Sativex Oromucosal Spray

(delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))

Prescribing information can be found on the last page of this document

UK.PH.SM.SAT.2010.017 June 2010

FORMULARY INFORMATION 1. DETAILS OF DRUG

Approved name, strength and form: Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in an oromucosal spray. Each 100 microlitre spray contains: 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD)1. Manufacturer: GW Pharmaceuticals (marketed in the UK by Bayer Schering Pharma). Yes Yes Brand name: Sativex

Is the drug licensed in the UK? Is the drug licensed for the proposed use?

2. INDICATIONS/PHARMACOLOGY
Licensed indication for this drug (see Summary of Product Characteristics (SPC))1: Sativex is indicated as add-on treatment, 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 significant improvement in spasticity related symptoms during an initial trial of therapy1. As above.

Indication for which product is requested: Mechanism of action: (brief pharmacology)1,2

In the last two decades, a natural cannabinoid receptor system has been discovered in the human body. It is by interacting with these receptors that cannabinoids exert many of their pharmacological effects. There are at least two types of cannabinoid receptors in mammalian tissues, CB1 and CB2.

Mechanism of action: (brief pharmacology)1,2 (continued)

CB1 receptors are widely distributed but are particularly abundant in some areas of the brain including those concerned with movement and postural control, pain and sensory perception, memory, cognition, emotion, autonomic and endocrine functions. The second type of receptor, the CB2 receptor, can mediate regulation of cytokine release from immune cells and of immune cell migration in a manner that seems to reduce inflammation and certain kinds of pain. Cannabinoids act as ligands, conferring on them an ability to modulate a receptors behaviour and consequently its downstream biological pathways. Although the phytocannabinoids (cannabinoids derived from the cannabis plant) all have similar structures, they display a remarkably wide array of actions at each of the different receptors that are now thought to contribute to the endocannabinoid system (such as cannabinoid receptors, transient receptor potential (TRP) channels, melatonin and serotonin receptors, the peroxisome proliferator activated receptors (PPARs) and a host of orphan G-coupled receptors). CB1 and CB2 receptors are found predominantly at nerve terminals where they have a role in retrograde regulation of synaptic function. THC acts as a partial agonist at both CB1 and CB2 receptors, mimicking the effects of the endocannabinoids, which may modulate the effects of neurotransmitters (e.g. reduce effects of excitatory neurotransmitters such as glutamate).

FIGURE 1 MODE OF ACTION OF THC AND ENDOCANNABINOIDS ADAPTED FROM PEREZ 2006, PAGE 4963
GABAergic neuron
Action potential

Glutamatergic neuron
Action potential

1
Ca2+

THC THC

1
Ca2+

8 8 9
Ca2+ ECB Ca2+

2 9

3 3
Ca2+

4 5

4
Excitatory signal

Ca2+

5
Inhibitory signal Ca2+ channel CB1-R iGlu-R GABA-R

7
ECB

Enzyme

Lipid Lipid Enzyme

Postsynaptic neuron

When an action potential arrives at the presynaptic nerve terminal (1), calcium flows into the nerve ending through Ca 2+ channels (2), causing neurotransmitter release from vesicles within the nerve terminal (3). GABA and glutamate are the two transmitters being released here. These then bind to post-synaptic receptors (GABA-R and iGlu-R) (4), resulting in inhibitory and excitatory signals respectively in the post-synaptic cell (5). Activation of the post-synaptic glutamate receptor, together with the high calcium influx presynaptically, stimulates endocannabinoid (ECB) synthesis (6 and 7). ECBs then bind to pre-synaptic cannabinoid receptors (CB1-R) (8), resulting in inhibition of further calcium ion influx (9), and hence inhibition of neurotransmitter release. In this way, cannabinoids bring about retrograde (backwards) inhibition of nerve impulse tranmission.

3. EXISTING DRUGS
Existing method(s) for the management of spasticity The following medicines are recommended for use in the management of spasticity4: Oral treatments include: baclofen, gabapentin (unlicensed use5), tizanidine, diazepam, clonazepam (unlicensed use6) and dantrolene. Invasive therapies include: botulinum toxin, phenol injections and intrathecal baclofen.

4. GUIDELINES
Is the drug recommended by any national organisations? If yes, state which and the nature of the recommendation. Not at this time in the UK as recently licensed. Prior to licensing, it has been available on prescription in the UK on a named patient basis. NICE guidelines on the management of multiple sclerosis, including a section on spasticity4, are due to be updated later in 2010.

5. REASON(S) FOR REQUEST

Please classify reason(s) Unmet need Symptoms of spasticity are not always adequately controlled with current oral treatments and some of these are unlicensed for spasticity5,6. Combination therapy with >1 oral agent is required in 35% people with moderate spasticity and 46% of people with severe/total spasticity7.

Please classify reason(s) (continued)

An effective, tolerable, non-invasive therapy would be advantageous when patients have not gained adequate relief with oral treatments or have suffered intolerable side effects and whose only option is costly and invasive therapy. Burden of disease Spasticity is a common symptom associated with multiple sclerosis (MS)8 and is a major contributor to disability 9. In a survey, 84% of people with MS reported symptoms of spasticity7. Moderate, severe or total spasticity is reported in 34% of individuals7. Spasticity and its consequences can contribute to decreased independence and a decreased quality of life10. It may also result in difficulty for carers e.g. transferring the patient10. Ineffectively treated spasticity can have serious, longterm complications e.g. pressure sores9,10 and make other symptoms more difficult to manage10.

Advantage(s)

A non-invasive treatment option when oral therapies have failed to provide adequate relief from the symptoms of spasticity Can be added to existing anti-spasticity therapy1 An option for patients when the only therapeutic alternative is costly invasive therapy Pharmacologically active cannabinoids are provided in a licensed pharmaceutical formulation The number of sprays can be titrated by the patient to achieve the optimum dose (up to a maximum of 12 sprays per day) and these can be spread throughout the day according to response and tolerability1 It is possible to identify the majority of patients for whom Sativex will be effective by monitoring results during a short initial trial of therapy

6. SUPPORTING EVIDENCE
Details of evidence for these advantages in terms of EFFICACY, SAFETY, CONVENIENCE or COST EFFECTIVENESS. Copies of the key papers referred to should be submitted with the application.
There are several other studies conducted in patients with multiple sclerosis the following are those which primarily investigate efficacy and safety in spasticity associated with multiple sclerosis.

Collin C, Davies P, Mutiboko IK, et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. European Journal of Neurology 2007;14:290-29611.
Study design Multicentre, Phase III, double blind, randomised, parallel group study of 6 weeks duration (eight centres were within the UK). Study treatment and dose Sativex oromucosal spray. The placebo preparation was identically flavoured. Subjects were instructed to titrate their daily dose as required over two weeks to a maximum of 48 sprays per day. Subjects Subjects with a documented diagnosis of MS and stable disease for at least 3 months before study entry. They were required to have significant spasticity in at least two muscle groups with an Ashworth score of two or more; have failed to gain adequate relief using current therapy; be on stable treatment for at least 30 days before entry and during the study. Number of subjects Of 226 subjects entering the study, 189 patients were randomised; 124 randomised to Sativex and 65 randomised to placebo (randomisation in a 2:1 ratio). The intention-totreat (ITT) population totalled 184 subjects and the safety population totalled 189 subjects. Primary outcome measure Change from baseline in the severity of spasticity based on a daily diary assessment by the subject on a 010 Numerical Rating Scale (NRS) of spasticity.

Secondary outcome measures Change from baseline in: a composite score of the Ashworth Scale and Motricity Index in muscles affected by spasticity; mean daily spasm scores; the patients global impression of change (PGIC) in their disease.

The Ashworth Scale is measured by an observer stretching the selected muscle group passively and scoring the resistance to movement. Motricity Index is a validated measure of muscle power assessing pinch grip, elbow flexion, shoulder abduction, ankle dorsiflexion, knee extension and hip flexion. N.B. There was a change in primary endpoint measure in this study, from Ashworth Scale to NRS, made following the publication by Zajicek J et al of evidence that the Ashworth Scale is a poor measure of treatment effect in spasticity12.
Efficacy results The adjusted mean change in NRS spasticity scores for the Sativex group at the end of treatment showed a reduction of 1.18 points from a mean baseline period score of 5.49 points. The placebo group showed an adjusted mean decrease of 0.63 points from a mean baseline period score of 5.39 points. The estimated treatment difference in favour of Sativex was statistically significant (p=0.048; 95% CI: -1.029, -0.004 points). See graph below.
0 -0.2 -0.4 -0.6 -0.8 -1 -1.2 -1.4 -1.6 -1.8 -2 0 1 2

Mean & 95% C.I. by week

NRS spasticity score: changes from baseline

Sativex Week
3

Placebo
4 5 Week 6 End of treatment

Adapted from reference 11

The responder analysis showed that in the Sativex group 48 (40%) subjects experienced a 30% reduction in NRS spasticity over the study, compared with 14 (21.9%) on placebo (difference in favour of Sativex=18.1%; 95% CI: 4.73, 31.52; p=0.014). It is notable that this improvement was gained over and above the concomitant anti-spasticity medication being taken by the subjects. Secondary efficacy measures were all in favour of Sativex but did not achieve statistical significance. Sixty-six (57%) subjects on Sativex rated global impression of change as improved, compared with 31 (48%) controls. Change in mean from baseline to visit 4 Measure Ashworth Spasm frequency Motricity Index (legs) Motricity Index (arms)
Adapted from reference 11

Sativex -0.64 -0.39 5.71 3.91

Placebo -0.53 -0.22 1.85 2.61

Difference (95% CI) 0.11 (-0.29, 0.07) 0.17 (-0.39, 0.06) 3.86 (-0.06, 7.78) 1.30 (-7.47, 10.07)

SE 0.09 0.11 1.99 4.33

P-value 0.218 0.141 0.054 0.766

Safety results Treatment emergent adverse events (AEs) in the safety population occurred in 102 (82%) subjects on Sativex and 46 (71%) on placebo. CNS effects were more common in the Sativex group. The majority of adverse events were of mild or moderate severity. There were seven serious AEs, four in the Sativex group (3.2%) and three in the placebo group (4.6%). Only one was considered to be possibly related to treatment, a case of vomiting in a subject receiving Sativex. Only six (4.8%) subjects on Sativex and two (3.1%) on placebo withdrew due to AEs. There were no deaths.

Collin C et al. A double-blind, randomised placebo-controlled, parallelgroup study of Sativex in subjects with symptoms of spasticity due to multiple sclerosis. Neur Res 2010; 32(5):451-45913 . Abstract also available14.
Study design Multicentre, 15 week, double-blind, randomised, placebo controlled parallel group study. Study treatment Sativex oromucosal spray or placebo oromucosal spray. The maximum permitted dose of study medication was eight actuations in any three hour period and 24 actuations in any 24 hour period. Subjects were to self-titrate to their optimal dose based on efficacy, tolerability and the maximum permitted dose13. Subjects 337 patients with MS. Subjects had any disease sub-type of MS, of at least six months duration, and at least a three month history of spasticity due to MS, which was not wholly relieved with current therapy. Subjects also had a sum spasticity score of at least 24 on an 11 point (0 to 10) numerical rating scale (NRS), representing a daily mean spasticity severity of at least four, considered to be at least moderate in severity13. Primary outcome measure Change in mean spasticity NRS score from baseline to end of the treatment. Secondary outcome measures Spasticity NRS at clinic visits, Modified Ashworth Scale, timed 10 metre walk, Barthel activities of daily living, carer global impression of change (CGIC), quality of life questionnaires (EQ-5D, MSQoL-54), sleep quality, review of pain, tremor and fatigue, spasm severity and bladder symptoms. Efficacy results The mean NRS spasticity scores showed a statistically significant treatment difference of -0.46 points in favour of Sativex in the per protocol (PP) population (p=0.035; 95% CI: -0.88, -0.03). The ITT population showed a trend in favour of Sativex with a treatment difference of -0.23 points (p=0.219; 95% CI: -0.59, 0.14). In the PP population, 36% of patients achieved at least a 30% improvement in spasticity NRS with an odds ratio of 1.74 (95% CI: 0.005, 0.266). This trend was also

observed in the ITT population, with an odds ratio of 1.34 in favour of Sativex. The CGIC assessment was in favour of Sativex (odds ratio 1.25, p=0.270; 95% CI: 0.84, 1.85). Trends in favour of Sativex were found with spasticity and sleep assessments at clinic visits, Modified Ashworth Scale, timed 10-metre walk, quality of life questionnaire (EQ-5D), sleep quality, review of pain, tremor, spasm severity and bladder symptoms.

Wade DT, Collin C, Stott C, Duncombe P. Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Multiple Sclerosis 2010;16(6):707-71415.
The results from three randomised, placebo controlled, double blind, parallel group studies were combined for analysis. 666 patients with MS and spasticity were randomised and included in the analysis. All patients had insufficient benefit from their existing anti-spasticity medication. Sativex or placebo were administered as add-on therapy. A 0-100 mm Visual Analogue Scale (VAS, transformed to a 0-10 scale) or a 0-10 Numerical Rating Scale (0-10 NRS) was used to measure spasticity. Patients achieving a 30% improvement from baseline in their spasticity score were defined as responders. Global impression of change (GIC) at the end of treatment was also recorded. The adjusted mean change from baseline in a 0-10 NRS spasticity score for patients receiving Sativex was -1.30, compared with -0.97 for placebo in the ITT population. This difference was statistically significant when analysed using a linear model (treatment difference = -0.32 [95% CI: -0.61, -0.04, p=0.026]). There was a statistically significant difference in the proportions of patients receiving Sativex who achieved a 30% or greater improvement from baseline in a 0-10 NRS spasticity score, compared with those taking placebo (odds ratio = 1.62, 95% CI: 1.15 to 2.28; p=0.0073). The odds ratio for patients reporting improvement on the GIC in the active group compared with placebo was 1.67 (95% CI: 1.05 to 2.65; p=0.030)15.

Robson P et al. Cannabis-based medicinal extract (Sativex) produced significant improvements in a subjective measure of spasticity which were maintained on long-term treatment with no evidence of tolerance. Presented at the IACM 3rd conference on Cannabinoids in Medicine, Leiden University, September 200516.
This abstract reports the follow-up of patients who had participated in a double-blind, placebo controlled trial of Sativex in the symptomatic treatment of MS and elected to enter a long-term open-label follow-up trial. 160 patients completed the acute study, with 39 patients having spasticity as their primary symptom. In these 39 patients, visual analogue scale (VAS) spasticity scores fell by 31.2mm following Sativex and by 8.4mm following placebo (95% CI for difference -35.52, -10.07; SE 6.26; p=0.001). Diary scores produced similar results (p=0.009). Sixty-six patients with spasticity completed 82 weeks of Sativex treatment. At entry to the acute study this group had a mean VAS spasticity score of 69.5, which had reduced to 34.2 on entry into the long-term study. After 82 weeks, the mean score was 31.8 and average daily dose had reduced marginally from 12 sprays on entry to 10 sprays at the last assessment. This suggests that the beneficial effect of Sativex on spasticity in MS seems to be maintained over long-term treatment, with no evidence of tolerance. GWSP060417 [NCT00681538]

Novotna I et al. A randomised, double-blind, placebo-controlled, parallelgroup, enriched-design study of nabiximols (Sativex), in subjects with spasticity due to multiple sclerosis. Submitted for publication17.
Objective To compare Sativex with placebo in relieving spasticity due to MS, in patients who have shown a capacity to respond to treatment. Study design Four-week single-blind treatment period (Phase A) performed to identify initial responders to Sativex (20% reduction in spasticity score on a 0-10 numerical rating scale [NRS]). Responders then entered a 12-week double-blind, randomised, placebocontrolled, parallel-group study (Phase B).

Rationale for study design1,17 In the setting where a proportion of patients do not respond to treatment, the conventional randomised controlled trial (RCT) may underestimate the true effect of treatment, since such non-responding patients would be unlikely to stay on therapy. It was postulated that a clinically important treatment effect in some patients was being partly masked by data from non-responders in the analyses of mean changes. In analyses comparing NRS scores with patient global impression of change (PGIC), a 19% NRS response was estimated to represent a clinically relevant improvement on the PGIC and a response of 28% much improved on the PGIC. In post hoc exploratory combined analyses of two of the above studies11,13,14, a 4-week trial period using a 20% NRS response threshold was found to be a good predictor of eventual response defined as a 30% reduction. Study treatment Phase A Sativex oromucosal spray Phase B Sativex oromucosal spray or placebo oromucosal spray Subjects were restricted to a maximum of 12 sprays in any 24 hour period Subjects Subjects diagnosed with MS of any sub-type of at least 6 months duration with symptoms of spasticity due to MS of at least 3 months duration and gaining insufficient benefit from their existing anti-spasticity medication. Subjects had to have at least moderately severe spasticity, as defined by a score of 4 using a single spasticity 0-10 severity NRS at screening. 572 patients were enrolled into Phase A: 272 (48%) were identified as initial responders, of whom 241 continued into phase B (124 randomised to Sativex; 117 to placebo). Primary outcome measure The primary endpoint was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomised, controlled phase of the study. Secondary outcome measure Daily dose, spasm frequency, sleep disruption, Modified Ashworth Score, quality of life, mood and safety measures were recorded throughout. Barthel Activities of Daily Living (ADL) Index, Motricity Index, Timed Ten Metre Walk (TTMW) and carer, physician and subject Global Impression of Change were also assessed. Responder analyses at 30% and 50% levels of improvement from baseline were evaluated.

Efficacy results The mean change in spasticity 0-10 NRS score at the end of 4 weeks single-blind treatment with Sativex was a decrease (improvement) of 3.01 points. In Phase B, the primary endpoint was significantly in favour of Sativex (p=0.0002), with an improvement of -0.04 in spasticity NRS compared with a 0.81 deterioration in placebo patients. The positive outcome of the primary efficacy measure was supported by secondary outcome measures and the findings from functional assessments.

7.5 7.0

Sativex

Placebo

MEAN SPASTICITY 0-10 NRS (SE)

6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Screening Baseline End of study 10 11 12 1 2 3 4 5 6 7 8 -3 -2 -1 9 Phase A Single-blind Sativex Phase B Randomised period Sativex or Placebo p=0.0002

STUDY PERIOD (WEEK)

Effect of Sativex in responders. Phase A (n = 241) - single-blind active treatment period. Phase B-responders continued on Sativex (n = 124) or switched to placebo (n = 117) (during the randomised double blind period).

74% of Phase B Sativex-treated patients improved 30% or more from Phase A baseline compared with 51% on placebo. The odds of an improvement in spasticity were higher for the Sativex group than the placebo group, with an odds ratio of 2.73 (p=0.0003).

Spasm frequency, sleep disruption NRS, and Physician, Carer and Subject Global Impression of Change and Barthel ADL were all significantly in favour of Sativex (p=0.0046, p<0.0001, p=0.0045, p=0.0053, p=0.0234 and p=0.0067 respectively). The mean dose of Sativex in Phase B was 8.3 sprays/day. Patients who demonstrated a 20% improvement in mean spasticity NRS during a four-week trial period went on to show a 46% improvement in spasticity after a total of 16 weeks of treatment.

Screening (PreTreatment) Spasticity NRS Spasm Frequency 6.81 11.49

End of Treatment (week 16) 3.68 5.56

Mean Change from Baseline -3.13 -5.94

Mean % Change from Baseline -46.0% -51.7%

Changes in efficacy measures from pre-treatment baseline with Sativex (n=124).

Safety results In Phase A, 268 of 572 patients (47%) reported at least one AE within the first four weeks of treatment, including the 10-day up-titration period, the most common being dizziness (14%). 92.5% of the 268 patients had events that were mild/ moderate in severity. Nineteen subjects (3.3%) withdrew due to an AE. Of the 241 Phase B patients, 66 (53%) on Sativex and 57 (49%) on placebo reported at least one AE. The majority of AEs in the Sativex subjects were mild or moderate (89%)18. Eight Sativex subjects (6.5%) withdrew due to an AE. The most common treatment related AEs occurring in 3% of subjects or more during Phase B are shown in the table on the next page.

System organ class Preferred term

Treatment-related number (%) of subjects Sativex (n=124) Placebo (n=117) 18 (15%) 6 (5%) 4 (3%) 0 7 (6%) 3 (3%) 1 (1%) 2 (2%) 1 (1%) 1 (1%) 1(1%) 2(2%)

Total subjects with at least one AE Nervous system disorders Headache Somnolence Gastrointestinal disorders Diarrhoea Dry mouth Psychiatric disorders Euphoric mood Ear and labyrinth disorders Vertigo General disorders

33 (27%) 11 (9%) 1 (1%) 4 (3%) 10 (8%) 0 4 (3%) 9 (7%) 4 (3%) 6 (5%) 6 (5%) 9 (7%)

A therapeutic trial of treatment for four weeks appears to be sufficient to identify responders, with an approximate number needed-to-treat (NNT) of 217.

Montalban X, Wright S. Trial period for new symptomatic treatments: lessons learnt from a Sativex in MS spasticity clinical trial. Presented at ECTRIMS September 200919.
This abstract describes the change from pre-treatment baseline for the primary efficacy outcome of Novotna et al. in those that responded to the 4 week trial. The 4 week responders achieved the following changes from pre-treatment baseline to the end of the study (4+12 weeks): Main endpoint: spasticity NRS (0-10): from 6.81 to 3.68, SD 1.83 (-46%). Sleep disruption NRS (0-10): from 4.36 to 1.71 (-61%) Spasms (episodes/day): from 11.49 to 5.56 (-52%) Ashworth Scale 1.44 to 1.09 (-24%) 10m walking time: from 28s to 20s (-29%) QoL EQ-5D (0-1) from 0.48 to 0.57 (+19%) QoL SF-36 Role Physical (0-100): from 35.1 to 48.1 (+37%) The 4 week trial period enabled the identification of patients that showed clinically relevant improvements in the primary and also secondary efficacy endpoints after a further 12 week randomised treatment period. A 4 week trial period with Sativex can effectively detect MS spasticity patients who will demonstrate positive outcomes in longer-term treatment. GWSP0702 20,21 [NCT00702468]

Notcutt W et al. Results of a randomised withdrawal study of subjects with spasticity due to multiple sclerosis who were receiving long-term Sativex. Presented at ECTRIMS September 200921. Submitted for publication.
Objective To assess the maintenance effect of Sativex compared with placebo in relieving spasticity due to MS in subjects who had been receiving long-term benefit from Sativex.

Study design Five-week (one week baseline and four weeks randomised treatment period), multicentre, placebo-controlled, parallel-group, randomised withdrawal study. Study subjects Subjects were identified by investigator centres from those who were currently receiving Sativex obtained through either Supply of Unlicensed Sativex or Named Patient Supply programmes for the relief of spasticity and had been receiving Sativex for at least 12 weeks prior to study entry. 36 patients were enrolled (n=18 per group). Mean duration of MS >16 years, spasticity >12 years and EDSS of 7.0. Mean duration of Sativex use was 3.6 years. Study treatment Subjects commenced a seven day open-label baseline period, continuing with a stable dosing of Sativex at their current effective dose level. At the end of the seven days, subjects ceased Sativex dosing and were randomised to receive either Sativex or placebo (randomised withdrawal period) and continued stable dosing at their current effective dose as identified at the start of the baseline period for the next four weeks. Primary outcome measure The primary endpoint was time to treatment failure (defined as: withdrawal without completing the 28-day randomised treatment period, worsening of spasticity, or an increase in anti-spasticity/disease-modifying medication after randomisation). Secondary endpoints Spasticity severity 0-10 Numeric Rating Scale (0-10 NRS), Sleep Disruption 0-10 NRS, Modified Ashworth Scale (MAS), Timed 10m walk, Motricity Index, and Carer and Subjects Global Impression of Change (CGIC & SGIC). Efficacy results Mean doses of study medication were 7.3 and 9.2 sprays per day respectively for Sativex and placebo. Three patients (16.7%) on Sativex withdrew from the study whilst 16 (88.9%) withdrew on placebo. Eight Sativex patients (44.4%) were treatment failures compared with 17 (94.4%) on placebo. Time to treatment failure was significantly in favour of Sativex (p=0.013; hazard ratio=0.335; 90% CI: 0.162, 0.691).

Time to Treatment Failure

1.0 0.9 0.8 0.7 HR (90% C.I.) = 0.335 (0.162, 0.691) : p = 0.013

Probability of Failure

0.6 0.5 0.4 0.3 0.2 0.1 0.0 No. of subjects at risk: Sativex = 18 Placebo = 18 10 4 10 3 10 1 Treatment Placebo Sativex

14

21

28

Days on Treatment

Adapted from reference 20

Time to treatment failure.

All secondary endpoints (except the MAS) showed trends in favour of Sativex, reaching statistical significance in the SGIC and CGIC (functional ability) scales (i.e. a greater worsening on placebo; p=0.017 and 0.001 respectively). Withdrawal of Sativex treatment precipitated significant worsening in spasticity in a significant number of patients switched onto placebo. Maintenance of long-term efficacy was demonstrated with Sativex compared with placebo in this randomisedwithdrawal setting. There was no evidence of a withdrawal syndrome in those subjects who stopped Sativex despite a prolonged period on the medication.

Schoedel K et al. Abuse potential of Nabiximols Oromucosal Spray in Recreational Marijuana Users. Oral presentation at the 71st Annual Scientific Meeting of the College on Problems of Drug Dependence. Nevada, USA, 2009. Submitted for publication22.
Objective To evaluate the abuse potential of Sativex (nabiximols oromucosal spray) vs dronabinol (Marinol) and placebo. N.B. Dronabinol, a synthetic tetrahydrocannabinol (THC), is not available in the UK and not indicated for spasticity. Study design Randomised, double-blind, six-period crossover study.

Study subjects Thirty recreational marijuana users were randomised and 23 completed the study. Study treatment Sativex - 4, 8 and 16 sprays (10.8, 21.6 & 43.2 mg THC/10, 20 & 40 mg CBD) Dronabinol (Marinol) 20 and 40 mg THC Placebo Primary outcome measures Drug Liking Visual Analogue Scale (DL VAS), Subjective Drug Value (SDV) and Addiction Research Center Inventory Morphine Benzedrine Group (ARCI MBG). One or more of peak effects (Emax), trough effects (Emin) and area under the effect curve (AUEC) were analysed for each measure. Secondary endpoints Secondary endpoints included other subjective measures and cognitive/motor performance (Choice Reactive Time [CRT]), Divided Attention [DA] and Sternberg Short-Term Memory [STM]) tests. Results Sativex and dronabinol showed dose-dependent effects on the primary endpoints. Four sprays of Sativex were not significantly different to placebo on any of the primary outcome measures. In general Sativex 8 sprays showed numerically smaller effects than dronabinol 20 mg and Sativex 16 sprays showed numerically smaller effects than dronabinol 40 mg. Secondary endpoints showed a similar pattern of results. Sativex (all doses) and dronabinol 20 mg had no significant effects on CRT, DA and STM, while dronabinol 40 mg had a small, but statistically significant effect on STM. Conclusions Sativex and dronabinol showed dose-dependent effects on abuse potential endpoints; 4 sprays Sativex showed abuse potential similar to placebo. On a doseper-dose basis, Sativex showed numerically smaller effects compared to dronabinol. Importantly, Sativex did not exhibit any adverse cognitive/motor effects.

7. ANTICIPATED PLACE IN THERAPY

Please give a clear guideline including algorithms or flowcharts as necessary, indicating EXACTLY which group(s) of patients should be eligible to receive this drug (and those not, highlighting contraindications), including details of whether the drug is first line or not, and the suggested criteria for selecting the drug.
In accordance with its licensed indication, Sativex will be used as add-on treatment for patients with moderate to severe spasticity who have not gained adequate symptom improvement from one or more oral therapies or where these therapies have resulted in intolerable side effects. Treatment must be initiated and supervised by a physician with specialist expertise in treating this patient population1. It is possible to identify the majority of patients for whom Sativex will be effective by monitoring results during an initial trial of therapy. The patients response to Sativex should be reviewed after four weeks of treatment. If a clinically significant improvement in spasticity related symptoms is not seen during this initial trial of therapy, then treatment should be stopped. In the clinical trials this was defined as at least a 20% improvement in spasticity related symptoms on a 0-10 patient reported numeric rating scale1. Sativex is contraindicated in patients1: With hypersensitivity to cannabinoids or to any of the excipients. With any known or suspected history or family history of schizophrenia, or other psychotic illness; history of severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition. Who are breast feeding (in view of the considerable levels of cannabinoids likely in maternal breast milk and the potential adverse developmental effects in infants).

Sativex should not be used during pregnancy unless the potential risks to the fetus and/or embryo are considered to be outweighed by the benefit of treatment1. Men and women of child bearing potential should use reliable contraception for the duration of therapy and for three months after discontinuation of therapy. Sativex is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data1. For special warnings and precautions for use, please refer to the full Summary of Product Characteristics (SPC)1.

8. PRESCRIBING AND MONITORING

Dosage regimen proposed for this application1: Dosage and frequency: A titration period is required to reach optimal dose. The number and timing of sprays will vary between patients, up to a maximum of 12 sprays per day. Refer to SPC for the recommendations for titration. Following the titration period, patients are advised to maintain the optimum dose achieved. The median dose in clinical trials for patients with multiple sclerosis was eight sprays per day. Once the optimum dose has been achieved, patients may spread the doses throughout the day according to individual response and tolerability. Doses of greater than 12 sprays per day are not recommended and should only be used where the potential benefits outweigh the risks. Likely duration of treatment: The patients response to Sativex should be reviewed after four weeks of treatment. If a clinically significant improvement in spasticity related symptoms is not seen during this initial trial of therapy, then treatment should be stopped. The value of long term treatment should be reevaluated periodically.

Monitoring requirements (including criteria for stopping treatment) and implications for continued care1:

A thorough evaluation of the severity of spasticity related symptoms and of the response to standard anti-spasticity medication should be performed prior to initiation of treatment. Treatment should be initiated and supervised by a physician with specialist expertise in treating this patient population. The patients response to Sativex should be reviewed by a specialist physician after four weeks of treatment. If a clinically significant improvement in spasticity related symptoms is not seen during this initial trial of therapy, then treatment should be stopped. In the clinical trials this was defined as at least a 20% improvement in spasticity related symptoms on a 0-10 patient reported numeric rating scale. The value of long term treatment should be re-evaluated periodically. Frequent clinical evaluation by a clinician is recommended in patients with significant hepatic or renal impairment.

Who will initiate the prescribing? Who will undertake maintenance prescribing? Is there a need for a shared care protocol?

Specialist physician / Hospital Doctor/ General Practitioner / Non-medical Prescriber.

Specialist physician / Hospital Doctor/ General Practitioner (GP) / Non-medical Prescriber.

Yes/No (see template attached).

9. FINANCIAL ASPECTS
Cost of the product: The price of Sativex is 1.39 per dose. Using the following assumptions, it can be estimated that there may be nine Sativex users per 100,000 population. If nine patients were treated for one month and then four patients continued on treatment, the annual cost per 100,000 population, assuming a dose of eight sprays per day would be approximately 17,800. Assumptions 100,000 people with MS in the UK 23 84,000 (84%) are affected by spasticity8 28,560 (34%) have moderate/severe/total spasticity7 21,134 (69% with moderate, and 79% with severe spasticity) use medication for spasticity7 11,567 (35% of patients with moderate and 46% with severe/total spasticity) require combination therapy with more than one oral agent7 5,784 (50%) may be eligible for Sativex UK population of 61 million24 48% of patients respond to a four week therapeutic trial of Sativex (according to a large Phase III study)17,18 and would be eligible to continue therapy

Applicants signature:

Date:

Reference List 1. Sativex Summary of Product Characteristics. 2010. 2. GW Pharmaceuticals. Mechanism of action. 2010. Available at: http://www. gwpharm.com/mechanism-of-action.aspx (Last accessed: 18/3/2010). 3. Perez J. Drugs Today 2006;42(8):495-503. 4. National Institute for Health and Clinical Excellence. Multiple Sclerosis. Management of multiple sclerosis in primary and secondary care. Clinical Guideline 8. 2003. Available at: http://www.nice.org.uk/nicemedia/pdf/ cg008guidance.pdf (Last accessed: 18/3/2010). 5. Pfizer Ltd. SPC. Neurontin capsules and tablets. March 2010. 6. Roche Products Limited. SPC. Rivotril tablets. October 2008. 7. Rizzo MA et al. Mult Scler 2004;10(5):589-95.

8. Multiple Sclerosis Trust. Multiple Sclerosis Information for Health and Social Care Professionals. 2007. Available at: http://www.mstrust.org.uk/downloads/ ms_information_for_hps.pdf (Last accessed: 18/3/2010). 9. Beard S et al. Health Technol Assess 2003;7(40). 10. Multiple Sclerosis International Federation. MS in focus. Spasticity in MS. Issue 12. 2008. Available at: http://www.msif.org/docs/MSinFocusIssue12EN.pdf (Last accessed: 18/3/2010). 11. Collin C et al. European Journal of Neurology 2007;14:290-6. 12. Zajicek J et al. The Lancet 2003;362:1517-26. 13. Collin C et al. Neurological Research 2010; 32(5):451-459. 14. Collin C et al. A randomised controlled study of Sativex in patients with symptoms of spasticity due to multiple sclerosis. Multiple Sclerosis Supplement. Abstract from ECTRIMS. 2006. 15. Wade DT et al. Mult Scler 2010; 16(6):707-714. 16. Robson P. Cannabis-based medicinal abstract (Sativex) produced significant improvements in a subjective measure of spasticity which were maintained on long term treatment with no evidence of tolerance. Presented at the IACM 3rd conference on Cannabinoids in Medicine, Leiden University. 2005. 17. Novotna I et al. 2010. Submitted for publication.

18. Ambler Z. A two-phase study of Sativex in the relief of spasticity due to multiple sclerosis: phase A single-blind response assessment followed by phase B double-blind, randomised, placebo-controlled, parallel-group study. Abstract presented at the 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS).Dusseldorf, Germany. 2009. 19. Montalban X and Wright S. Trial period for new symptomatic treatments: lessons learnt from a Sativex in MS spasticity clinical trial. Abstract presented at the 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS). Dusseldorf, Germany. 2009. 20. GW Pharmaceuticals. Data on file. 2009. 21. Notcutt W et al. Results of a randomised withdrawal study of subjects with spasticity due to multiple sclerosis who were receiving long-term Sativex. Presented at ECTRIMS, September. 2009. 22. Schoedel K et al. Abuse Potential of Nabiximols Oromucosal Spray in Recreational Marijuana Users. Oral presentation at the 71st Annual Scientific Meeting of the College on Problems of Drug Dependence. Nevada, USA. 2009. 23. Multiple Sclerosis Society. About MS. 2010. Available at: http://www.mssociety. org.uk/about_ms/index.html (Last accessed: 18/3/2010). 24. Office for National Statistics. Mid-2008 Population Estimates: United Kingdom; estimated resident population by single year of age and sex. 2009.

Sativex Oromucosal Spray Prescribing Information (refer to full Summary of Product Characteristics (SmPC) before prescribing). Presentation: 1mL contains: 38-44mg and 3542mg of two extracts from Cannabis sativa L., (Cannabis leaf and flower) corresponding to 27mg delta-9-tetrahydrocannabinol (THC) and 25mg cannabidiol (CBD). Each 100 microlitre spray contains: 2.7mg THC and 2.5mg CBD. Indication(s): as add-on treatment, 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 significant improvement in spasticity related symptoms during an initial trial of therapy. Posology and method of administration: oromucosal use only. Treatment must be initiated and supervised by a physician with specialist expertise in MS. Direct spray at different sites on the oromucosal surface, changing site for each use of product. May take up to 2 weeks to find optimal dose, review response after 4 weeks of treatment. Re-evaluate long term treatment periodically. Adults: titration period necessary; number/timing of sprays will vary between patients. Number of sprays increased daily according to SmPC table, up to maximum of 12 sprays per day with minimum 15 minutes between sprays. Children and adolescents: not recommended. Elderly: no specific studies but CNS side effects may be more likely (see Warnings and precautions) Significant hepatic or renal impairment: no specific studies but effects of Sativex may be exaggerated or prolonged. Frequent clinical evaluation recommended. Contraindications: hypersensitivity to cannabinoids or excipients. Breast feeding. Known/suspected history or family history of schizophrenia/other psychotic illness. History of severe personality disorder/other significant psychiatric disorder other than depression due to underlying condition. Warnings and precautions: not recommended in patients with serious cardiovascular disease. Caution in patients with history of epilepsy/ recurrent seizures. THC and CBD are metabolised in the liver. Several THC metabolites may be psychoactive. Contains approx. 50% v/v ethanol. Risk of falls if spasticity/muscle strength no longer sufficient to maintain posture/gait. CNS side effects e.g. dizziness, somnolence could impact personal safety, e.g. hot food and drink preparation. Theoretical risk of additive effect with muscle-relaxing agents, not seen in clinical trials but warn patients risk of falls may increase. No effect seen on fertility but cannabinoids shown to affect spermatogenesis in animals. Female patients of child-bearing potential/male patients with a partner of child-bearing potential should use reliable contraception. Patients with a history of substance abuse may be more prone to abuse Sativex. Withdrawal symptoms following

abrupt withdrawal of long-term Sativex are likely to be limited to transient disturbances of sleep, emotion or appetite. No increase in daily dosage observed in long-term use; self-reported levels of intoxication low; dependence on Sativex unlikely. Interactions: no clinically apparent drug-drug interactions seen. Co-administration with food results in mean increase in Cmax, AUC and half-life (increase less than between-subject variability in these parameters). Concomitant ketoconazole increases Cmax and AUC of THC (and primary metabolite) and CBD. Increase less than betweensubject variability. Risk of additive sedation and muscle relaxing effects with hypnotics, sedatives and drugs with sedating effects. Pregnancy and lactation: do not use in pregnancy unless benefit outweighs potential risks. Do not use if breast feeding. Insufficient experience of effects on reproduction - use reliable contraception during therapy and for 3 months after discontinuation. Effects on ability to drive and use machines: do not drive, operate machinery or engage in any hazardous activity if experiencing significant CNS side effects; warn patients may cause loss of consciousness. Side effects: very common dizziness, fatigue; common anorexia, decreased or increased appetite, depression, disorientation, dissociation, euphoria, amnesia, balance disorder, disturbance in attention, dysarthria, dysgeusia, lethargy, memory impairment, somnolence, blurred vision, vertigo, constipation, diarrhoea, dry mouth, glossodynia, mouth ulceration, nausea, oral discomfort/pain, vomiting, application site pain, asthenia, feeling abnormal/ drunk, malaise, fall; uncommon hallucination, illusion, paranoia, suicidal ideation, delusional perception, syncope, palpitations, tachycardia, hypertension, pharyngitis, throat irritation, upper abdominal pain, oral mucosal disorders e.g. discolouration, exfoliation, stomatitis, tooth discolouration, application site irritation; unknown frequency psychiatric symptoms e.g. anxiety and mood changes, transient psychotic reactions, possible leukoplakia (unconfirmed): inspect oral mucosa regularly in long term use. Prescribers should consult the SmPC for further information on side effects. Overdose: symptomatic and supportive treatment required. Special precautions for storage: refrigerate (2 to 8C); once opened refrigeration is unnecessary but do not store above 25C. Legal Category: POM Package quantities and basic NHS costs: 3 x 10mL 375.00. MA holder: GW Pharma Ltd, Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ MA number(s): PL 18024/0009 Further information available from: Bayer Schering Pharma, Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA United Kingdom. Telephone: 01635 563000. Date of preparation: March 2010. Sativex is a registered trademark of GW Pharma Ltd.

Adverse events should be reported. Reporting forms and information can be found at www. yellowcard.gov.uk. Adverse events should also be reported to GW Pharma Ltd. Tel: 01353 616636, Fax: 01353 616638