risk of these substances, a final evaluation of the risk cannot be made due to the short duration of the study and the low number of cases.

4. Costs of treatment

a) Add-on combination therapy in combination with metformin, when metformin, together with diet and exercise, do not provide adequate glycaemic control:

Duration of treatment:

Description of therapy Mode of treatment

Number of treatments per

patient per year treatment (days) Duration per Treatment days per patient per year Pharmaceutical evaluated in combination with metformin

Lixisenatide ongoing, 1 x daily ongoing 365 365 Metformin ongoing, 2 – 3 x daily ongoing 365 365

Appropriate comparator (glibenclamide or glimepiride + metformin) Glibenclamide or glimepiride ongoing, 1 – 2 x daily ongoing, 1 x daily ongoing ongoing 365 365 365 365 Metformin ongoing, 2 – 3 x daily ongoing 365 365 Consumption:

Description of therapy Strength

Pharmaceutical evaluated in combination with metformin

Number/amount per

pack (tablets)1, 2 Average annual consumption _(tablets)2

Lixisenatide 20 µg 6 pre-mixed pens3 27 pre-mixed pens

1

Largest pack.

2

Tablets, if not indicated otherwise.

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Description of therapy Strength Number/amount per pack (tablets)1, 2 Average annual consumption _(tablets)2

Metformin 1,000 mg 180 365 – 1,095

Appropriate comparator (glibenclamide or glimepiride + metformin) Glibenclamide4 or glimepiride Metformin5 Costs: Cost of pharmaceutical: 3.5 mg 1 mg – 6 mg 1,000 mg 180 180 180 182.5 – 1,095 365 365 – 1,095 Cost after

Description of therapy Cost (pharmacy retail price)6

legally mandated rebates

Lixisenatide €324.29 €282.79

[€1.857_{; €39.65}8_]

Metformin9 _€18.78 _€16.31

[€1.857; €0.628] Appropriate comparator (glibenclamide or glimepiride + metformin)

Glibenclamide9 _or glimepiride9 €14.93 €16.87 – €82.53 €12.77 [€1.857; €0.318] €14.55 – €75.02 [€1.857; €0.47 – €5.668] Metformin9 €18.78 €16.31 [€1.857; €0.628] "Lauer-Taxe", effective 1 August 2013

Costs for additional, necessary statutory health insurance (SHI) benefits: none Annual treatment costs:

Description of therapy Annual treatment costs per patient

Lixisenatide + metformin €1,305.63 – €1,371.77 Appropriate comparator (glibenclamide or glimepiride + metformin)

Glibenclamide + metformin or glimepiride + metformin

€46.02 – €176.90 €62.58 – €251.34

patient per year treatment (days) Duration per Treatment days per patient per year Pharmaceutical evaluated in combination with another oral anti-diabetic medication (except metformin)10

Lixisenatide ongoing, 1 x daily ongoing 365 365 Glibenclamide or glimepiride ongoing, 1 – 2 x daily ongoing, 1 x daily ongoing ongoing 365 365 365 365 4

A strength of 3.5 mg was assumed for the calculation; doses according to product information: 1.75 – 10.5 mg.

5

A strength of 1,000 mg was assumed for the calculation; doses according to product information: 1 – 3 g.

6

Largest pack.

7

Rebate in accordance with SGB V, section 130.

8

Rebate in accordance with SGB V, section 130a.

9

Reference price

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patient per year treatment (days) Duration per Treatment days per patient per year Appropriate comparator (glibenclamide or glimepiride + metformin)

Glibenclamide or glimepiride ongoing, 1 – 2 x daily ongoing, 1 x daily ongoing ongoing 365 365 365 365 Metformin ongoing, 2 – 3 x daily ongoing 365 365 Consumption:

Number/amount per pack (tablets)1, 2

Average annual consumption (tablets)2

Pharmaceutical evaluated in combination with another oral anti-diabetic medication (except metformin)10

Lixisenatide 20 µg 6 pre-mixed pens3 _{27 pre-mixed pens}

Glibenclamide4 or glimepiride 3.5 mg 1 mg – 6 mg 180 180 182.5 – 1,095 365 Appropriate comparator glibenclamide or glimepiride + metformin

Glibenclamide4 or glimepiride 3.5 mg 1 mg – 6 mg 180 180 182.5 – 1,095 365 Metformin5 _{1,000 mg} ₁₈₀ _{365 – 1,095} Costs: Cost of pharmaceutical:

Cost after legally mandated rebates

Pharmaceutical evaluated in combination with another oral anti-diabetic medication (except metformin)10

Lixisenatide €324.29 €282.79 [€1.857; €39.658] Glibenclamide9 or glimepiride9 €14.93 €16.87 – €82.53 €12.77 [€1.857; €0.318] €14.55 – €75.02 [€1.857; €0.47 – €5.668] Appropriate comparator (glibenclamide or glimepiride + metformin)

Glibenclamide9 _or glimepiride9 €14.93 €16.87 – €82.53 €12.77 [€1.857; €0.318] €14.55 – €75.02 [€1.857; €0.47 – €5.668] Metformin9 €18.78 €16.31 [€1.857; €0.628] "Lauer-Taxe", effective 1 August 2013

Pharmaceutical evaluated

Lixisenatide + glibenclamide or glimepiride €1,285.50 – €1,350.24 or €1,302.06 – €1,424.68 Appropriate comparator (glibenclamide or glimepiride + metformin)

Glibenclamide + metformin or glimepiride + metformin

€46.02 – €176.90 €62.58 – €251.34

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c) Add-on triple combination with an oral anti-diabetic medication, when it, together with diet and exercise, does not provide adequate glycaemic control:

Number of treatments per patient per year

Duration per treatment (days)

Treatment days per patient per year Pharmaceutical evaluated in triple combination with an oral anti-diabetic medication11

Lixisenatide ongoing, 1 x daily ongoing 365 365 Metformin ongoing, 2 – 3 x daily ongoing 365 365 Glibenclamide or glimepiride ongoing, 1 – 2 x daily ongoing, 1 x daily ongoing ongoing 365 365 365 365 Appropriate comparator (metformin + human insulin, or only human insulin, if applicable)

Human insulin (NPH insulin) ongoing, 1 – 2 x daily ongoing 365 365 Metformin ongoing, 2 – 3 x daily ongoing 365 365

Therapy only with human insulin if metformin is insufficiently effective or not tolerated Conventional insulin therapy (combination insulin) Consumption: ongoing, 1 – 2 x daily ongoing 365 365

Pharmaceutical evaluated in triple combination with an oral anti-diabetic medication10

Lixisenatide 20 µg 6 pre-mixed pens3 _{27 pre-mixed pens}

Metformin5 _{1,000 mg} ₁₈₀ _{365 – 1,095} Glibenclamide4 or glimepiride 3.5 mg 1 mg – 6 mg 180 180 182.5 – 1,095 365 Appropriate comparator (metformin + human insulin, or only human insulin, if applicable)

Human insulin (NPH insulin)12

100 IU/ml 3,000 IU 13,797 – 27,594 IU

Metformin5 1,000 mg 180 365 – 1095

Therapy only with human insulin if metformin is insufficiently effective or not tolerated Conventional

insulin therapy

Combination insulin12 100 IU/ml 3,000 IU 13,797 – 27,594 IU Costs:

Cost of pharmaceutical:

Cost after legally mandated rebates Lixisenatide €324.29 €282.79 [€1.857; €39.658] Metformin9 €18.78 €16.31 [€1.857; €0.628] Glibenclamide9 _or glimepiride9 €14.93 €16.87 – €82.53 €12.77 [€1.857; €0.318] €14.55 – €75.02 [€1.857; €0.47 - €5.668] 11

Metformin + sulfonylurea (glibenclamide, glimepiride) are named as examples of further anti-diabetic medications in lixisenatide add-on triple combination therapy.

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Appropriate comparator (metformin + human insulin, or only human insulin, if applicable) Human insulin9 (NPH insulin) €89.64 €81.57 [€1.857; €6.228] Metformin9 _€18.78 _€16.31 [€1.857; €0.628] Therapy only with human insulin if metformin is insufficiently effective or not tolerated

Conventional insulin therapy

Combination insulin9 €89.64 €81.57

[€1.857; €6.228] "Lauer-Taxe", effective 1 August 2013

Costs for additional, necessary statutory health insurance (SHI) benefits: Description

of therapy

Additional necessary SHI expense items

Description Cost/pack13 _Number/day _{Consumption/year} _Cost/year

Combination therapy with human insulin (or therapy only with human insulin, if applicable) Blood sugar strips €13.90 1 – 3 365 – 1,095 €101.47 – €304.41 Lancets €3.80 1 – 3 365 – 1,095 €6.94 – €20.80

Annual treatment costs:

Pharmaceutical evaluated in triple combination with an oral anti-diabetic medication11 Lixisenatide + metformin + glibenclamide or

glimepiride

€1,318.58 – €1,449.46 or €1,335.13 – €1,523.90 Appropriate comparator (human insulin + metformin, or only human insulin if applicable) human insulin (NPH insulin) + metformin €408.21 – €849.49 Therapy only with human insulin if metformin is insufficiently effective or not tolerated Conventional insulin therapy

(combination insulin)

€375.14 – €750.28 Costs for additional, necessary

statutory health insurance (SHI) benefits (blood sugar test strips)

€101.47 – €304.41

Costs for additional, necessary

statutory health insurance (SHI) benefits

€6.94 – €20.80

d) Add-on combination with a basal insulin (with or without metformin when basal insulin (with or without metformin), together with diet and exercise, does not provide adequate glycaemic control:

patient per year treatment (days) Duration per Treatment days per patient per year Pharmaceutical evaluated in combination with basal insulin and metaformin, if applicable

Lixisenatide ongoing, 1 x daily ongoing 365 365 Human insulin (NPH insulin) ongoing, 1 – 2 x daily ongoing 365 365

Metformin, if applicable ongoing, 2 – 3 x daily

ongoing 365 365

Appropriate comparator (human insulin + metformin; only human insulin, if applicable) Human insulin (NPH insulin) ongoing, 1 – 2 x daily ongoing 365 365 Metformin ongoing, 2 – 3 x daily ongoing 365 365

Therapy only with human insulin if metformin is insufficiently effective or not tolerated

13

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Description of therapy Mode of treatment Number of treatments per patient per year treatment (days) Duration per Treatment days per patient per year Conventional insulin therapy (combination insulin) ongoing, 1 – 2 x daily ongoing 365 365 Consumption:

Pharmaceutical evaluated in combination with basal insulin and metaformin, if applicable

Lixisenatide 20 µg 6 pre-mixed pens 27 pre-mixed pens Human insulin

(NPH insulin)12

100 IU/ml 3,000 IU 13,797 IU – 27,594 IU Metformin, if applicable5 _{1,000 mg} ₁₈₀ _{365 – 1,095}

Appropriate comparator (human insulin + metformin; only human insulin, if applicable) Human insulin

(NPH insulin)12

100 IU/ml 3,000 IU 13,797 – 27,594 IU

Metformin5 1,000 mg 180 365 – 1,095

Therapy only with human insulin if metformin is insufficiently effective or not tolerated Conventional

insulin therapy

Combination insulin12 100 IU/ml 3,000 IU 13,797 – 27,594 IU Costs:

Cost of pharmaceutical:

Pharmaceutical evaluated in combination with basal insulin and metaformin, if applicable

Lixisenatide €324.29 €282.79 [€1.857; €39.658] Human insulin (NPH insulin)9 €89.64 €81.57 [€1.857; €6.228] Metformin, if applicable9 €18.78 €16.31 [€1.857; €0.628] Appropriate comparator human insulin + metformin; only human insulin, if applicable

Human insulin (NPH insulin)9 €89.64 €81.57 [€1.857_{; €6.22}8_] Metformin, if applicable9 €18.78 €16.31 [€1.857_{; €0.62}8_]

Therapy only with human insulin if metformin is insufficiently effective or not tolerated Conventional insulin therapy

Combination insulin9 €89.64 €81.57

[€1.857; €6.228] "Lauer-Taxe", effective 1 August 2013

Pharmaceutical evaluated in combination with basal insulin + metformin, if applicable Lixisenatide + human insulin (NPH insulin) €1,647.69 – €2,022.82 Lixisenatide + human insulin, if applicable

(NPH insulin) + metformin

€1,680.76 – €2,122.04 Appropriate comparator (human insulin + metformin, or only human insulin if applicable) human insulin (NPH insulin) + metformin €408.21 – €849.49 Therapy only with human insulin if metformin is insufficiently effective or not tolerated Conventional insulin therapy

(combination insulin)

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II.

This resolution takes effect on the day of its publication in the internet on the website of the Federal Joint Committee on 5 September 2013.

The justification for this resolution will be published on the website of the Federal Joint Committee at www.g-ba.de. Berlin, 5 September 2013

The Federal Joint Committee in accordance with SGB V, section 91

The Chair Hecken

(9)

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

Lixisenatide

From 23 January 2014

In its session on 23 January 2014, 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 14 January 2014 (Federal Gazette, AT 28.01.2014 B4) as follows:

I.

In appendix XII, the information on the benefit assessment of the active ingredient lixisenatide shall be amended in point “4. Costs of treatment” as follows:

1. In subsection a the information “none” under the header “Costs for additional, necessary SHI benefits” shall be replaced by the following chart:

Designation of therapy

Additional necessary SHI benefits

Designation Cost/pack9a _{Number/day Consumption/ye} _Cost/year

Pharmaceutical evaluated (lixisenatide) in combination with metformin

Single-use

needles €22.80 1 365 €83.22

2. Footnote 9a shall be added after footnote 9 as follows:

“9a_{Number of single-use needles/pack = 100; least expensive pack according to "Lauer-Taxe"; effective: 15 August}

2013”

3. In subsection a, under the header “annual treatment costs” the following line shall be added to the chart after the line

Lixisenatide + metformin €1,305.63 – €1,371.77

:

Costs for additional, necessary SHI benefits:

Single-use needles €83.22

4. In subsection b the information “none” under the header “Costs for additional, necessary SHI benefits” shall be replaced by the following chart:

Pharmaceutical evaluated (lixisenatide) in combination with another oral anti-diabetic medication (except metformin)

Single-use

needles €22.80 1 365 €83.22

2013”

6. In subsection b under the header “Annual treatment costs”, the following line shall be added to the information in the chart after the line

Lixisenatide + glibenclamide or

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:

7. The chart in subsection c under the header “Costs for additional, necessary SHI benefits” shall be replaced by the following chart:

Designation Cost/pack13 _Number/day _{Consumption/year Cost/year}

Pharmaceutical evaluated (lixisenatide) in triple combination with an oral anti-diabetic

Single-use

needles €22.80

13a ₁ ₃₆₅ _€83.22

Combination therapy with human insulin (or therapy only with human insulin)

Blood sugar test strips €12.00 13a ₁_–₃ ₃₆₅_–_1,095 _€87.60_– €262.80 Lancets €3.8013a ₁ – 3 365 – 1,095 €6.94 – €20.80 Single-use needles €22.80 13a ₁_–₂ ₃₆₅_–₇₃₀ _€83.22_– €166.44 8. Footnote 13 shall read as follows:

9. “13 _{Number of test strips/pack = 50 (2 x 25); number of blood lancets/pack = 200; number of single-use needles/pack}

= 100”

“13a _{Least expensive pack according to 'Lauer-Taxe' effective: 15 August 2013”}

11. The chart in subsection c under the header “Annual treatment costs” shall be replaced by the following chart:

Designation of therapy Annual treatment costs per patient

Lixisenatide + metformin + glibenclamide or glimepiride

€1,318.58 – €1,449.46 or €1,335.13 – €1,523.90 Costs for additional, necessary SHI benefits

Appropriate comparator (human insulin + metformin; only human insulin, if applicable)

Human insulin (NPH insulin) + metformin €408.21 – 849.49

Therapy only with human insulin if metformin is insufficiently effective or not tolerated: Conventional insulin therapy

(combination insulin) €375.14 – €750.28

Costs for additional, necessary (SHI) benefits Blood sugar test strips

Lancets

Single-use needles

€87.60 – €262.80 €6.94 – €20.80 €83.22 – €166.44

12. In subsection d the information “none” under the header “Costs for additional, necessary SHI benefits” shall be replaced by the following chart:

Pharmaceutical evaluated (lixisenatide) in combination with basal insulin and metformin, if

Single-use

needles €22.80 1 365 €83.22

13. Footnote 9a shall read as follows:

2013”

14. In subsection d under the header “Annual treatment costs”, the following line shall be added to the information in the chart after the lines

Lixisenatide + human insulin (NPH insulin) €1,647.69 – €2,022.82 or lixisenatide + human insulin (NPH insulin) + metformin €1,680.76 – €2,122.04

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:

II.

This resolution takes effect on the day of its publication in the internet on the website of the Federal Joint Committee on 23 January 2014.

The justification for this resolution will be published on the website of the Federal Joint Committee at www.g-ba.de. Berlin, 23 January 2014

The Federal Joint Committee in accordance with SGB V,

section 91 The Chair Hecken