4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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.

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 (see section 4.4).

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).

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 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.

Day

Number of sprays in the morning

Number of sprays in the evening

Total number of sprays per day

1

0

1

1

2

0

1

1

3

0

2

2

4

0

2

2

5

1

2

3

6

1

3

4

7

1

4

5

8

2

4

6

9

2

5

7

10

3

5

8

11

3

6

9

12

4

6

10

13

4

7

11

14

5

7

12

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 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.

Paediatric population

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 (see section 5.1).

Elderly

No specific studies have been carried out in elderly patients, although patients up to 90 years of age have been included in clinical trials. Elderly patients may be more prone to develop some CNS adverse reactions (see section 4.4).

Hepatic 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 5.2).

Renal impairment

No data with multiple dosing are available in subjects with renal impairment. Lower daily doses of Sativex may be needed in patients with moderate or severe renal impairment because of increased exposures observed in a severe renal impairment study (see section 5.2).

Frequent clinical evaluation by a clinician is recommended in both hepatic and renal patient populations.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Dizziness

Mild or moderate dizziness is commonly reported. This most frequently occurs in the first few weeks of treatment.

Cardiovascular effects

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.

Neuropsychiatric symptoms

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 symptoms have completely resolved.

Risk of falls and central nervous system (CNS) adverse reactions

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 could potentially have an impact on various aspects of personal safety.

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.

Until further information is available, caution should be taken when treating patients with a history of epilepsy, or recurrent seizures.

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.

Substance use disorder, substance misuse or dependence

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.

Application site reactions

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 in clinical trials but neither was confirmed histologically; a third case was unrelated. 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.

Travelling with medication

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.

Excipients

Each 100 microlitre of Sativex contains up to 40 mg of ethanol, equivalent to 50% by volume ethanol, that is approximately 480 mg per maximal daily dose (for an adult weighing 70 kg) equivalent to around 10 mL of beer or 5 mL 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.

4.5. Interaction with other medicinal products and other forms of interaction

Potential for Sativex to affect other drugs/medicines

Effect of Sativex on midazolam

In an open-label, fixed-sequence crossover clinical study, co-administration of multiple doses of Sativex with a sensitive CYP3A4 substrate (midazolam) did not result in changes in plasma concentrations of midazolam compared to midazolam administered alone. No clinically relevant effect on the pharmacokinetics of the CYP3A4 substrates is therefore expected.

Cytochrome P-450 enzyme inhibition

In vitro, Sativex was observed to be a reversible inhibitor of 1A2, 2B6, 2C9 and 2C19 at concentrations far in excess of those likely to be achieved clinically.

Cytochrome P-450 enzyme induction

Data from an in vitro CYP induction study indicated that plasma concentrations of THC and CBD arising from clinical doses of Sativex, could be sufficient to cause induction of CYP1A2 and CYP2B6 at the mRNA level. When sensitive CYP1A2 and CYP2B6 substrates are co-administered with Sativex, review of their dosing regimen is advised.

UGT enzymes

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.

Strong CYP3A4 inhibitor

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).

Strong CYP2C9 inhibitor

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.

Strong CYP3A4 inducer

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.

General

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.

Hormonal contraceptives

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.

4.6. Fertility, pregnancy and lactation

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 (see section 5.3).

Therefore, men and women of childbearing 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.

Pregnancy

Sativex should not be used during pregnancy unless the potential risks to the foetus and/or embryo are considered to be outweighed by the benefit of treatment.

Breast-feeding

Available pharmacodynamics / toxicological data in animals have shown excretion of Sativex and its metabolites in milk (see section 5.3).

A risk to the breastfed child cannot be excluded. Sativex is contraindicated during breast-feeding (see section 4.3).

Fertility

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 (see section 5.3).

4.7. Effects on ability to drive and use machines

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 their ability to drive.

• They should not drive until they know how the medicine affects them.

• It is an offence to drive while under the influence of this medicine.

• However, they would not be committing an offence (called 'statutory defence') if:

o the medicine has been prescribed to treat a medical problem, and

o they 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 their ability to drive safely.

4.8. Undesirable effects

The Sativex clinical program has so far involved over 1 500 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).

MedDRa SOC

Very Common ≥ 1/10

Common ≥ 1/100 to < 1/10

Uncommon≥ 1/1 000 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

Vascular disorders

hypertension

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

* 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 via the Yellow Card Scheme - website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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.