CD4.1 medicine

Sativex is an authorised medicine and therefore is not part of the MCAP (Medicinal Cannabis Access Programme). This is a CD4.1 medicine, and so the usual CD4.1 prescription writing requirements apply, including: the name of the controlled drug; the dose to be taken; the form; strength; and in both words and figures, either the total quantity of the drug, or preparation or the number of dosage units to be supplied — this is not required in the practitioner’s own handwriting. In the case of a prescription for a total quantity intended to be dispensed in instalments, the prescription must specify the number of instalments and the intervals at which the instalments may be dispensed.

The requirements to store in the controlled drugs safe or to keep a record in the controlled drugs register do not apply to CD4.1 medicines.

Mode of action

As part of the human endocannabinoid system, 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 (for example, reduce effects of excitatory neurotransmitters such as glutamate). In animal models of MS and spasticity, CB receptor agonists have been shown to improve limb stiffness and motor function.

Posology and route of administration

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. Sativex is not recommended for use in children under 18 years of age.

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.

Sativex is for oromucosal use only. 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.

It can take up to two weeks to find the optimal dose and undesirable effects can occur during this time, most commonly dizziness. These effects are usually mild and resolve in a few days. However, physicians should consider maintaining the current dose, reducing the dose or interrupting 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.

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 4.00 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.

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.

A thorough evaluation of the severity of 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 is not seen during the four weeks, 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.

Contraindications

Sativex is contraindicated in patients:

• 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; or
• Who are breastfeeding.

Warnings and precautions for use

• 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. When the recommended dose titration schedule was used, the incidence of dizziness and fatigue in the first four weeks was much reduced;
• Alterations in pulse rate and blood pressure have been observed so caution during initial dose titration is essential. Fainting episodes have been observed. Use of Sativex is not recommended in patients with serious cardiovascular disease;
• 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;
• Disorientation, 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;
• In patients with significant impaired hepatic or renal function the effects of Sativex may be exaggerated or prolonged;
• 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;
• 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. However, patients should be warned of this possibility;
• Sativex may reduce the effectiveness of hormonal contraceptives. Women of childbearing potential must use highly effective contraception while taking Sativex;
• 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;
• Patients who have a history of substance abuse, may be more prone to abuse Sativex as well;
• The abrupt withdrawal of long-term Sativex treatment has not resulted in 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 type reactions may occur and consist of mainly mild to moderate stinging at the time of application. 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 encouraged to check the legal status before travelling with Sativex as it may not be legal for them to possess the product in some countries;
• 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; and
• 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.

HPRA authorisation and pack size details

Sativex Oromucosal Spray was first authorised by the HPRA in 2014 and has been available in Ireland, but without reimbursement, until now. The High-Tech number is 89296. The medicine is available in a pack size of 3 x 10ml sprays. Each 10ml pack size allows delivery after priming of up to 90 actuations (sprays) of 100 microlitres.

The spray should be stored in the refrigerator (2-8C). Once opened and in use, refrigeration is not necessary, however it should not be stored above 25°C.  Sativex should be discarded 42 days from the date of first opening.