Consumer medicine information

Sativex

Cannabidiol; Tetrahydrocannabinol; Nabiximols

BRAND INFORMATION

Brand name

Sativex

Active ingredient

Cannabidiol; Tetrahydrocannabinol; Nabiximols

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sativex.

What is in this leaflet

This leaflet answers some common questions about SATIVEX.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up-to-date information on the medicine. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you using SATIVEX against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What SATIVEX is used for

SATIVEX is used to improve symptoms related to muscle stiffness (spasticity) in multiple sclerosis (MS). Health professionals sometimes talk about 'spasticity' when describing the muscle stiffness that you may experience. Spasticity means there is an increase in 'muscle tone'. In other words, when the muscle is moved, there is more resistance to this movement than there normally would be. Muscles feel more rigid.

SATIVEX is used when other medicines have not worked to relieve your muscle stiffness.

SATIVEX is a mouth spray (oromucosal spray) which contains the active ingredient nabiximols which consists of cannabis extracts called cannabinoids.

Your doctor may prescribe SATIVEX for another purpose.

Ask your doctor if you have any questions about why SATIVEX has been prescribed for you.

This medicine is only available with a doctor's prescription.

Dependence on SATIVEX is unlikely.

Before you use SATIVEX

When you must not use it

Do not use SATIVEX if:

  • You are allergic (hypersensitive) to cannabis extracts or any of the other ingredients of SATIVEX (listed in Section 6).
    Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
  • You or anyone directly related to you has any mental health problems such as schizophrenia, psychosis or other significant psychiatric disorder. This does not include depression due to your multiple sclerosis.
  • You are breast-feeding.
  • Do not use SATIVEX during pregnancy, unless advised to by your doctor.
  • Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If you are pregnant or breast-feeding always ask your doctor for advice before taking any medicine.

Do not use this medicine if any of the above applies to you.

If you are not sure whether you should start using SATIVEX, talk to your doctor.

Before you start to use it

Tell your doctor if:

  • You are pregnant or plan to become pregnant.
  • You are under 18 years of age.
  • You have epilepsy or regular fits (seizures).
  • You have liver or kidney problems.
  • You have a serious heart problem such as angina, a previous heart attack, poorly controlled high blood pressure or a problem with your heart rate or heart beat.
  • You are elderly, especially if you have problems doing everyday activities such as making hot food and drinks.
  • You have previously abused any drug or substance.

If you have not told your doctor about any of the above, tell them before you start using SATIVEX.

Important information about some of the ingredients of SATIVEX

  • SATIVEX contains a small amount of ethanol (alcohol). The amount of alcohol in the maximum daily dose for most people (12 sprays) is equal to about one teaspoon of wine. This should normally be an insignificant amount but you may need to take this into account if you have to avoid alcohol completely.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. You should also tell any health professional who is prescribing a new medication for you that you are taking SATIVEX.

Some medicines may interfere with SATIVEX. These include:

  • Medicines to relax your muscles such as baclofen or diazepam. This is because taking SATIVEX with these medicines may increase the risk of you falling over.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before using SATIVEX.

If you see a different doctor or go into hospital, let them know all the medicines you are using.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking SATIVEX.

How to use SATIVEX

Always use SATIVEX exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Only use SATIVEX in your mouth – on the inside of your cheek or under your tongue.

You can use SATIVEX with or without food.

Your 4 week trial of SATIVEX
Only a specialist physician can start you on treatment with SATIVEX. The specialist will assess you from time to time to see if you should carry on taking it.

  • Before you start using SATIVEX your specialist doctor will conduct a thorough assessment of how bad your spasticity is and how it has responded to other treatments.
  • You will then have a 4 week trial of SATIVEX after which your specialist will do another assessment to see whether SATIVEX is helping you.
  • Only if you have shown a significant improvement in your spasticity related symptoms after these 4 weeks should you continue to be treated with SATIVEX.

Your doctor will assess you from time to time to see if you should carry on taking it.

Opening your spray and getting it ready to use

  1. Take your spray out of the refrigerator (see ’Storage’ for important information on storing SATIVEX).
  2. Write the date that you open your spray on the sticker provided in the box. Stick the sticker on the spray so that you can check the date. Do not use the spray after it has been open for more than 6 weeks (42 days).
  3. Shake the spray container gently before use.
  4. Remove the protective cap.
  5. Hold the spray between your thumb and second finger. Put your first finger on the nozzle.
  6. Holding it upright, practice spraying into a tissue 2 or 3 times until a fine spray appears. These sprays prime the pump and ensure it is working properly.
  7. The spray is now ready to use. You will not need to do any more priming sprays until you open a new spray container.

Using your spray

  1. Hold the spray between your thumb and second finger. Put your first finger on the nozzle.
  2. Hold it upright and point into your mouth. Point the nozzle under your tongue or onto the inside of your cheek. Change the area in your mouth where you spray each time. This helps to stop any discomfort in one place.
  3. Press the nozzle down firmly. Do not take more than one spray at a time, even if you feel that you only got a small amount of spray.
  4. Replace the protective cap.

If you get spray in your eyes by accident, wash them as soon as possible with water.

  • Do not breathe in the spray.
  • Do not spray near children or pets.
  • Do not use the spray near naked flames or heat sources.

How much to use

Working out how much to use
The number of sprays you need each day depends on you as an individual. Each person needs a different number of sprays to give them the best relief from their muscle stiffness, with the fewest unwanted effects.

When you first start using SATIVEX, you need to follow the days and times in the table below until you find the best number of sprays for you.

Stop increasing your sprays when you find the best number of sprays for you. This may only take a few days or it may take up to 2 weeks. Aim to use this number of sprays each day. You can then spread your sprays evenly over the whole day.

  • Always leave at least 15 minutes between sprays.
  • Do not over-exert yourself during the first couple of days of using SATIVEX until you know how it affects you.
  • If you start to feel unwanted effects (usually dizziness) use one less spray each day until you find the best symptom relief with the fewest unwanted effects.
  • When you find the best number of sprays for you, aim to use this number each day. You can then spread your sprays out evenly over the whole day, in a way that suits you. Still leave at least 15 minutes between sprays.

Knowing if your spray is nearly empty

After the 3 priming sprays, your spray contains up to 90 measured sprays (10 mL). When the spray is becoming empty, the noise of the spray action may change. You may also find the spray feels different in your mouth. This is because your spray is nearly empty. When this happens you should open a new spray container.

How long to use it

Continue to use this medicine for as long as your doctor tells you to.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

If you forget to use it

If you forget a dose, use a spray as soon as you remember or when you feel you need a spray.

Do not use 2 sprays at the same time to make up for a missed spray.

If you have trouble remembering when to use your medicine, ask your pharmacist for hints.

If you use too much (overdose)

Australian patients:
Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much SATIVEX.

New Zealand patients:
Immediately telephone your doctor or the National Poisons Centre (telephone 0800 POISON or 0800 764 766), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much SATIVEX.

Do this even if there are no signs of discomfort or poisoning.

If you accidentally use more of this medicine than you normally do you may:

  • See or hear things that are not there (hallucinations).
  • Feel dizzy, sleepy or confused.
  • Feel your heart rate change.

If you get any of the above and they get serious, please tell your doctor or pharmacist.

While you are using SATIVEX

Things you must do

  • If you are about to be started on any new medicine tell your doctor that you are taking SATIVEX.
  • Take special care if you drink alcohol while using SATIVEX. Using SATIVEX and alcohol together may increase their effects (such as loss of balance or ability to respond quickly). If you drink alcohol with SATIVEX, see what effect it has on you. You can then decide how much alcohol you can drink.
  • Talk to your doctor before using this medicine if you are pregnant or plan to become pregnant.
  • Whether male or female you must use a reliable contraceptive method while using this medicine. Keep doing this for at least 3 months after your treatment has stopped.
  • If you have any further questions on the use of this product, ask your doctor or pharmacist.

Things you must not do

  • Do not give SATIVEX to anyone else, this medicine is for you. Even if they have the same condition as you, do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
  • Do not use SATIVEX while breast-feeding / do not use SATIVEX during pregnancy, unless advised to by your doctor.

Things to be careful of

Using SATIVEX with food and drink

  • Take special care if you drink alcohol while using SATIVEX. Using SATIVEX and alcohol together may increase their effects (such as loss of balance or ability to respond quickly). If you drink alcohol with SATIVEX, see what effect it has on you. You can then decide how much alcohol you can drink.
  • You can use SATIVEX with or without food.

Driving and using machines

Australia:

  • You must not drive or use machinery when you are taking SATIVEX.
  • SATIVEX may cause you to feel sleepy or dizzy, which may impair your judgment and performance of skilled tasks.

New Zealand:

  • You must not drive or use machinery when you first start to take SATIVEX and until you are established on a stable daily dose.
  • SATIVEX may cause you to feel sleepy or dizzy, which may impair your judgment and performance of skilled tasks. It has also rarely been reported to cause a brief loss of consciousness.
  • Once you are more used to taking SATIVEX and your dose is stable, you should still not drive or use machinery if SATIVEX causes effects such as sleepiness or dizziness that could impair your ability to perform these tasks. If you are not sure, do not drive or operate machines.

Foreign travel with SATIVEX

  • Check that it is legal for you to take this medicine into any countries you are travelling to and countries you are travelling through. SATIVEX is a Controlled Drug and its legal status will vary between countries.
  • Driving while taking SATIVEX might be illegal in some countries.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using SATIVEX.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

You are more likely to get side effects when you start your treatment. They are usually mild and wear off within a few hours.

If you get any of the following side effects, use less sprays or stop using SATIVEX until you feel normal again.

When you start using the medicine again, go back to the number of sprays where you did not feel these unwanted effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them. Ask your doctor or pharmacist to answer any questions you may have. Tell your doctor if you notice any of the following side effects and they worry you

Very Common (affecting more than 1 in 10 people)

  • feeling dizzy or tired

Common (affecting less than 1 in 10 people)

  • lack of energy or feeling weak or generally unwell
  • problems with your memory or having trouble concentrating
  • feeling abnormal or drunk
  • feeling sleepy or drowsy
  • blurred vision
  • constipation or diarrhoea
  • feeling or being sick
  • loss of balance or falling over
  • changed sense of taste or a dry mouth
  • mouth problems, including burning, pain or mouth ulcers

Uncommon (affecting less than 1 in 100 people)

  • tummy pain
  • sore throat or throat irritation
  • mouth or teeth changing colour
  • irritation where SATIVEX is sprayed
  • red and swollen mouth or peeling inside it. Do not keep spraying onto these areas.

Tell your doctor as soon as possible if you notice any of the following:

Common (affecting less than 1 in 10 people)

  • feeling depressed or disorientated
  • feeling over-excited or losing touch with reality
  • difficulty speaking
  • eating more or less than usual
  • seeing or hearing things that are not there (hallucinations)

Uncommon (affecting less than 1 in 100 people)

  • believing ideas that are not true
  • feeling that other people are against you
  • fast or irregular heart beats, also called palpitations
  • fainting.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following happen:

  • thoughts of suicide
  • you develop signs of allergy such as swelling of the face, lips, tongue or other part of the body; severe dizziness or fainting; redness, itching or rash on the skin.

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet. Some side effects may only be found when your doctor does tests from time to time.

After using SATIVEX

Storage

  • Do not use SATIVEX after the expiry date shown on the product packaging. The expiry date refers to the last day of that month.
  • Store unopened SATIVEX upright in its carton in a refrigerator (2°C to 8°C). If it is not stored in a refrigerator it will become unstable and is unlikely to work.
  • Store opened SATIVEX in an upright position below 25°C. Keep away from heat and direct sunlight.
  • Do not use SATIVEX after it has been open for 42 days (10 mL).
  • Unless your doctor tells you to, do not keep medicines that you no longer need.

Keep out of the reach and sight of children. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Medicines should not be disposed of via wastewater or household waste. Any unused medicine or medicine past its expiry date, as shown on the dispensing label or packaging, should be returned to the pharmacy.

Product description

What it looks like

SATIVEX is provided as a liquid in an amber 10 mL glass spray container with a brown plastic coating and a pump. The pump is protected with a plastic cap.

The number of measured sprays in the container is up to 90 sprays (after 3 priming sprays) for the 10 mL container.

SATIVEX is packed as 3 spray containers in each carton.

Ingredients

Active ingredients:
The active substances are cannabis extracts. Each millilitre (mL) contains 38-44 mg and 35-42 mg of two extracts (as soft extracts) from Cannabis sativa L., leaf and flower, corresponding to 27 mg/mL delta-9-tetra-hydrocannabinol (THC) and 25 mg/mL cannabidiol (CBD). Each 100 microlitre spray contains 2.7 mg THC and 2.5 mg CBD.

Inactive ingredients:
The other ingredients are ethanol absolute, propylene glycol and peppermint oil.

Sponsor Details

SATIVEX is supplied in Australia by:

Chiesi Australia Pty Ltd
Suite 3, 22 Gillman Street
Hawthorn East, VIC 3123

Australian Register Number: AUST R 181978

SATIVEX is supplied in New Zealand by:

Chiesi New Zealand Ltd
Bellingham Wallace Ltd
Suite 1, 470 Parnell Road
Parnell
Auckland 1052

Distributed in New Zealand by:

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Mangere
Auckland 2022

Email: [email protected]
Website: www.chiesi.com.au

SATIVEX is a registered trademark of GW Pharma Limited, United Kingdom.

Date of Preparation

This leaflet was prepared in October 2022.

Published by MIMS January 2023

BRAND INFORMATION

Brand name

Sativex

Active ingredient

Cannabidiol; Tetrahydrocannabinol; Nabiximols

Schedule

S8

 

1 Name of Medicine

Nabiximols.

2 Qualitative and Quantitative Composition

Each mL Sativex oromucosal spray contains:
80 mg of extracts (nabiximols) from Cannabis sativa L., folium cum flore (Cannabis leaf and flower), corresponding to 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD) and lesser amounts of other cannabinoids (56 mg total cannabinoids).
The name 'dronabinol' is used for pure, synthetically-derived delta-9-tetrahydrocannabinol rather than the extracted delta-9-tetrahydrocannabinol present in Sativex.
Extraction solvent: Liquid carbon dioxide.
Each 100 microlitre spray contains 2.7 mg THC and 2.5 mg CBD.
Each 100 microlitre spray also contains up to 0.04 g alcohol.
Sativex contains ethanol absolute, propylene glycol and peppermint oil as inactive ingredients.

3 Pharmaceutical Form

Sativex is supplied as a solution in a spray container and is for use as an oromucosal spray only.
The drug substances are produced from cultivated Cannabis sativa L. plants. The drug substances are partially purified extracts, therefore botanical drug substances (BDS). The plants have been specifically bred to produce two separate chemotypes, expressing their cannabinoid content as high delta-9-tetrahydrocannabinol (THC) or high cannabidiol (CBD) chemotypes. The physical descriptions of both THC BDS and CBD BDS are brown, viscous, semi-solid (soft) extracts with a characteristic odour of cannabis and are almost insoluble in water, but exhibit good solubility in most organic solvents.

4 Clinical Particulars

4.1 Therapeutic Indications

Sativex is indicated as treatment, for symptom improvement in 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 Dose and Method of Administration

Patients being considered for treatment with Sativex should be assessed by a neurologist or rehabilitation physician. Patients who then commence a trial of Sativex should be reassessed by a neurologist or rehabilitation physician after 4 weeks of treatment. Patients who do not show a clinically significant improvement in spasticity on reassessment should not continue Sativex.
Treatment must be initiated and supervised by a specialist neurologist or rehabilitation physician with expertise in treating patients with spasticity due to multiple sclerosis.
Sativex is for oromucosal use only.
Sativex is intended to be used in addition to the patient's current anti-spasticity medication.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Dosage.

Adults. 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 Interactions with Other Medicines and Other Forms of Interactions).

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 Table 1. 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. The maximum number of consecutive sprays must not exceed 7 within a 3 hour period.

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 was 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 must not exceed 12 sprays in any 24-hour period.

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 Pharmacodynamic Properties, Clinical trials). The value of long term treatment should be re-evaluated periodically.
Children. Sativex is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data.
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. 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. 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. Sativex can be administered to patients with mild hepatic impairment without any dose adjustment and cautiously to patients with moderate and severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use.)

Method of administration.

Priming.

The spray container needs to be primed before first use and if not used for more than 21 days. To this end, the spray container should be shaken gently and the protective cap removed. The vial then needs to be held in an upright position while the actuator is pressed firmly and quickly for two or three times, directing into a tissue until a fine spray appears. Normal use: 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.

4.3 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.
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. See Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

4.4 Special Warnings and Precautions for Use

Identified precautions.

Individual response to Sativex varies widely and patients being considered for treatment with Sativex should therefore be assessed by a neurologist or rehabilitation physician. Patients who then commence a trial of Sativex should be reassessed by a neurologist or rehabilitation physician after 4 weeks of treatment. Patients who do not show a clinically significant improvement in spasticity on reassessment should not continue Sativex.
Mild or moderate dizziness is commonly reported. This most frequently occurs in the first few weeks of treatment.
Sativex is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data.
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 adverse events.

Psychiatric adverse events including disorientation (4.1% vs 0.8%), depression (2.9% vs 2.0%), euphoric mood (2.2% vs 0.9%), and dissociation (1.7% vs 0.1%) occurred more frequently in patients given Sativex than in those given placebo in clinical trials. Approximately 10% more patients given Sativex experienced a psychiatric adverse event than those given placebo (17.6% vs 7.8%). Patients with a personal or family history of psychotic illness should not receive Sativex. Patients with a history of depression should be closely monitored and Sativex discontinued if clinically significant worsening of symptoms occurs on therapy.
In a few cases a causal association between Sativex administration and suicidal ideation could not be ruled out. In this circumstance, Sativex should be stopped immediately and the patient monitored until the symptom has completely resolved.
The maximum recommended dose should not be exceeded. Serious psychiatric adverse events including transient psychosis occurred in 4/41 healthy volunteers given 18 actuations of Sativex twice daily.
Sativex contains approximately 50% v/v of ethanol. Each actuation contains up to 0.04 g of ethanol. A small glass of wine (125 mL) of nominal ethanol content 12% v/v would contain approximately 12 g ethanol. Most patients respond at doses up to and including 12 sprays a day which would contain less than 0.5 g of ethanol, but may be harmful for those suffering from the more severe forms of alcohol use disorder.
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, 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 Interactions with Other Medicines and Other Forms of Interactions). 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.6 Fertility, Pregnancy and Lactation).

Pregnancy and lactation.

See Section 4.6 Fertility, Pregnancy and Lactation.
Patients who have a history of substance abuse may be more prone to abuse Sativex as well (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
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.

Use in hepatic impairment.

In a specific study in subjects with hepatic impairment, a single oromucosal dose of 4 sprays of Sativex (10.8 mg THC and 10 mg CBD) was well tolerated. Sativex can be administered to patients with mild hepatic impairment without any dose adjustment and cautiously to patients with moderate and severe hepatic impairment. Frequent evaluation by a clinician is recommended in this patient population (see Section 4.2 Dose and Method of Administration).
THC and CBD are metabolised in the liver, and approximately one third of the parent drugs and their metabolites are excreted in the urine (the remainder via the faeces). Several THC metabolites may be psychoactive. Thus, the systemic exposure and the effects of Sativex are dependent on both renal and hepatic function and in patients with significant impaired hepatic or renal function the effects of Sativex may be exaggerated or prolonged (see Section 5.2 Pharmacokinetic Properties, Metabolism). Frequent clinical evaluation by a clinician is recommended in these patient populations.

Use in renal impairment.

No specific studies have been carried out in patients with significant renal impairment, therefore if Sativex is used by such patients, frequent review by a clinician is recommended.

Use in the elderly (> 65 years).

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. In clinical trials patients aged over 65 years were three times more likely to have a CNS adverse event on Sativex than on placebo, and more than a third of all elderly subjects on active treatment had a CNS adverse event.

Paediatric use (< 18 years).

Sativex is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data.

Effect on laboratory tests.

During clinical trials with Sativex, no clinically relevant effects on laboratory tests were observed.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potential for Sativex to affect other drugs/medicines.

In an in vitro study, the two main components of nabiximols produced a broad-spectrum inhibition of most CYP450 enzymes at concentrations in excess of those likely to be achieved clinically. 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 medications is advised.
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, CYP2B6 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.

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 P450 enzyme system.
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 figures for CBD were 3.3-and 5.1-fold.

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 11-OH-THC (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 Dose and Method of Administration).

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 11-OH-THC (85% and 87% reduction, respectively), and CBD (50% and 60% reduction, respectively), were observed. Therefore, if concomitant drug treatment with strong enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John's Wort) is started or stopped during treatment with Sativex, a new dose titration may be required.
Concomitant treatment with the CYP2C19 inhibitor omeprazole resulted in no notable change in any of the pharmacokinetic parameters.
In vitro, the components of nabiximols did not have any effect on a range of human ABC transporters, uptake transporters or P-gp inhibition at clinically relevant plasma concentrations.
Based on in vitro data an inhibition of p-glycoprotein at the intestinal level by CBD cannot be excluded. Therefore, caution is recommended upon concomitant treatment with digoxin and other drugs being substrates for p-glycoprotein.

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 additive CNS effects may increase the risk of falls and other accidents.

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

Effects on fertility.

Fertility in rats was unaffected by oral treatment with a 1:1 mixture of THC BDS and CBD BDS, at doses up to 12.5 mg/kg/day or each active component. This dose resulted in estimated exposures that were well in excess of that expected in humans with the maximum recommended dose (> 300 fold based on AUC). Effects on various male reproductive parameters have been reported with cannabinoids in some animal studies, but findings were inconsistent or observed at high/toxic doses and their clinical significance is uncertain.
Patients on hormonal contraceptives should be advised to use an additional alternative, non-hormonal/reliable barrier method of birth control during Sativex therapy.
(Category B2)
There is insufficient experience in humans regarding the effects of Sativex on reproduction. 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.
There was no evidence for teratogenicity in rats and rabbits treated with oral doses of a 1:1 THC BDS and CBD BDS mixture of up to 12.5 mg/kg/day of each active component. This dose resulted in respective THC and BDS exposures (based on AUC) that were approximately 490 and 320 fold (rats) or 12.5 and 3 fold (rabbits) those expected in humans with the maximum recommended dose. The highest dose was maternotoxic in rabbits and resulted in a slightly lower foetal weight and impaired skeletal ossification. Reduced foetal weights and increased incidences of skeletal variants were seen in rabbits, associated with maternal toxicity which was apparent with all doses tested.
Oral treatment of rats with 4 mg/kg/day of a 1:1 THC BDS and CBD BDS mixture from the time of implantation to weaning of the offspring resulted in a lower pup body weight gain and slightly impaired righting reflex on day 5 of lactation. The NOEL for these findings (2 mg/kg/day) was below the maximum recommended human dose in terms of body surface area.
 High concentrations of THC and CBD were measured in the milk of lactating rats after oral treatment with a 1:1 mixture of THC BDS and CBD BDS, as may be expected due to the lipophilic nature of cannabinoids. Oral treatment of rats with a 1:1 THC BDS and CBD BDS mixture from the time of implantation to weaning was associated with impaired nursing behaviour and pup survival at doses of 5 mg/kg/day or greater (less than the maximum recommended human dose in terms of body surface area).
Following repeat dosing, high levels of cannabinoids are concentrated in breast milk. Doses in excess of normal clinical doses may affect growth rates of breast-fed infants.
In view of the considerable levels of cannabinoids likely in maternal breast milk and the potential adverse developmental effects in infants, Sativex is contraindicated in breast feeding mothers (see Section 4.3 Contraindications).

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. Therefore, given the combination of existing disability from MS plus the common effects of Sativex, patients taking Sativex should not drive, operate dangerous machinery or engage in hazardous activities.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

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 Dose and Method of Administration). When the recommended dose titration schedule was used, the incidence of dizziness and fatigue in the first four weeks was much reduced.
Treatment emergent all-causality adverse events with an incidence of at least 1% for Sativex in placebo controlled trials in patients with MS are given in Table 2 (some of these adverse events may be part of the underlying condition).
A single case of ventricular bigeminy has been reported though this was in the context of acute nut allergy.

Description of selected adverse reactions.

Abuse potential.

In a study designed to identify its abuse potential, Sativex at a dose of 4 sprays taken at one time, did not differ significantly from placebo. At 8 sprays there was a moderate effect, significantly different from placebo, and the results were more marked at 16 sprays. Sativex taken at the maximum recommended doses of up to twelve sprays per day sprays has moderate potential for abuse. Patients with a history of substance abuse may abuse Sativex and if Sativex is being considered for these patients close monitoring is recommended.

Psychiatric and cognitive adverse effects.

In a QTc study a dose of Sativex 4 sprays over 20 minutes twice daily was well-tolerated, but a substantially supratherapeutic dose of 18 sprays over 20 minutes twice daily resulted in significant psychoactivity and cognitive impairment. 4/41 (9.7%) patients taking substantial multiples of the therapeutic dose experienced psychiatric adverse effects including hallucinations, delusions, and homicidal and suicidal ideation.
See Section 4.4 Special Warnings and Precautions for Use.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

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 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other Analgesics and Antipyretics.
ATC Code: N02BG10.

Mechanism of action.

There are at least two types of cannabinoid (CB) receptors as part of the human endocannabinoid system. CB1 is found mainly in nerve terminals in the CNS where it modulates neurotransmitter release and CB2 is found primarily in cells of the immune system. THC, the main psychotropic constituent of cannabis, acts as a partial agonist at both CB1 and CB2 receptors.
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.
CBD has little activity at cannabinoid receptors, but does have neuroprotective properties, most likely mediated by its ability to modulate intra-cellular calcium. It is also able to modulate the course of the disease in animal models of MS. The key pharmacology of CBD in MS probably relates to its ability to inhibit microglial activity and T-cell proliferation. It is unknown whether CBD in Sativex has a facilitating or antagonising effect on the anti-spasticity action of THC.

Clinical trials.

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 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 not great. 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. Of these, 272 subjects (48%) responded with a reduction of at least 20% on the spasticity symptom NRS, with a mean change from the start of treatment of -3.0 points on the 10 point NRS. Of these, 241 patients were eligible to be 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 score for patients switched to placebo increased towards pre-treatment levels (mean change in NRS score +0.64). The difference* between treatment groups was 0.84 (95% CI -1.29, -0.40).
(*Difference adjusted for centre, baseline NRS and ambulatory status). Thus, the primary outcome measure was highly statistically significantly in favour of Sativex (p = 0.0002).
Of those patients who had at least a 20% reduction from screening in NRS spasticity score at week 4 and who continued in the trial to receive randomised treatment, 74% (Sativex) and 51% (placebo) achieved a 30% reduction at week 16. Thus, the attributable response rate was 23% in the randomised cohort (which equates to around 10% of the original cohort).
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 begin to decline back to pre-treatment levels.
Modified Ashworth Score: 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.
Subject global impression of change (OR = 1.71), carer global impression of change (OR = 2.40) and physician global impression of change (OR = 1.96) all showed highly statistically significant superiority of Sativex over placebo.
The benefit of continued treatment in the long-term was studied in a placebo controlled, parallel group, randomised withdrawal trial, in subjects taking long-term Sativex. Thirty-six patients with a mean duration of Sativex use prior to the trial of 3.6 years were randomised to either continue with Sativex treatment or switch to placebo for 28 days. The primary endpoint was time to treatment failure, defined as the time from the first day of randomised treatment to a 20% increase in NRS or premature withdrawal from randomised treatment. Treatment failure was experienced by 44% of Sativex patients and 94% of placebo patients, hazard ratio 0.335 (95% CI 0.16, 0.69). The primary efficacy endpoint was significantly in favour of Sativex (p = 0.013). It is possible that some treatment failures on placebo could have reflected temporary factors associated with drug withdrawal. It is not known whether such patients would have improved again if they had remained off Sativex.

5.2 Pharmacokinetic Properties

Absorption.

Following 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 nanogram/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.
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 0.97-9.34 nanogram/mL) and a 58.5% CV for AUC (range 4.2-30.84 h*nanogram/mL). Similarly the % CV for CBD was 64.1% (range 0.24-2.57 nanogram/mL) and 72.5% (range 2.18-14.85 nanogram/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-tau = 5.34-15.01 h*nanogram/mL) for THC and 75.7% (Cmax range 0.34-3.39 nanogram/mL) and 46.6% (AUC0-tau = 2.40-13.19 h*nanogram/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 nanogram/mL within minutes of administration, with significant psychoactivity. (See Table 3.)

Distribution.

As 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.

Metabolism.

THC and CBD are metabolised in the liver, and approximately one third of the parent drugs and their metabolites are excreted in the urine (the remainder via the faeces). Several THC metabolites may be psychoactive. 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-delta-9-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 oxidised metabolite identified is CBD-7-oic acid containing a hydroxyethyl side chain.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for information on drug interaction and metabolism by the cytochrome P450 enzyme system.

Excretion.

From 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.

5.3 Preclinical Safety Data

Genotoxicity.

Sativex or a mixture of its component extracts was not genotoxic in in vitro tests for bacterial reverse mutation and in vivo micronucleus tests for clastogenicity in mice and rats, or in an ex vivo assay for unscheduled DNA synthesis in rat hepatocytes. No consistent genotoxicity was seen in an in vitro test for forward mutation in mouse L5178Y cells.

Carcinogenicity.

A long-term carcinogenicity study has been conducted in rats with CBD BDS using dietary doses of 5-50 mg/kg/day, with no oncogenic response being observed. The highest dose resulted in estimated CBD and THC exposures (based on AUC) that were respectively 350 and 40 times that expected in humans with the maximum recommended dose. No studies were conducted with Sativex or its other component, THC BDS, but results were available from a published source for mouse and rat studies with oral administration of THC. Doses of THC used in the mouse were 125, 250 and 500 mg/kg/day (17, 35 and 70 times the maximum recommended human dose in terms of body surface area). There was an increase in thyroid follicular cell adenomas in males and females, but only with the lowest dose and the significance of this finding is uncertain. No oncogenic responses were seen in rats with THC doses of 12.5-50 mg/kg/day (3-14 times the maximum recommended human dose based on body surface area), associated with estimated exposures (AUC) of 90-550 times that expected in humans with the maximum recommended dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 8°C (Refrigerate). Store upright. Keep away from heat and direct sunlight.
Once the spray container is opened and in use, refrigerated storage is not necessary but do not store above 25°C.
Use within 42 days from date of opening.

6.5 Nature and Contents of Container

Sativex is a yellow-brown oromucosal spray solution containing 27 mg/mL of THC and 25 mg/mL of CBD. The Type I amber glass spray container with brown plastic coating is fitted with a metering pump possessing a polypropylene dip tube and elastomer neck covered with a polypropylene cap. The metering pump delivers 100 microlitres per spray.
Pack Size: 10 mL.
10 mL pack size allows delivery after priming of up to 90 actuations (sprays) of 100 microlitres.
1 or 3 glass spray containers per carton.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The chemical structures of THC and CBD are shown:

CAS number.

THC is trans-delta[9]-tetrahydrocannabinol. The molecular formula of THC is C21H30O2, its molecular weight is 314.47, and it is assigned CAS Number 1972-08-3.
CBD is cannabidiol. The molecular formula of CBD is C21H30O2, its molecular weight is 314.47 and it is assigned CAS Number 13956-29-1.

7 Medicine Schedule (Poisons Standard)

Poison schedule: Controlled Drug - Schedule 8.

Summary Table of Changes