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 (active ingredient combination: delta-9-tetrahydrocannabinol and cannabidiol) from June 0 In its session on June 0, the Federal Joint Committee resolved to amend the Pharmaceutical Directive (AM-RL), version published 8 December 008/ January 009 (Federal Gazette, number 49a of 3 March 009), last amended on 7 June 0 (Federal Gazette, AT 3 July 0, B), as follows: I. Appendix XII shall be amended in alphabetical order to include extract of cannabis sativa L., folium cum flore (active ingredient combination: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)): L., folium cum flore (active ingredient combination delta-9-tetrahydrocannabinol and cannabidiol) Therapeutic indication: Sativex is indicated for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medication and who demonstrate clinically major improvement in spasticity related symptoms during an initial trial of therapy.. Additional benefit of the pharmaceutical over appropriate comparator Appropriate comparator: Optimized standard therapy with baclofen or tizanidine or active ingredients authorized for the treatment of spasticity with underlying neurological disease, in the authorized dosages, following at least two previous treatment attempts with different oral antispasmodics, including at least one pharmaceutical with baclofen or tizanidine in optimized dosage. Extent and probability of additional benefit over optimized standard therapy with baclofen or tizanidine or active ingredients authorized for the treatment of spasticity with underlying neurological disease, in the authorized dosages: Hint of minor additional benefit. Study results according to endpoints: Endpoint Group difference/ odds ratio [95%-CI] extract of cannabis sativa + current antispasmodic medication vs. placebo + current antispasmodic medication p-value Mortality Overall mortality.6% vs. 0% Morbidity Absolute change in degree of spasticity (NRS score) -0.84 [-.9; -0.4] 0.000 Number of patients with clinically relevant reduction in severity of spasticity on NRS Min. 30%.73 [.59; 4.69] 0.0003 Min. 50%.65 [0.98;.78] 0.06 Number of spastic episodes per day -.53 [-4.7; -0.79] 0.004 Sleep disturbance due to spasticity (NRS)
Endpoint Medical condition (VAS of EQ-5D) Daily activities (Barthel index) Group difference/ odds ratio [95%-CI] extract of cannabis sativa + current antispasmodic medication vs. placebo + current antispasmodic medication -0.88 [-.5; -0.5].4 [-3.0; -5.5].84 [0.0; 3.66] p-value <0.00 0.5644 0.0479 Global assessment of clinical change (GIC scales) SGIC (by patient).703 [.075;.698] CGIC (by carer) Functional capacity.40 [.9; 4.44] PhGIC (by physician).958 [.3; 3.] 0.034 0.0053 0.0045 Change in ability to walk (0 metre walking test) -3.34 [-6.95; -0.6] 0.0687 Quality of life (SF-36) Health function -0.46 [-3.73;.8] Health role -.30 [-7.06; 4.47] Headache 5.0 [-0.; 0.3] Overall health.3 [-.06; 4.70] Vitality.9 [-.0; 6.38] Social function -0.65 [-6.97; 5.67] Emotional role -.78 [-8.56;.99] Mental health 0.74 [-.84; 4.33] 0.789 0.658 0.0596 0.444 0.3057 0.8403 0.343 0.686 Side effects Number of patients with AE 53% vs. 49% 0.504 Number of patients with serious AE 4.8% vs. 0.9% 0.06 Termination due to AE 7.3% vs. 0% 0.094 Abbreviations used: CGIC= carer global impression of change; GIC = global impression of change; CI = confidence interval; NRS = numeric rating scale; PhGIC = physician global impression of change; SGIC = subject global impression of change; AE = adverse event; VAS = visual analog scale. Number of patients and criteria for defining patients eligible for treatment Number of patients: approx. 3,400 38,500 3. Requirements for quality-assured administration The specifications outlined in the product information are to be followed.
4. Costs of treatment Duration of treatment: Description of therapy Mode of treatment Number of treatments per patient per year sativa initial treatment attempt non- Duration per treatment (days) Number of treatment days per patient per year 8 sprays per day ongoing 8 8 8 sprays per day Appropriate comparator/previous therapy continued Baclofen oral Dantrolene Pridinol Tetrazepam Tizanidine Tolperisone 4 x daily 4 x daily x daily 4 x daily 3 4 x daily 3 x daily Average daily dose according to Sativex product information, irrespective of titration phase The figures for the appropriate comparator/previous therapy continued are listed for each pharmaceutical; different dosages/combinations of active ingredients are possible due to the variability of a standard therapy optimized for individual patients. Consumption: Description of therapy Strength (mg) Amount/number per pack Average annual consumption sativa initial treatment attempt non-.7 mg THC and 0 ml 3 9 ml.5 mg CBD/0. ml (,90 sprays).7 mg THC and 0 ml 3.4 ml.5 mg CBD/0. ml (4 sprays) Appropriate comparator/previous therapy continued 4 Baclofen oral 0 5 00 tablets,095 tablets 5 Dantrolen 6 5 50 00 capsules 730,460 capsules Pridinol 4 00 tablets 365 730 tablets Tetrazepam 50 00 tablets 365,460 tablets Tizanidine 4 6 00 tablets,095,460 tablets Tolperisone 50 50 96 00 tablets,095 tablets Largest pack One spray equals 0. ml according to product information. 3 3 x 0 ml glass spray bottles per carton; one bottle with 0 ml delivers up to 90 sprays. 4 The figures for the appropriate comparator/previous therapy continued are listed for each pharmaceutical; different dosages/combinations of more than one active ingredient are possible due to the variability of a standard therapy optimized for individual patients. 5 The basis for the calculation was 3 individual doses; according to the product information the daily dosage is divided into 4 individual doses. 6 Defined daily dose (DDD) = 00 mg
Costs: Cost of pharmaceutical: Description of therapy Cost Cost after (pharmacy retail price) legally mandated rebates sativa non- 597.4 50.85 [.05 ; 74.4 3 ] 597.4 50.85 [.05 ; 74.4 3 ] Appropriate comparator/previous therapy continued Baclofen oral 6.67 6.66 4 4.3 3.33 [.05 ; 0.49.8 3 ] Dantrolene 73.89 9.93 54.66 73.57 [.05 ; 7.8 7.3 3 ] Pridinol.54 97.57 [.05 ;.9 3 ] Tetrazepam 0.96 4 8.08 [.05 ; 0.83 3 ] Tizanidine 0.96 6.66 4 8.08 3.33 [.05 ; 0.83.8 3 ] Tolperisone 3.4 8.63 7.60 76.0 [.05 ;.77 3.38 3 ] 3 4 Largest pack Rebate in accordance with SGB V, section 30 Rebate in accordance with SGB V, section 30a Reference price ("Lauer-Taxe", effective May 0 Costs for additional, necessary statutory health insurance (SHI) benefits: none. Annual treatment costs: Description of therapy non- Annual treatment costs per patient (after legally mandated rebates) 5,63.89 50.85 Appropriate comparator/previous therapy continued Baclofen oral 54.7 55.46 Dantrolene 537.06 798.04 Pridinol 356.3 7.6 Tetrazepam 65.99 63.97 Tizanidine 97.98 340.6 Tolperisone 34.8 834.39
II. Validity. This resolution takes effect on the day of its publication in the internet on the website of the Federal Joint Committee on June 0.. This resolution remains valid until June 05. The justification for this resolution will be published on the website of the Federal Joint Committee at www.g-ba.de. Berlin, June 0 The Federal Joint Committee in accordance with SGB V, section 9 The Chair Hess