- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults:The spray container should be shaken before use and the spray should be directed at different sites on the oromucosal surface changing the application site each time the product is used. Patients should be advised that it might take up to two weeks to find the optimal dose and that undesirable effects can occur during this time, most commonly dizziness. These undesirable effects are usually mild and resolve in a few days. However, physicians should consider maintaining the current dose, reducing the dose or interrupting, at least temporarily, the treatment depending on seriousness and intensity. To minimise variability of bioavailability in the individual patient, administration of Sativex should be standardised as far as possible in relation to food intake (see section 4.5). In addition, starting or stopping some concomitant medicinal products may require a new dose titration (see section 4.5).
Titration period:A titration period is required to reach optimal dose. The number and timing of sprays will vary between patients. The number of sprays should be increased each day following the pattern given in the table below. The afternoon/evening dose should be taken at any time between 4 pm and bedtime. When the morning dose is introduced, it should be taken at any time between waking and midday. The patient may continue to gradually increase the dose by one spray per day, up to a maximum of 12 sprays per day, until they achieve optimum symptom relief. There should be at least a 15 minute gap between sprays.
|Day||Number of sprays in the morning||Number of sprays in the evening||(Total number of sprays per day)|
Maintenance period:Following the titration period, patients are advised to maintain the optimum dose achieved. The median dose in clinical trials for patients with multiple sclerosis is 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. Re-titration upwards or downwards may be appropriate if there are any changes in the severity of the patient's condition, changes in their concomitant medication or if troublesome adverse reactions develop. Doses of greater than 12 sprays per day are not recommended.
Review by the physicianA 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. Sativex is only indicated in patients with moderate to severe spasticity that have responded inadequately to other anti-spasticity medication. The patient's 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 scale (see section 5.1). The value of long term treatment should be re-evaluated periodically.ChildrenSativex is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data.ElderlyNo specific studies have been carried out in elderly patients, although patients up to 90 years of age have been included in clinical trials. However, as elderly patients may be more prone to develop some CNS adverse reactions, care should be taken in terms of personal safety such as preparation of hot food and drinks.
Patients with significant hepatic or renal impairmentThere are no studies in patients with impaired hepatic or renal function. However, in these sub-populations the effects of Sativex may be exaggerated or prolonged. Frequent clinical evaluation by a clinician is recommended in these patient populations (see section 4.4).
PregnancySativex 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 treatment.
LactationAvailable pharmacodynamics / toxicological data in animals have shown excretion of Sativex / metabolites in milk (for details see section 5.3). A risk to the breastfed child cannot be excluded. Sativex is contraindicated during breast-feeding (see section 4.3).
FertilityIn fertility studies in rodents, there was no effect of treatment with Sativex in males or females. There was no effect on fertility of the offspring from mothers treated with Sativex.
|MedDRa SOC||Very Common ≥ 1/10||Common ≥ 1/100 to < 1/10||Uncommon≥ 1/1000 to < 1/100|
|Infections and infestations||pharyngitis|
|Metabolism and nutrition disorders||anorexia (including appetite decreased), appetite increased|
|Psychiatric disorders||depression, disorientation, dissociation, euphoric mood,||hallucination (unspecified, auditory, visual), illusion, paranoia, suicidal ideation, delusional perception*|
|Nervous system disorders||dizziness||amnesia, balance disorder, disturbance in attention, dysarthria, dysgeusia, lethargy, memory impairment somnolence||syncope|
|Eye disorders||vision blurred|
|Ear and labyrinth disorders||vertigo|
|Cardiac disorders||palpitations, tachycardia|
|Respiratory, thoracic and mediastinal disorders||throat irritation|
|Gastrointestinal disorders||constipation, diarrhoea, dry mouth, glossodynia, mouth ulceration, nausea, oral discomfort, oral pain, vomiting||abdominal pain (upper), oral mucosal discolouration*, oral mucosal disorder, oral mucosal exfoliation*, stomatitis, tooth discolouration|
|General disorders and administration site conditions||fatigue||application site pain, asthenia, feeling abnormal, feeling drunk, malaise||application site irritation|
|Injury, poisoning and procedural complaints||fall|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme - Website: www.mhra.gov.uk/yellowcard
Mechanism of actionAs part of the human endocannabinoid system (ECS), cannabinoid 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).In animal models of MS and spasticity CB receptor agonists have been shown to ameliorate limb stiffness and improve motor function. These effects are prevented by CB antagonists, and CB1 knockout mice show more severe spasticity. In the CREAE (chronic relapsing experimental autoimmune encephalomyelitis) mouse model, Sativex produced a dose-related reduction in the hind limb stiffness.
Clinical experienceSativex has been studied at doses of up to 48 sprays/day in controlled clinical trials of up to 19 weeks duration in more than 1500 patients with MS. In the pivotal trials to assess the efficacy and safety of Sativex for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) the primary efficacy measure was a 0 to 10 point Numeric Rating Scale (NRS) on which patients indicated the average level of their spasticity related symptoms over the last 24 hours where 0 is no spasticity and 10 is the worst possible spasticity. In a first Phase 3 placebo controlled trial over a 6-week treatment period the difference from placebo reached statistical significance but the difference between treatments of 0.5 to 0.6 points on the 0-10 point NRS was of questionable clinical relevance. In a responder analysis 40% Sativex and 22% placebo responded to treatment using the criterion of greater than a 30% reduction in NRS score. A second 14 week Phase 3 study failed to show a significant treatment effect. The difference from placebo on the NRS score was 0.2 points.It was postulated that a clinically useful treatment effect in some patients might be partly masked by data from non-responders in the analyses of mean changes. In analyses comparing NRS scores with patient global impression of change (PGI), a 19% NRS response was estimated to represent a clinically relevant improvement on the PGI and a response of 28% much improved on the PGI. In post hoc exploratory combined analyses of the above two studies, a 4-week trial period using a 20% NRS response threshold was predictive of eventual response defined as a 30% reduction. A third Phase 3 trial incorporated a formalised 4-week therapeutic trial period prior to randomisation. The aim of the trial was to assess the benefit of continued treatment for patients who achieve an initial response to treatment. 572 patients with MS and refractory spasticity all received single blind Sativex for four weeks. After four weeks on active treatment 273 achieved a reduction of at least 20% on the spasticity symptom NRS, of which 241 met the entry criteria for randomisation, with a mean change from the start of treatment of -3.0 points on the 10 point NRS. These patients were then randomised to either continue to receive active or switch to placebo for the 12 week double-blind phase, for a total of 16 weeks treatment overall. During the double-blind phase the mean NRS scores for patients receiving Sativex generally remained stable (mean change from randomisation in NRS score -0.19), while the mean NRS scores for patients switched to placebo increased (mean change in NRS score was +0.64 and median change was +0.29). The difference* between treatment groups was 0.84 (95% CI -1.29, -0.40). * Difference adjusted for centre, baseline NRS and ambulatory statusOf those patients who had a 20% reduction from screening in NRS score at week 4 and continued in the trial to receive randomised treatment, 74% (Sativex) and 51% (placebo) achieved a 30% reduction at week 16. The results over the 12-week randomised phase are shown below for the secondary endpoints. The majority of secondary endpoints showed a similar pattern to the NRS score, with patients who continued to receive Sativex maintaining the improvement seen from the initial 4-week treatment period, while patients switching to placebo declined:
|Modified Ashworth Score for spasticity:||Sativex -0.1; Placebo +1.8 ; Adjusted Difference -1.75 (95% CI -3.80, 0.30)|
|Spasm frequency (per day):||Sativex -0.05; Placebo +2.41 Adjusted Difference -2.53 (95% CI -4.27, -0.79)|
|Sleep disruption by spasticity: (0 to 10 NRS)||Sativex -0.25; Placebo +0.59 ; Adjusted Difference -0.88 (95% CI -1.25, -0.51)|
|Timed 10 metre walk (seconds):||Sativex -2.3; Placebo +2.0; Adjusted Difference -3.34 (95% CI -6.96, 0.26)|
|Motricity index (arm and leg):||No differences between treatment groups were seen.|
|Barthel Activities of Daily Living:||Odds ratio for improvement: 2.04|
AbsorptionFollowing administration of Sativex (four sprays), both THC and CBD are absorbed fairly rapidly and appear in the plasma within 15 minutes after single oromucosal administration. With Sativex, a mean Cmax of about 4 ng/mL was reached some 45-120 minutes after a single dose administration of a 10.8 mg THC dose, and was generally well tolerated with little evidence of significant psychoactivity.When Sativex is co-administered with food the mean Cmax and AUC for THC were 1.6- and 2.8-fold higher compared with fasting conditions. Corresponding parameters for CBD increased 3.3- and 5.1-fold. There is a high degree of variability in pharmacokinetic parameters between patients. Following a single dose administration of Sativex (four sprays) under fasted conditions, the mean plasma level of THC showed a 57.3% CV for Cmax (range 0.97-9.34ng/mL) and a 58.5% CV for AUC (range 4.2-30.84 h*ng/mL). Similarly the %CV for CBD was 64.1% (range 0.24-2.57ng/mL) and 72.5% (range 2.18-14.85 ng/mL) for the same parameters respectively. After nine consecutive days of dosing the % CV values for the same parameters were 54.2% (Cmax range = 0.92-6.37) and 37.4% (AUC0-t = 5.34-15.01 h*ng/mL) for THC and 75.7% (Cmax range 0.34-3.39 ng/mL) and 46.6% (AUC0-t = 2.40-13.19 h*ng/mL) for CBD respectively.There is a high degree of variability in pharmacokinetic parameters within patients following single and repeat dosing. Of 12 subjects who received four sprays of Sativex as a single dose, eight had reductions in Cmax after nine days of multiple dosing, whilst three had increases (1 drop-out). For CBD, seven had reductions in Cmax after multiple dosing, whilst four had increases.When Sativex is administered oromucosally, plasma levels of THC and other cannabinoids are lower compared with the levels achieved following inhalation of cannabinoids at a similar dose. A dose of 8 mg of vaporised THC extract, administered by inhalation resulted in mean plasma Cmax of more than 100 ng/mL within minutes of administration, with significant psychoactivity.
Table to show PK parameters for Sativex, for vaporised THC extract and smoked cannabis
|Cmax THC ng/mL||Tmax THC minutes||AUC (0-t) THC ng/mL/min|
|Sativex (providing 21.6 mg THC)||5.40||60||1362|
|Inhaled vaporised THC extract (providing 8 mg THC)||118.6||17.0||5987.9|
|Smoked cannabis* (providing 33.8 mg THC)||162.2||9.0||No data|
DistributionAs cannabinoids are highly lipophilic, they are quickly absorbed and distributed into body fat. The resultant concentrations in the blood following oromucosal administration of Sativex are lower than those obtained by inhaling the same dose of THC because absorption is slower and redistribution into fatty tissues is rapid. Additionally some of the THC undergoes hepatic first pass metabolism to 11-OH-THC, the primary metabolite of THC, and CBD similarly to 7-OH-CBD. Protein binding of THC is high (~97%). THC and CBD may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream, then metabolised and excreted via the urine and faeces.
MetabolismTHC and CBD are metabolised in the liver. Additionally some of the THC undergoes hepatic first pass metabolism to 11-OH-THC, the primary metabolite of THC, and CBD similarly to 7-OH-CBD. Human hepatic P450 2C9 isozyme catalyses the formation of 11-OH-THC, the primary metabolite, which is further metabolised by the liver to other compounds including 11-nor-carboxy-Δ9-THC (THC-COOH), the most abundant metabolite in human plasma and urine. The P450-3A subfamily catalyses the formation of other hydroxylated minor metabolites. CBD is extensively metabolised and more than 33 metabolites have been identified in urine. The major metabolic route is hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups. The major oxidized metabolite identified is CBD-7-oic acid containing a hydroxyethyl side chain.See section 4.5 for information on drug interaction and metabolism by the cytochrome P450 enzyme system.
EliminationFrom clinical studies with Sativex, a non-compartmental PK analysis shows that the first order terminal elimination half life from plasma is 1.94, 3.72 and 5.25 hours for THC and 5.28, 6.39 and 9.36 for CBD following the administration of 2, 4 and 8 sprays respectively.From the literature, elimination of oral cannabinoids from plasma is bi-phasic with an initial half-life of approximately four hours, and the terminal elimination half-lives are of the order of 24 to 36 hours or longer. Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life.
GW Pharma Ltd
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