SATIVEX

1 Dosing Considerations • SATIVEX® is for buccal use only. • The spray should be directed to below the tongue, or towards the inside of the cheeks. The site should be varied. • The patient should be advised not to direct the spray towards the pharynx and not to inhale the spray.

It must not be sprayed into the nose. 2 Recommended Dose and Dosage Adjustment Treatment initiation and stabilization • On day one of treatment, patients should take one spray during the morning and one spray during the afternoon/evening.

The morning dose can be taken at any time between waking up and 12 noon and the afternoon dose can be taken at any time between 4 pm and bedtime. • On subsequent days the patient may gradually increase the total number of sprays, by one spray each day, as needed and tolerated.

There should be at least a 15 minute gap between sprays. During initial titration, sprays should be evenly spread out over the day. • If unacceptable adverse reactions such as dizziness or other CNS-type reactions develop at any time, dosing should be suspended until they have resolved.

Some patients may be able to continue therapy at the dose reached by increasing the interval between doses; others may require their subsequent doses reduced. Patients should then carefully re- titrate to a tolerated dosage regimen that gives acceptable relief.

Page 5 of 38 Protected B / Protégé B Following the titration period, patients are advised to maintain the optimal dose achieved. Re- titration upwards or downwards may be appropriate if there are any changes in the severity of the patient’s conditions, changes in his/her concomitant medication or if unacceptable side effects develop.

The usual dose ranges between 4-8 sprays daily. The majority of patients require 12 sprays or less; dosage should be adjusted as needed and tolerated. There is limited experience with doses higher than 12 sprays per day. Some patients may require and may tolerate a higher number of sprays.

1 Priming 1. Shake the vial gently before use. 2. Remove the protective cap. 3. Holding the vial in an upright position, prime the SATIVEX® vial by pressing on the actuator two or three times firmly and quickly, directing into a tissue until a fine spray appears.

Important - Point the spray safely away when priming it into a tissue. Do not prime it near children, pets or an open flame. 2 Administration 1. Shake the vial gently before use. 2. Remove the protective cap. 3. Hold the vial in the upright position and direct into the mouth.

1 Adverse Reaction Overview SATIVEX® has been administered to 805 multiple sclerosis patients in placebo-controlled studies and to 1016 patients during long-term open-extension studies. Over 300 subjects with MS have more than six months exposure, and 231 subjects with MS have been exposed to SATIVEX® for over one year.

9%). 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from Page 12 of 38 Protected B / Protégé B clinical trials is useful for identifying drug-related adverse events and for approximating rates. The following data summarise the adverse events in patients in clinical trials with various neurological conditions.

7% on placebo. In most patients, adverse events have resolved without treatment, and some on a reduction of dosage of SATIVEX®. The studies from which these figures are derived incorporate a period of titration to optimal therapeutic and/or maximum tolerated dose during which unwanted effects are likely to be maximal.

Because SATIVEX® is self-titrated to effect, patients are likely to experience a higher incidence of adverse events during the titration period than when the optimal dose is established. Treatment-emergent adverse events that occurred in 1% or more of patients treated with SATIVEX®, and at an incidence greater than (or equal to) 1% more frequently than placebo, in the acute phase in all Phase III trials, are given below in Tables 1 and 2.

Table 1 includes all adverse events related to the application site, as the placebo used in studies contained the same excipients (ethanol and propylene glycol) as used in SATIVEX®. 1 Application Site Application site type events were reported by approximately 14% of patients receiving SATIVEX® or placebo.

Please see the Serious Warnings and Precautions Box at the beginning of Part I:

Health Professional Information. General During the initial self-titration period, patients may experience unacceptable adverse events, including dizziness. These should resolve with down-titration or interruption of treatment (see “OVERDOSAGE, Signs and Symptoms”).

Careful dose titration and monitoring are advised if SATIVEX® is used in patients on a drug product containing fentanyl, or its analogues such as alfentanil and sufentanil (see DRUG INTERACTIONS). Care should be taken with sedatives, drugs with sedating or psychotropic effects and hypnotics as co-administration with SATIVEX® may have an additive effect.

Buccal Mucosa Regular inspection of the oral mucosa is advised. Patients should be advised not to continue spraying on to sore or inflamed mucosa. Administration site irritation was common both during short-term and long-term use of SATIVEX®.

Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Buccal Buccal spray delta-9-tetrahydrocannabinol 27mg/mL (from Tetranabinex® - Cannabis sativa L. extract) and cannabidiol 25mg/mL (from Nabidiolex® - Cannabis sativa L.

extract) Ethanol anhydrous Peppermint oil Propylene glycol Page 8 of 38 Protected B / Protégé B Carcinogenesis and Mutagenesis See Part II – TOXICOLOGY. Cardiovascular Cannabinoids have cardiovascular effects that include tachycardia, and transient changes in blood pressure, including episodes of postural hypotension.

Use of SATIVEX® is contraindicated in patients with pre-existing cardiovascular disease, such as ischaemic heart disease, arrhythmias, poorly controlled hypertension or severe heart failure. Dependence/Tolerance Recreational cannabis is known to produce dependence in some users.

THC is a psychotropic agent which may produce physical and psychological dependence and has the potential to be abused. SATIVEX® contains THC and should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence.

SATIVEX® is contraindicated in: • patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.

• patients with cardiovascular diseases, such as ischemic heart disease, arrhythmias, poorly controlled hypertension or severe heart failure • patients with a history of schizophrenia or any other psychotic disorder • children under 18 years of age • women of child-bearing potential not on a reliable contraceptive or fertile men not on a reliable contraceptive (see “Use in Women of Child-Bearing Potential”) • pregnant or nursing women (see “Use in Women of Child-Bearing Potential”).

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