Real-life data confirm nabiximols as an effective and well-tolerated treatment option for resistant MSS in clinical practice. Sativex Oromucosal Spray – Summary of Product Characteristics (SmPC) by GW Pharma Ltd
Nabiximols (THC/CBD oromucosal spray, Sativex®) in clinical practice–results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity
Background: Nabiximols (Sativex®), a cannabinoid-based oromucosal spray, is an add-on therapy for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other medications. The primary objective was to provide real-life observational data of clinical experience of nabiximols in contrast to formal clinical trials of effectiveness.
Methods: This was an observational, prospective, multicenter, non-interventional study with a follow-up period of 3-4 months, conducted in routine care setting in Germany. Patients with moderate to severe MSS were included at nabiximols’ initiation. Structured documentation forms, questionnaires and validated instruments were used for data collection at inclusion, 1 and 3 months after inclusion.
Results: Overall, 335 patients were assessed of whom 276 fitted the criteria and were included in the effectiveness analysis. After 1 month, nabiximols provided relief of resistant MSS in 74.6% of patients according to specialist assessment; mean spasticity 0-10 numerical rating scale (NRS) score decreased from 6.1 ± 1.8 to 5.2 ± 2.0 points; in patients with NRS improvement ≥20% mean NRS score decreased by 40%. After 3 months, 55.3% of patients had continued to use nabiximols and the mean NRS score had decreased by 25% from baseline. 17% of patients reported adverse events.
Conclusion: Real-life data confirm nabiximols as an effective and well-tolerated treatment option for resistant MSS in clinical practice.
© 2014 S. Karger AG, Basel.
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Sativex Oromucosal Spray
38-44 mg and 35-42 mg of two extracts (as soft extracts) from Cannabis sativa L., folium cum flore (Cannabis leaf and flower) corresponding to 27 mg delta-9-tetrahydrocannabinol and 25 mg cannabidiol.
Extraction solvent: Liquid carbon dioxide.
Each single100 microlitre spray contains:
2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD) from Cannabis sativa L.
Excipient(s) with known effect:
Each 100 microlitre spray contains up to 40 mg ethanol.
Each 100 microlitre spray contains 52 mg propylene glycol.
For the full list of excipients, see section 6.1.
Oromucosal spray, solution.
A yellow/brown solution in a spray container.
Sativex is indicated as treatment for symptom improvement in adult 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.
Sativex is for oromucosal use only.
Sativex is intended to be used in addition to the patient’s current anti-spasticity medication.
Treatment must be initiated and supervised by a physician with specialist expertise in treating this patient population.
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 2 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).
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 1 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.
Number of sprays in the morning
Number of sprays in the evening
(Total number of sprays per day)
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 physician
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. 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.
Sativex is not recommended for use in children or adolescents below 18 years of age. A randomised placebo-controlled trial was performed in children and adolescents with cerebral palsy or traumatic central nervous system injury and its results regarding efficacy were negative. The data is described in section 5.1
No 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 impairment
No data with multiple dosing are available in subjects with hepatic impairment. Sativex can be administered to patients with mild hepatic impairment without any dose adjustment. Administration to patients with moderate or severe hepatic impairment is not advised due to the lack of information on the potential for accumulation of THC and CBD with chronic dosing (see section 4.4 and 5.2).
There are no studies in patients with impaired 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).
Sativex is contraindicated in patients:
• With hypersensitivity to cannabinoids or to any of the excipients listed in section 6.1.
• 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).
Mild or moderate dizziness is commonly reported. This most frequently occurs in the first few weeks of treatment.
Alterations in pulse rate and blood pressure have been observed following initial dose introduction so caution during initial dose titration is essential. Fainting episodes have been observed with use of Sativex. Use of Sativex is not recommended in patients with serious cardiovascular disease. However, following dosing in healthy volunteers with Sativex up to 18 sprays twice daily, there were no clinically relevant changes in QTc, PR or QRS interval duration, heart rate, or blood pressure.
Until further information is available, caution should be taken when treating patients with a history of epilepsy, or recurrent seizures.
Psychiatric symptoms such as anxiety, illusions, changes in mood, and paranoid ideas have been reported during treatment with Sativex. These are likely to be the result of transient CNS effects and are generally mild to moderate in severity and well tolerated. They can be expected to remit on reduction or interruption of Sativex medication.
Disorientation (or confusion), hallucinations and delusional beliefs or transient psychotic reactions have also been reported and in a few cases a causal association between Sativex administration and suicidal ideation could not be ruled out. In any of these circumstances, Sativex should be stopped immediately and the patient monitored until the symptom has completely resolved.
There is a risk of an increase in incidence of falls in patients whose spasticity has been reduced and whose muscle strength is insufficient to maintain posture or gait. In addition to an increased risk of falls, the CNS adverse reactions of Sativex, particularly in elderly patients, could potentially have an impact on various aspects of personal safety, such as with food and hot drink preparation.
Although there is a theoretical risk that there may be an additive effect with muscle-relaxing agents such as baclofen and benzodiazepines, thereby increasing the risk of falls, this has not been seen in clinical trials with Sativex. However, patients should be warned of this possibility.
Women of childbearing potential
Sativex may reduce the effectiveness of hormonal contraceptives (See section 4.5)
Women of childbearing potential must use highly effective contraception while taking Sativex. It is currently unknown whether Sativex may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should use an additional method of contraception for the duration of therapy and for three months after discontinuation of therapy (see sections 4.5 and 4.6).
Pregnancy and lactation: refer to section 4.6
Patients who have a history of substance abuse, may be more prone to abuse Sativex as well (see section 5.1).
The abrupt withdrawal of long-term Sativex treatment has not resulted in a consistent pattern or time-profile of withdrawal-type symptoms and the likely consequence will be limited to transient disturbances of sleep, emotion or appetite in some patients. No increase in daily dosage has been observed in long-term use, and patient self-reported levels of ‘intoxication’ are low. For these reasons, dependence on Sativex is unlikely.
Adverse reactions have been reported which could be associated with the route of administration of the medicine. Application site type reactions consisted of mainly mild to moderate stinging at the time of application. Common application site reactions include application site pain, oral pain and discomfort, dysgeusia, mouth ulceration and glossodynia. Two cases of possible leukoplakia were observed but neither was confirmed histologically; a third case was unrelated. In view of this, patients who observe discomfort or ulceration at the site of application of the medicine are advised to vary the site of application within the mouth and should not continue spraying onto sore or inflamed mucous membrane. Regular inspection of the oral mucosa is also advised in long-term administration. If lesions or persistent soreness are observed, medication should be interrupted until complete resolution occurs.
Patients should be advised that if they travel to another country it may not be legal for them to take this medicine into some countries. They should be encouraged to check the legal status before travelling with Sativex.
Each actuation contains up to 40 mg of ethanol, equivalent to 50% by volume of ethanol, that is approximately 480mg per maximal daily dose (for an adult weighing 70 kg) equivalent to around 10 mL of beer or 5mL of wine. The small amount of alcohol in this medicine will not have any noticeable effects.
This medicine contains 52 mg propylene glycol in each 100 microlitre spray
Potential for Sativex to affect other drugs/medicines
In vitro, Sativex was observed to be a reversible inhibitor of CYP3A4, 1A2, 2B6, 2C9 and 2C19 at concentrations far in excess of those likely to be achieved clinically. In vitro investigations also demonstrated that Sativex had the potential for time dependent inhibition of CYP3A4 at clinically relevant concentrations. The rate of the inactivation of the CYP3A4 enzyme is expected to be rapid.
Co-administration of Sativex with other CYP3A4 substrates may result in an increase in plasma concentration of the concomitant drug. A review of the dosing regimen of such medication is advised.
An in vitro, CYP induction study data indicated that plasma concentrations of THC and CBD arising from clinical doses of Sativex, could be sufficient to cause induction of CYP1A2, 2B6 and CYP3A4 at the mRNA level. Co-administration of Sativex with other drugs that are metabolised through these cytochrome P-450 enzymes may accelerate the metabolism and reduce the activity of these other drugs such as coumarins, statins, beta-blockers and corticosteroids. When sensitive CYP substrates are co-administered with Sativex, review of their dosing regimen is advised.
In an in vitro study Sativex was found to inhibit the UGT enzymes UGT1A9 and UGT2B7 at concentrations that could be achieved in the clinic. Care should be taken when prescribing Sativex with concomitant medications which are solely metabolised by both or either of these UGTs (e.g. Propofol and certain antivirals). Patients with genetic glucuronidation disorders (e.g. Gilbert’s disease) may exhibit increased serum concentrations of bilirubin and must be treated with caution when Sativex is co-administered.
Potential for Sativex to be affected by other drugs/medicines
The two main components of Sativex, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are metabolised by the cytochrome P-450 enzyme system.
Cytochrome P-450 enzyme inhibition
Concomitant treatment with the CYP3A4 inhibitor ketoconazole produced an increase in Cmax and AUC of THC (1.2- and 1.8-fold, respectively), its primary metabolite (3- and 3.6-fold, respectively) and of CBD (2- and 2-fold, respectively). Therefore, if concomitant drug treatment with CYP3A4 inhibitors (e.g. itraconazole, ritonavir, clarithromycin) is started or stopped during treatment with Sativex, a new dose titration may be required (see section 4.2).
Concomitant treatment of Sativex (4 sprays) with the CYP2C9 inhibitor fluconazole (200 mg capsule) resulted in an increase in mean THC Cmax of 22 % and mean AUC of 32 %. Exposure to the metabolite 11-OH-THC also increased by approximately 2.1-fold and 2.5-fold for Cmax and AUC respectively, indicating that fluconazole may inhibit its subsequent metabolism. The Cmax of CBD also increased by approximately 40 % but there was no significant change in AUC. There was no significant change in exposure to 7-OH-CBD either although an increase in the minor circulating metabolite of CBD, 6-OH CBD was noted (by up to 2.2-fold based on Cmax and AUC) .The clinical relevance of this drug-drug interaction is not fully understood, however care should be taken when co-administering Sativex with potent CYP2C9 inhibitors as it may lead to an increase in exposure to THC, CBD and their metabolites.
Cytochrome P-450 enzyme induction
Following treatment with the CYP3A4 inducer rifampicin reductions in Cmax and AUC of THC (40% and 20% reduction, respectively), its primary metabolite (85% and 87% reduction, respectively) and CBD (50% and 60% reduction, respectively) were observed. Therefore, concomitant treatment with strong enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s Wort) should be avoided whenever possible. If deemed necessary, careful titration is recommended, notably within the two weeks following the stop of the inducer.
Care should be taken with hypnotics, sedatives and drugs with potential sedating effects as there may be an additive effect on sedation and muscle relaxing effects.
Although there has been no greater rate of adverse events in patients already taking anti-spasticity agents with Sativex, care should be taken when co-administering Sativex with such agents since a reduction in muscle tone and power may occur, leading to a greater risk of falls.
Sativex may interact with alcohol, affecting co-ordination, concentration and ability to respond quickly. In general, alcoholic beverages should be avoided whilst using Sativex, especially at the beginning of treatment or when changing dose. Patients should be advised that if they do drink alcohol while using Sativex the additive CNS effects may impair their ability to drive or use machines, and increase the risk of falls.
Sativex has been observed to induce drug metabolizing enzymes and transporters in vitro.
Sativex may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add an additional second barrier method.
There is insufficient experience in humans regarding the effects of Sativex on reproduction. Although no effect has been seen on fertility, independent research in animals found that cannabinoids affected spermatogenesis (section 5.3).
Therefore men and women of child bearing potential should take reliable contraceptive precautions for the duration of therapy and for three months after discontinuation of therapy.
Patients on hormonal contraceptives should be advised to use an additional alternative, non-hormonal/reliable barrier method of birth control during Sativex therapy.
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 treatment.
Available 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).
In 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.
Sativex may produce undesirable effects such as dizziness and somnolence which may impair judgement and performance of skilled tasks. Patients should not drive, operate machinery or engage in any hazardous activity if they are experiencing any significant CNS effects such as dizziness or somnolence. Patients should be aware that Sativex has been known to cause a few cases of loss of consciousness.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called ‘statutory defence’) if:
o The medicine has been prescribed to treat a medical problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
o It was not affecting your ability to drive safely
The Sativex clinical program has so far involved over 1500 patients with MS in placebo controlled trials and long-term open label studies in which some patients used up to 48 sprays per day.
The most commonly reported adverse reactions in the first four weeks of exposure were dizziness, which occurs mainly during the initial titration period, and fatigue. These reactions are usually mild to moderate and resolve within a few days even if treatment is continued (see section 4.2). When the recommended dose titration schedule was used, the incidence of dizziness and fatigue in the first four weeks was much reduced.
The frequency of adverse events with a plausible relationship to Sativex, from placebo controlled trials in patients with MS, according to System Organ Classes (SOC) are given below (some of these adverse events may be part of the underlying condition).
Infections and infestations
Metabolism and nutrition disorders
anorexia (including appetite decreased), appetite increased
depression, disorientation, dissociation, euphoric mood,
hallucination (unspecified, auditory, visual), illusion, paranoia, suicidal ideation, delusional perception*
Nervous system disorders
amnesia, balance disorder, disturbance in attention, dysarthria, dysgeusia, lethargy, memory impairment somnolence
Ear and labyrinth disorders
Respiratory, thoracic and mediastinal 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
application site pain, asthenia, feeling abnormal, feeling drunk, malaise
application site irritation
Injury, poisoning and procedural complaints
* reported in long-term open-label studies:
A single case of ventricular bigeminy has been reported though this was in the context of acute nut allergy.
See also sections 4.4, 4.5 and 4.7.
Reporting of suspected adverse reactions
Reporting 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 viaYellow Card Scheme – Website: www.mhra.gov.uk/yellowcard
There is no experience of deliberate overdose with Sativex in patients. However, in a Thorough QT study of Sativex in 257 subjects, with 18 sprays taken over a 20-minute period twice daily, signs and symptoms of overdose/poisoning were observed. These consisted of acute intoxication produced CB1 agonism type reactions including dizziness, hallucinations, delusions, paranoia, tachycardia or bradycardia with hypotension. In three of 41 subjects dosed at 18 sprays twice a day, this presented as a transient toxic psychosis which resolved upon cessation of treatment. Twenty-two subjects who received this substantial multiple of the recommended dose successfully completed the 5-day study period.
In the case of overdose, treatment should be symptomatic and supportive.
Pharmacotherapeutic Group: Other Analgesics and Antipyretics
ATC Code: N02BG10
The European Medicines Agency has deferred the obligation to submit the results of studies with Sativex in one or more subsets of the paediatric population in spasticity. See section 4.2 for information on paediatric use.
Mechanism of action
As 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.
Sativex 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 status
Of 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: