Version History Policy Title Drugs for MS.Drug fact box cannabis extract (Sativex) Version 1.0 Author West Midlands Commissioning Support Unit Publication Date Jan 2013 Review Date Supersedes/New (Further fields as required by local organisations) Previous Versions Version Date Changes
What is this drug for? 1 Who is this drug for? 1 Drugs for multiple sclerosis Summaries of key information and evidence for efficacy and safety January 2013 Drug Facts box for Cannabis extract (Sativex) Improvement of the symptoms of spasticity caused by multiple sclerosis People with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of Sativex therapy. Patients under age 18. Who should not be taking this drug? 1 Patients with severe cardiovascular disease. How is this drug Oromucosal spray What dose of this 1 spray contains 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg drug is cannabidiol (CBD) in 0.04 g ethanol. How often is this drug Sprays administered as needed with at least 15 minutes between sprays. The maximum recommended dose is 12. What is the cost of this drug? A 10 ml bottle of Sativex (100 sprays) = 125.00 For 6 to 12, the cost per patient per year is 2,737 to 5,475. What are the adverse Most commonly: dizziness and fatigue reactions associated Application site reactions: mild to moderate stinging or burning, oral pain, with this drug? dysgeusia (taste distortion), mouth ulceration Licensing timeline Launched in the UK in June 2010 Other information: Sativex is currently a Schedule 1 drug under the Misuse of Drugs Act 2001. It is due to be reclassified. Prescriptions for Sativex must be written in the same way as they are for Schedule 2 drugs, with specific criteria to be met. 2 Studies Summary of methods Three published, double-blind,, controlled trials (RCTs) 3-5 compared Sativex with placebo for the treatment of symptoms of spasticity in patients with confirmed MS who did not obtain adequate relief with current therapy. Eligible patients had significant spasticity in at least two muscle groups, with an Ashworth score 2 or a score 4 on a patient-rated 0-to-10 scale of severity of spasticity. One of the trials had an enriched design and included only patients showing a response to Sativex treatment during a 4-week single-blind screening period. 5 The trials lasted six, 15 and 19 weeks. 3-5 Patients assessed and recorded the severity of their symptoms of spasticity and spasm frequency on a 0-to-10 numerical rating scale (NRS) daily. The primary outcome measure was the change in mean weekly NRS spasticity scores compared with the mean scores in the last seven days of baseline treatment. Quality of the trials The design of the trials was fair, because of the subjective nature of the outcomes, and the inclusion of only patients who had previously responded to Sativex in one of the trials. Main results Compared with placebo, Sativex treatment was associated with a statistically greater improvement in the patient-rated spasticity score in two trials 3,5 but there was no difference in the third trial. 4 However, the clinical importance of the improvements has been questioned. The mean differences in the changes from baseline in spasticity scores (on a 0 to 10 scale) between the Sativex groups and the placebo groups were 0.52, 3 0.84 5 and -0.23 4 points in the three trials. The proportions of patients who were classified as responders ranged from 31% to 74% in the Sativex groups and from 22% to 51% in
the placebo groups. Adverse events The most common adverse events occurring more frequently with Sativex than placebo were: dizziness, fatigue, somnolence, nausea and dry mouth. References 1. GW Pharma Ltd. Sativex Oromucosal Spray. SPC. 2010. http://www.medicines.org.uk/emc/medicine/23262/spc/sativex+oromucosal+spray/ 2. A guide to good practice in the management of controlled drugs in primary care (England). National Prescribing Centre. 2010. http://www.npc.nhs.uk/controlled_drugs/resources/controlled_drugs_third_edition.pdf 3. Collin C, Davies P, Mutiboko IK et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007;14:290-6. 4. Collin C, Ehler E, Waberzinek G et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res 2010;32:451-9. 5. Novotna A, Mares J, Ratcliffe S et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols (Sativex), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 2011.
Table 1. Cannabis extract (Sativex): study design Study (n ) Collin et al., 2007 3 (12) 189 calculation Collin et al., 2010 4 (23) 337 calculation Inclusion criteria All patients had a diagnosis of MS, with spasticity that was not relieved by current therapy Stable MS for at least 3 months Spasticity in at least 2 muscle groups with an Ashworth score 2 No use of cannabis or cannabinoids in 30 days before trial entry 3-month history of spasticity due to MS Exclusion criteria Psychosis or severe psychiatric disorder other than depression Severe cardiovascular disorder including poorly controlled hypertension History of seizures Symptoms of spasticity not due to MS Any patient with a concurrent history of significant psychiatric, renal, hepatic, cardiovascular or convulsive disorders Duration of study 6 weeks including 2- week baseline 15 weeks including 1- week baseline Treatment arms, Mean number of (number of patients treated) Sativex 9.4 (SD 6.4) (124) Placebo 14.7 (SD 8.4) (65) Sativex, 8.5,, range 1-22 (167) Placebo, 15.4, range 2-23 (170) Main outcomes Primary outcomes Selected secondary outcomes Difference in mean change from baseline between Sativex and placebo in spasticity scores (0-to-10 NRS): 0.52 points (95% CI -1.029 to -0.004) * Proportion of patients who were treatment responders (Sativex vs. placebo): 40% vs. 22% * Mean daily spasm scores on a 0 to 5-point scale (p = ns) Patients global impression of change (p = ns) Difference in mean change from baseline between Sativex and placebo in mean spasticity scores (0-to-10 NRS) (last 14 days of the treatment period minus mean score at baseline): -0.23 points, p = 0.219 Proportion of patients who were treatment responders: 31% vs. 25%, p = 0.213 Barthel Activities of Daily Living index (p = ns) Caregiver s Global Impression of Change (p = ns) Symptom severity: spasm, pain, fatigue, tremor, bladder symptoms, sleep quality (p = ns)
Novotna, et al., 2011 5 (51) 241 calculation 3-month history of spasticity due to MS Moderately severe spasticity (score 4 on a 0 to 10 patient-rated NRS) No use of cannabis or cannabinoids in 30 days before trial entry Symptoms of spasticity not due to MS Any patient with a concurrent history of significant psychiatric, renal, hepatic, cardiovascular or convulsive disorders 4-week single-blind phase to identify responders, 12-week double-blind treatment, 2-week follow up Sativex, 8.3 (SD 2.43) (124) Placebo, 8.9 (2.31) (117) Difference between Sativex and placebo mean spasticity scores (0 to 10 NRS) from randomisation: 0.84 points (95% CI -1.29 to -0.4) *** Proportion of patients who were treatment responders: 74% vs. 51% *** Spasm frequency ** Sleep disruption NRS *** Barthel Activities of Daily living ** Physician and subject global impression of change * Carer global impression of change in function ** There were no significant differences between Sativex and placebo in any trial for other secondary outcomes: Modified Ashworth Scale, Motricity index, timed 10-metre walk test and quality of life measures (EQ-5D, SF-36, MSQoL-54) DB, double-blind; EQ-5D, health-related quality of life questionnaire; ITT, intention-to-treat analysis; MS, multiple sclerosis; MSQoL-54, Multiple Sclerosis Quality of Life-54; NRS, numerical rating scale; RCT, controlled trial; SD, standard deviation; SF-26, short-form 36 question quality of life questionnaire * p < 0.01; *** p < 0.001 vs. control; ns, not significant