Active ingredients: Delta-9-tetrahydrocannabinol, Cannabidiol
Sativex Spray for oral mucosa
Why is Sativex used? What is it for?
What is Sativex
Sativex is an oral spray that contains cannabis extracts called cannabinoids.
What is Sativex used for
Sativex is used in multiple sclerosis (MS) to relieve the symptoms of muscle stiffness, also called "spasticity". Spasticity means that there is an increase in normal muscle tone that makes the muscle feel harder or stiffer. This means that moving the muscles is more difficult than normal.
Sativex is used when other medicines have not improved the stiffness of the muscles.
Its 4 week trial with Sativex
Only a specialist doctor can prescribe Sativex treatment.
- Before starting Sativex therapy, the specialist will assess the severity of your muscle stiffness. It will evaluate how effectively other therapies have worked.
- The trial treatment with Sativex will then begin for a duration of four weeks. Subsequently, the specialist will perform another evaluation to ascertain whether Sativex has improved your muscle stiffness.
- You will only be able to continue treatment with Sativex if after these four weeks you have demonstrated that you have achieved significant improvements in the symptoms associated with spasticity.
Contraindications When Sativex should not be used
Do not use Sativex:
- If you are allergic to cannabis extracts or any of the other ingredients of this medicine (listed in section 6).
- If you or a direct relative have mental problems such as schizophrenia, psychosis or other significant psychiatric disorders; this does not include the depression associated with multiple sclerosis.
- If you are breast-feeding.
If any of the above apply to you, do not take this medicine. If in doubt, consult your doctor or pharmacist before using Sativex.
Precautions for use What you need to know before taking Sativex
Talk to your doctor or pharmacist before using Sativex:
- if you are pregnant or plan to become pregnant. Whether you are male or female, you must use effective contraception when taking this medicine (see also "Pregnancy, breastfeeding and contraception (men and women)" below)
- if you are under 18
- if you have epilepsy or regularly suffer from seizures (fits)
- have liver or kidney problems
- if you have severe heart failure such as angina pectoris, if you have previously had a myocardial infarction, if you have uncontrolled hypertension or have heart rate problems
- if you are elderly, particularly if you find it difficult to carry out daily activities such as preparing hot food and drinks
- if you have in the past abused drugs or drugs.
If any of the above apply to you (or you are not sure), consult your doctor or pharmacist before using Sativex.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Interactions What medications or foods may change the effect of Sativex
Other medicines and Sativex
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. Because Sativex can affect the way some other medicines work, some other medicines can affect the way Sativex works.
In particular, tell your doctor or pharmacist if you are taking or have taken any of the following medicines:
- Medicines that reduce anxiety (sedatives) or make you sleep better (hypnotics). These medicines can increase the side effects of Sativex and may increase the risk of falls or other accidents.
- Medicines to relax muscles, such as baclofen or diazepam, because taking Sativex with these medicines can increase the risk of falls.
If you think any of the above events apply to you, consult your doctor or pharmacist before using Sativex. If you see other doctors or are hospitalized, please tell them about all the medicines you are taking.
Sativex with food, drink and alcohol
- Generally, alcoholic beverages should be avoided when taking Sativex, especially at the start of treatment or when changing the dose. If you drink alcohol while taking Sativex, be aware that using Sativex together with alcohol may increase its effects. collateral (eg loss of balance or less ability to react quickly) which can increase the risk of falls and other accidents.
- You can take Sativex with or without food (but first read section 3 "How to use Sativex" below).
Warnings It is important to know that:
Pregnancy, breastfeeding and contraception (men and women)
- If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
- Sativex should not be used during pregnancy unless your doctor specifically recommends it.
- Both women and men taking this medicine must use a reliable method of contraception. Continue to use it for at least three months after stopping therapy.
- Sativex should not be taken while breastfeeding.
If you are pregnant or breastfeeding, always ask your doctor for advice before taking any medicine.
Driving and using machines
- When you start taking Sativex you should not drive or use machines until you take a stable daily dose.
- Sativex can cause drowsiness or dizziness, which can affect your judgment and the performance of specialized work. In addition, rare cases of transient loss of consciousness have been reported.
- Once you have become accustomed to taking Sativex at a stable dose, you should not drive or operate machinery if Sativex causes effects such as sleepiness or dizziness that may affect your ability to perform these tasks. If you are unsure, do not drive or operate machinery. .
Travel abroad with Sativex
Before going abroad, check if you can legally carry this medicine. This also applies to transit countries.
- Sativex is a controlled drug, the legal status of which varies from country to country.
- In some countries it may be illegal to drive while taking Sativex.
Sativex contains ethanol and propylene glycol
- Sativex contains approximately 50% v / v ethanol (alcohol) eg. up to 40 mg per dose. The amount of alcohol present in the maximum daily dose for the majority of patients (12 sprays) is about the same as that contained in two teaspoons (10 ml) of beer and about one teaspoon (5 ml) of wine.
This medicine can be dangerous for those suffering from alcoholism.
- Sativex contains propylene glycol which can cause irritation.
Dose, Method and Time of Administration How to use Sativex: Posology
Always use this medicine exactly as the instructions on this leaflet or what your doctor has told you. If in doubt, consult your doctor or pharmacist.
Use Sativex only in the mouth, on the walls of the mouth or under the tongue.
- You can take Sativex with or without food. However, taking Sativex with food can affect the amount your body takes in. If possible, you should try to take Sativex the same way each time with regard to food so that you have the same effect every time.
Opening the spray bottle and ready for use
- Remove the spray bottle from the refrigerator (see important information on Sativex storage in section 5).
- Write the date you opened the bottle on one of the stickers in the box. Apply the sticker to the bottle so you can check the date. Do not use the spray after it has been opened for more than 6 weeks (42 days).
- Gently shake the spray bottle before use.
- Remove the protective cap.
- Hold the spray bottle between your thumb and middle finger, and place your index finger on the nozzle.
- Hold the bottle upright then spray two or three times on a paper towel until it produces a very fine spray. These sprays prime the pump and ensure it is working properly.
- The spray is now ready for use. You will not need to prime the pump again until you open a new spray bottle.
How to use the spray
- Hold the spray bottle between your thumb and middle finger and place your index finger on the nozzle.
- Hold it upright to direct the spray into your mouth. Direct the nozzle under your tongue or on the walls of your mouth. Each time you use the spray, direct the spray to a different point in your mouth to avoid localized discomfort.
- Press the nozzle firmly. Do not take more than one spray at a time, even if you think you only received a small amount of spray.
- Put the protective cap back on the bottle.
In case of accidental splashing of the eyes, wash them as soon as possible with water.
- Do not inhale the spray.
- Do not spray in the presence of children or pets.
- Do not use the spray near open flames or heat sources.
Decide how much spray to use
The number of sprays needed each day is up to you. Everyone needs a different number of sprays to get the best relief from their muscle stiffness, with the fewest side effects.
- When you start using Sativex you should observe the days and times shown in the table below until you find the number of puffs that are most suitable for you.
- When you think you have reached the number of puffs that are most suitable for you, do not increase the dosage any more. This can take a few days or up to two weeks. Try to use this number of sprays every day; it will then be able to distribute the sprays evenly throughout the day.
- Do not use more than one spray at a time. Always leave at least 15 minutes between sprays.
- During the first two days of using Sativex, avoid overworking until you know the extent of the impact of the medicine.
- If you start to feel side effects (usually dizziness) use one less spray each day until you find the best relief for muscle stiffness with the fewest side effects.
- Once you have found the most effective number of sprays, try to use it every day. You can then distribute the sprays evenly throughout the day, in the best way for you. Always leave at least fifteen minutes between each spray.
Do not use more than 12 sprays per day unless your doctor tells you to.
Overdose What to do if you have taken too much Sativex
If you use more Sativex than you should
If you accidentally take more Sativex than you normally need, you can:
- seeing or hearing things that are not there (hallucinations)
- feeling dizzy, sleepy or confused
- feel a change in heart rate.
- Tell your doctor or pharmacist if you have used more Sativex than you should.
If you forget to use Sativex
- If you forget to take a dose, apply a spray as soon as you realize it or when you feel the need to.
- Do not take a double dose to make up for a forgotten dose.
How to tell if the spray bottle is almost empty
After using the three primer sprays, the spray bottle holds up to 90 metered sprays. When the spray bottle is nearly empty, the noise you hear when using it may change. He may also notice a difference in the spray when he sprays it in his mouth. This happens because the spray bottle is almost empty. In this case, you will need to open a new spray bottle.
If you stop taking Sativex
If for any reason you decide to stop using Sativex, please tell your doctor or pharmacist. Stopping taking this medicine suddenly may temporarily affect your sleep, appetite or emotions. If you stop taking Sativex, muscle stiffness usually returns gradually.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Sativex
Like all medicines, this medicine can cause side effects, although not everybody gets them. These are more likely at the start of therapy. In most cases, side effects are quite mild and usually disappear within a few days.
- If you have any of the following side effects, use fewer puffs or stop using Sativex until you feel normal again.
- When you resume using your medicine, take the number of puffs you used when you did not feel these side effects.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Very common (affects more than 1 in 10 people)
- Dizziness or tiredness.
Common (affects less than 1 in 10 people)
- Sense of depression or confusion.
- Strong agitation or loss of contact with reality.
- Memory problems or difficulty concentrating.
- Drowsiness or lightheadedness.
- Blurred vision.
- Difficulty speaking.
- Eat more or less than usual.
- Change in sense of taste or dry mouth.
- Constipation or diarrhea.
- Feeling or having the sensation of being sick.
- Mouth problems, including burning, pain or ulcers.
- Lack of energy or a sense of weakness or general malaise.
- Feeling abnormal or intoxicated.
- Loss of balance or falling.
Uncommon (affects less than 1 in 100 people)
- Seeing or hearing things that are not there (hallucinations).
- Believe in ideas that are not true.
- Believing that others are against her.
- Thoughts of suicide.
- Fainting.
- Changes in pulse rate, heart rate or blood pressure.
- Sore throat or sore throat.
- Bellyache.
- Change in the color of the mouth or teeth.
- Irritation where Sativex is sprayed.
- Mouth red and swollen or peeled inside. Do not continue spraying on these areas.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the label and carton after {EXP}. The expiry date refers to the last day of that month.
- Before opening, Sativex must be stored upright in the box, in the refrigerator (between 2 ° C and 8 ° C). If not stored in the refrigerator it becomes unstable and is unlikely to be effective.
- When opened, Sativex should be stored in an upright position at a temperature not exceeding 25 ° C.
- Once opened, Sativex must be used within 42 days.
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This measure will help protect the environment.
Composition and pharmaceutical form
What Sativex contains
- The active ingredients are cannabis extracts. Each milliliter (ml) contains 38-44 mg and 35-42 mg of two extracts (soft extracts) of Cannabis sativa L., leaves and flowers, equivalent to 27 mg / ml delta-9-tetrahydrocannabinol (THC) and 25 mg / ml of cannabidiol (CBD). Each spray delivers 100 microliters containing 2.7 mg of THC and 2.5 mg of CBD.
- The other components (excipients) - are ethanol, propylene glycol and peppermint oil.
Description of what Sativex looks like and contents of the pack
Sativex is a yellow / brown liquid contained in a 10ml glass spray bottle equipped with a pump. The pump is protected by a plastic cap.
The bottle contains up to 90 metered sprays (after the three trigger sprays) Sativex is packaged in boxes of 1, 2, 3, 4, 5, 6, 10 or 12 spray bottles. Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SATIVEX SPRAY FOR ORAL MUCOSA
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
100 microliters of spray contain:
2.7 mg of delta-9-tetrahydrocannabinol (THC) and 2.5 mg of cannabidiol (CBD).
Each ml contains:
38-44 mg and 35-42 mg of two extracts (soft extracts) of the Cannabis sativa L., folium cum flore (cannabis leaves and flowers) corresponding to 27 mg of delta-9-tetrahydrocannabinol and 25 mg of cannabidiol.
Solvent extraction: liquid carbon dioxide.
Excipient (s) with known effect: 100 microliths of spray contain up to 0.04 g of ethanol.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Oral mucosal spray.
Yellow / brown solution in spray container.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Sativex is indicated as a treatment to relieve symptoms in adult patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other antispasmodics and who have shown clinically significant improvement in symptoms associated with spasticity. during an initial trial period of therapy.
04.2 Posology and method of administration
Sativex is indicated for oromucosal use only.
Sativex is to be used in addition to the patient's current anti-spasticity treatments.
Sativex treatment should be initiated and monitored by physicians experienced in the treatment of patients with this condition.
Adults
Shake the container before use and apply the spray to different sites of the oromucosal surface, changing the site of administration each time the product is used.
It is advisable to inform patients that in some cases it takes two weeks to find the optimal dose and that side effects may arise during this period, especially dizziness. These side effects usually occur in a mild form and disappear after a few days. However, physicians should consider maintaining the administered dose, reducing it or stopping treatment, at least temporarily, depending on the severity and intensity of the undesirable effects.
To minimize the variability of bioavailability in each patient, as far as possible, the administration of Sativex should be standardized with respect to food intake (see section 4.5). In addition, starting or stopping some concomitant medicinal products may require re-titration (see section 4.5). paragraph 4.5).
Titration period
A titration period is required to obtain the optimal dose. The number and frequency of spray applications vary from patient to patient.
The number of spray applications should be increased every day following the scheme below. The afternoon / evening dose should be administered any time between 4pm and bedtime. If a morning dose is added, it should be taken between waking up and midday. The patient can continue to gradually increase the dose up to a maximum of 12 spray applications per day, until optimal symptom relief is achieved. An interval of at least 15 minutes should be observed between one application and the next.
Maintenance period
Upon completion of the titration period, patients are advised to maintain the optimal dose achieved. The median dose administered in clinical studies in patients with multiple sclerosis is eight spray applications per day. Once the optimal dose is achieved, patients can apply the dose throughout the day depending on their individual response and tolerance level. Dose increases or decreases may be appropriate in the event of changes in the severity of the patient's disease, changes in concomitant medications administered or in the event of troublesome adverse reactions. Doses greater than 12 spray applications per day are not recommended.
Evaluation by the doctor
Before initiating therapy, a thorough assessment of the severity of symptoms associated with spasticity and response to usual antispasmodic drugs is recommended. The use of Sativex is only indicated in patients with moderate to severe spasticity who have not had an adequate response to other antispasmodic medicinal products. The patient's response to Sativex should be re-evaluated four weeks after the start of treatment. If there is no clinically significant improvement in symptoms associated with spasticity during the initial trial period of therapy, treatment with this medicinal product should be discontinued. In clinical trials, this was defined as an improvement of at least 20% in symptoms associated with spasticity using a patient self-assessment scale from 0 to 10 (see section 5.1).. The validity of the long-term treatment should be reviewed periodically.
Children
The use of Sativex is not recommended in children or adolescents below 18 years of age due to the lack of data on safety and efficacy.
Senior citizens
No specific studies have been performed in the elderly although patients up to 90 years of age have been included in clinical studies. As adverse reactions of the central nervous system are more likely to occur in elderly patients, care must be taken in terms of personal safety, for example when preparing hot food and drinks.
Patients with significant hepatic or renal impairment
No studies are available in patients with impaired hepatic or renal function. However, in these populations, the effects of Sativex can be broadened or prolonged. Frequent clinical evaluation is recommended in these patients (see section 4.4).
04.3 Contraindications
The use of Sativex is contraindicated in patients:
• with hypersensitivity to cannabinoids or to any of the excipients;
• with a known or suspected history or family history of schizophrenia or other psychotic illnesses, history of severe personality disorders or other significant psychiatric disorders, excluding depression associated with the concomitant illness;
• who are breastfeeding (due to the high levels of cannabinoids that may be present in breast milk and the potential adverse effects on the development of the baby).
04.4 Special warnings and appropriate precautions for use
Mild to moderate dizziness has been commonly reported. This effect occurs most frequently during the first few weeks of treatment.
The use of Sativex is not recommended in children or adolescents below 18 years of age due to the lack of data on safety and efficacy.
Alterations in heart rate and blood pressure have been observed after the first administration so it is essential to use caution after the initial dose of the titration period. Episodes of fainting have been observed. The use of Sativex is not recommended in patients with severe cardiovascular conditions. However, no clinically relevant changes in QTc, PR or QRS intervals, heart rate or blood pressure were found in healthy volunteers who were administered up to 18 spray applications of Sativex twice a day.
Caution is advised when treating patients with a history of epilepsy or recurrent seizures until further information is available.
Psychiatric symptoms such as anxiety, hallucinations, mood swings and paranoid disorders have been reported while using Sativex.These symptoms are likely due to transient CNS effects, are live-moderate in intensity and well tolerated. There may be remission by reducing the dose or stopping Sativex treatment.
Disorientation (or confusion), hallucinations and delusional symptoms or transient psychotic reactions have also been reported in some cases; in a few cases, a causal relationship between administration of Sativex and suicidal ideation could not be excluded. In all these situations, Sativex treatment should be stopped immediately until the related symptom has resolved completely.
No specific studies have been performed in patients with significant hepatic or renal impairment. THC and CBD are metabolized in the liver and approximately one third of the parent drugs and their metabolites are eliminated in the urine (and the remaining two thirds in the faeces). Some metabolites of THC may be psychoactive. As a result, systemic exposure and effects of Sativex are dependent on both renal and hepatic function and that in patients with impaired hepatic or renal function, the effects of Sativex may be excessive or prolonged. It is therefore recommended that these patients be subjected to frequent clinical evaluation.
Sativex contains approximately 50% v / v ethanol. Each dispensing contains up to 0.04 g of ethanol. A small glass of wine (125 ml) with a nominal ethanol content of 12% v / v contains approximately 12 g of ethanol. The majority of patients respond to doses of up to 12 spray applications per day that contain less than 0.5 g of ethanol.
There is a risk of an increased incidence of falls in patients whose spasticity has decreased and whose muscle strength is insufficient to maintain posture or gait. In addition to the increased risk of falls, adverse central nervous system reactions attributable to Sativex, particularly in the elderly, could potentially have an impact on various aspects of personal safety such as, for example, the preparation of hot food and drinks.
Although there is a theoretical risk of addiction to muscle relaxants such as baclofen and benzodiazepines, thereby increasing the risk of falling, this effect has not been found in any clinical study conducted with Sativex. However, it is necessary to warn patients of the existence of this possibility.
Although no effect on fertility was found, independent animal research has shown that cannabinoids affect spermatogenesis. Patients of childbearing potential and patients with partners of childbearing potential should ensure that they take safe contraceptive precautions for the duration of treatment and for three months following its discontinuation (see section 4.6).
Patients with a history of substance abuse may be more likely to abuse Sativex as well (see section 5.1).
Abrupt discontinuation of long-term Sativex treatment did not exhibit a consistent pattern or time profile of withdrawal-like symptoms and the eventual consequence is limited to temporary disturbances of sleep, emotion and appetite in some patients. No increase in daily dosage has been observed in long-term therapies and patient-reported levels of intoxication are low. For these reasons, dependence on Sativex is unlikely.
Adverse reactions associated with the route of administration of the product have been reported. Application site reactions were predominantly a mild to moderate stinging sensation at the time of application. Generally, application site reactions are pain, mouth pain and discomfort, dysgeusia, mouth ulcers, and glossodynia have been observed. two cases of leukoplakia that have never been confirmed histologically; a third case was found to be unrelated. For these reasons, patients who observe discomfort or ulceration at the product application site are advised to vary the application site within mouth and not to continue spraying the drug on ulcerated or inflamed membranes. Regular inspections of the oral mucosa are also recommended in the case of prolonged administration. If ulcers or lesions persist, discontinue administration until complete resolution. In the case of travel abroad, patients should be advised that this medicine may not be legal in some countries: they should therefore check its legal status before traveling with Sativex.
Pregnancy and lactation: see section 4.6.
04.5 Interactions with other medicinal products and other forms of interaction
The two active ingredients in Sativex, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are metabolized by the cytochrome P450 enzyme system.
In vitro, the inhibitory effects of Sativex on major enzymes CYP450, CYP3A4 and CYP2C19 occur at concentrations substantially higher than the maximum observed in clinical studies.
Therefore, interactions with other substances with action at the level of the CYP 3A4 isoenzyme are not expected
In a studio in vitro conducted with 1: 1% (v / v) THC and CBD botanical extracts, no relevant induction of cytochrome P450 enzymes was found for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzymes in human hepatocytes at doses up to 1mcM ( 314 ng / ml).
Concomitant treatment with ketoconazole, an inhibitor of CYP3A4, resulted in an increase in the Cmax and AUC of THC (1.2 and 1.8-fold, respectively) of its primary metabolite (equal to 3 and 3, respectively). 6 times) and CBD (equal to 2 and 2 times, respectively). Consequently, if treatment with CYP3A4 inhibitors (e.g. itraconazole, ritonavir, clarithromycin) is initiated or discontinued during treatment with Sativex, a new titration is required (see section 4.2).
Following treatment with rifampicin, an inducer of CYP3A4, a reduction in Cmax and AUC values of THC (40% and 20% respectively), its primary metabolite (85% and 87% respectively) and CBD was observed. (50% and 60% respectively). Consequently, concomitant treatment with strong enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) should be avoided whenever possible. If deemed necessary, a thorough titration within two weeks following the discontinuation of the inductor is recommended.
Caution is advised in the use of hypnotics, sedatives and drugs with potential sedating effects as they could have an additive effect of sedation and effects on muscle relaxation.
Although no increase in adverse events has been observed following the use of Sativex in patients already taking antispasmodic drugs, caution is advised when Sativex is administered concomitantly with such drugs as a reduction in tone and potency may occur. muscle resulting in a higher risk of falling.
Sativex may interact with alcohol, affecting coordination, concentration and reflexes. Generally alcoholic beverages should be avoided while using Sativex especially at the start of treatment or when changing the dose. Patients should be advised that if they drink alcohol while taking Sativex, the additive CNS effects may impair their ability to drive or use machines and increase the risk of falls.
04.6 Pregnancy and lactation
There is insufficient experience of the effects of Sativex on human reproduction. Men and women of childbearing potential should therefore use safe contraceptive precautions throughout the duration of treatment and for three months after its discontinuation.
Pregnancy
Sativex should not be used during pregnancy except in cases where the benefits offered by the treatment outweigh the possible risks to the fetus and / or embryo.
Feeding time
Available pharmacodynamic / toxicological data in animals have shown excretion of Sativex and its metabolites in breast milk (for details see section 5.3). A risk to the breast-fed infant cannot be excluded. Sativex is contraindicated during lactation. breast (see section 4.3).
Fertility
In rodent fertility studies, there was no effect of Sativex treatment in males and females. There was no effect on the fertility of births to mothers treated with Sativex.
04.7 Effects on ability to drive and use machines
Sativex can produce unwanted effects such as dizziness and sleepiness which could impair the ability to assess different situations and to carry out specialized work. Patients should not drive, operate machinery or perform hazardous activities if they experience central nervous system side effects such as dizziness or sleepiness. Patients should be aware that some cases of unconsciousness have been reported following administration of Sativex.
04.8 Undesirable effects
The Sativex clinical program has to date involved over 1,500 multiple sclerosis patients in placebo-controlled clinical trials and long-term open-label studies in which some patients have performed up to 48 sprays per day.
The most commonly seen 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 disappear within a few days even if treatment is continued (see section 4.2). Use of the recommended titration schedule resulted in a decrease in the incidence of symptoms of dizziness and fatigue in the first four weeks.
The table below indicates the frequency of adverse events, according to system organ class (SOC), which have a plausible correlation with Sativex administration resulting from placebo-controlled clinical trials conducted in patients with multiple sclerosis (some of these adverse events may be attributable to the concomitant disease).
* reported in long-term open-label clinical trials.
A single case of ventricular bigeminy has been reported albeit in the context of an "acute allergic reaction to nuts.
See also sections 4.4, 4.5 and 4.7.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions occurring after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions through the National Pharmacovigilance Network of Italian Medicines Agency, Website: www.agenziafarmaco.gov.it/it/responsabili
04.9 Overdose
There have been no reports of intentional overdose experiences with Sativex in patients. However, in a thorough QT interval study of Sativex in 257 subjects given 18 sprays over a 20 minute period twice daily, signs and symptoms of overdose / poisoning were observed. reactions similar to those caused by acute intoxication including dizziness, hallucinations, delusions, paranoia, tachycardia or bradycardia accompanied by hypotension. Of 41 subjects receiving doses of 18 sprays twice daily, three experienced these symptoms in the form of toxic psychosis temporary disappearance after discontinuation of treatment Twenty-two subjects administered this high multiple of the recommended dose successfully completed the 5-day study period.
In the event of an overdose, treatment should be symptomatic and supportive.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other analgesics and antipyretics.
ATC code: N02BG10.
The European Medicines Agency has deferred the obligation to submit the results of spasticity studies with Sativex in one or more subsets of the pediatric population. See section 4.2 for information on pediatric use.
Mechanism of action
Cannabinoid receptors and CB1 and CB2 receptors are part of the human endocannabinoid system (ECS) and as such are found primarily in nerve endings where they play a role in the retrograde regulation of synaptic function. THC acts as a partial agonist in both CB1 and CB2 receptors by mimicking the effects of endocannabinoids which may eventually modulate the effects of neurotransmitters (e.g. reduce the effects of excitatory neurotransmitters such as glutamate).
In animal models of multiple sclerosis and spasticity, CB receptor agonists have been shown to reduce limb stiffness and improve motor function. These effects are inhibited by CB receptor antagonists and the CB1 receptor knockout mouse exhibits more severe spasticity. In the CREAE (chronic relapsing experimental autoimmune encephalitis) mouse model, Sativex resulted in a dose-related reduction in hindlimb stiffness.
Clinical experience
Sativex has been studied at doses of up to 48 spray applications per day in controlled clinical trials conducted for up to 19 weeks in more than 1,500 patients with multiple sclerosis. In the pivotal studies performed to evaluate the efficacy and safety of Sativex used to relieve symptoms in patients with moderate to severe spasticity due to multiple sclerosis (MS), the primary efficacy measure was the numerical rating scale (NRS). with a score from 0 to 10 with which patients indicated the average level of their symptoms associated with spasticity over the last 24 hours.On this scale, 0 corresponds to the absence of spasticity and 10 to the highest degree of spasticity.
In a first phase III placebo-controlled study with a treatment period of 6 weeks, the difference from placebo was statistically significant while that between treatments ranged from 0.5 to 0.6 points on the NRS scale with a score of 0 to 10 was considered of questionable clinical relevance. An analysis of responding patients found that 40% of the subjects taking Sativex and 22% of the patients receiving placebo responded to treatment with a reduction in the NRS score of more than 30%.
A second 14-week phase III study did not show a significant therapeutic effect. The difference from placebo on the NRS scale was 0.2 points.
It has been postulated that a clinically useful therapeutic effect in some patients may be partially obscured by data from non-responding patients in the mean change analyzes. In analyzes comparing NRS scores with the patient's Patient Global Impression of Change (PGI), NRS responses of 19% and 28% were respectively interpreted as a clinically relevant improvement and as a "great improvement" over the PGI. In the combined exploratory analyzes performed after the two studies above, a 4-week study period conducted using a 20% NRS response limit was found to be predictive of a conclusive response defined as a 30% reduction.
A third phase III clinical trial included a 4-week experimental therapeutic period before proceeding to randomization. The clinical study aimed to evaluate the benefits of continuing treatment in patients who had achieved an initial response to treatment. 572 patients with multiple sclerosis and refractory spasticity were given single-blind Sativex for four weeks. After four weeks of active treatment, 273 patients achieved a reduction in spastic symptoms of at least 20% on the NRS scale, of these 241 patients met the admission criterion to randomization, with a mean change of -3.0 points out of 10 from " Treatment initiation These patients were randomized to either continue active treatment or switch to placebo for the 12-week double-blind phase, for a total treatment period of 16 weeks.
During the double-blind phase, mean NRS scores in patients taking Sativex remained stable (mean change in NRS score of -0.19 from randomization), while mean NRS scores in patients who switched from active treatment to taking Sativex. placebo were increased (mean change in NRS score of +0.64 and change in median +0.29). The difference * between the treatment groups was 0.84 (95% CI -1.29, -0.40).
* Difference adjusted for single center, NRS at baseline and when walking.
Of the patients who achieved a 20% reduction in NRS score in week 4 from screening values and who continued to receive randomized treatment in the clinical trial, 74% (Sativex treatment group) and 51 % (placebo) achieved a 30% reduction in week 16.
The following are the results achieved for the secondary endpoints during the 12-week randomized phase. Most of the secondary endpoints showed a similar pattern of the NRS score. Patients who continued to take Sativex maintained the improvement achieved in the initial 4-week treatment period while patients subsequently assigned to the placebo group experienced worsening.
Modified Ashworth Score: Sativex -0.1; placebo +1.8;
for spasticity 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 disturbed by spasticity: Sativex -0.25; placebo +0.59;
(NRS 0 to 10) Adjusted difference -0.88 (95% CI -1.25, -0.51)
Timed 10-meter walk (seconds): Sativex -2.3; placebo +2.0;
Adjusted difference -3.34 (95% CI -6.96, 0.26)
Motor index (arm and leg): No differences were found between the treatment groups.
Barthel Index - Activities of Daily Living: Odds ratio for improvement: 2.04
The patient's overall impression of the changes in his or her well-being (OR = 1.71), the care-giver's overall impression of the changes (OR = 2.40) and the physician's overall impression of the changes (OR = 1 , 96) all demonstrated statistically significant superiority for Sativex over placebo.
The long-term benefits of continuing treatment were evaluated in a randomized, placebo-controlled, parallel-group study of drug discontinuation in subjects taking long-term Sativex. 36 patients with a mean duration of taking Sativex of 3.6 years prior to the start of the study were randomized to either continue Sativex treatment or switch to placebo for 28 days. The primary endpoint was the time to treatment failure defined as the time elapsed between the first day of randomized treatment and achieving a 20% increase in the NRS score or between the first day of randomized treatment and premature withdrawal from randomized treatment. Treatment failure was reported in 44% of patients taking Sativex and 94% of patients assigned to the placebo group. The hazard ratio was 0.335 (95% CI 0.16, 0.69).
In a study designed to identify potential for abuse, Sativex taken at a dose of 4 spray applications in a single administration did not show results significantly different from those obtained with placebo. Higher doses of Sativex 8 to 16 spray applications in a single administration demonstrated a potential for abuse comparable to equivalent doses of dronabinol, a synthetic THC. In a QTc interval study, a dose of 4 spray applications of Sativex administered over 20 minutes twice daily was well tolerated while an extremely supratherapeutic dose of 18 spray applications over 20 minutes twice daily resulted in significant psychoactivity and cognitive impairment.
05.2 Pharmacokinetic properties
Absorption
Both THC and CBD are absorbed fairly quickly after Sativex intake (four spray applications) and appear in the plasma within 15 minutes of administering a single oromucosal dose. With Sativex, a mean Cmax value of approximately 4 ng / ml was reached 45-120 minutes after administration of a single dose of 10.8 mg THC and the drug was generally well tolerated with little evidence of significant psychoactivity.
When Sativex was given with food the mean Cmax and AUC for THC was 1.6 and 2.8 times higher than when given in the fasted state. Corresponding values for CBD increased 3.3 and 5.1 times.
Regarding the pharmacokinetic parameters, the degree of variability between patients is high. Following administration of a single dose of Sativex (four spray applications) in the fasted state, the mean plasma THC level was 57.3% CV for Cmax (range 0.97-9.34 ng / ml) and 58.5 % CV for AUC (range 4.2-30.84 h * ng / mL). Similarly, the percentage of CV for CBD was 64.1% (range 0.24-2.57 ng / mL) and 72.5% (range 2.18-14.85 ng / mL), respectively. for the same parameters. After nine consecutive days of dosing, the% CV values for the same parameters were 54.2% (range Cmax = 0.92-6.37) and 37.4% (AUC0-t = 5.34-15.01 h * ng / ml) for THC and 75.7% (range Cmax 0.34-3.39 ng / ml) and 46.6% (AUC0-t = 2.40-13.19 h * ng / ml) for CBD.
There is a high degree of variability in pharmacokinetic parameters between patients following single and repeat dosing. Of the 12 subjects who received four applications of Sativex in a single administration, eight reported a decrease in Cmax values after nine days of multiple dosing while three experienced an increase (with discontinuation in the case of 1 patient). CBD, seven subjects reported a decrease in Cmax values after multiple dosing and four patients an increase.
When Sativex is administered oromucosally, the plasma levels of THC and other cannabinoids are lower than those obtained following inhalation of similar doses of cannabinoids. An 8 mg dose of vaporized THC extract administered by inhalation gave values mean plasma values of Cmax greater than 100 ng / ml within a few minutes after administration with significant psychoactivity.
Table showing the pharmacokinetic parameters of Sativex, vaporized THC extract and smoked cannabis
* Huestis et al, Journal of Analytical Toxicology 1992; 16: 276-82.
Distribution
Cannabinoids are extremely lipophilic and as such are quickly absorbed and distributed in body fat. The relative concentrations in the blood following the oromucosal administration of Sativex are lower than those recorded following the inhalation of the same dose of THC as the absorption process is slower and the redistribution in adipose tissues is rapid. In addition, some of the THC. it is metabolized during the first pass through the liver (hepatic first pass metabolism) and converted into 11-OH-THC, the primary metabolite of THC; similarly CBD is transformed into 7-OH-CBD. THC has a high protein binding (~ 97%). THC and CBD can be stored for up to four weeks in adipose tissues from which they are slowly released at subtherapeutic levels into the bloodstream and then metabolized and eliminated in the urine and faeces.
Metabolism
THC and CBD are metabolized in the liver. Furthermore, part of the THC is metabolized during the first pass through the liver (hepatic first pass metabolism) and converted into 11-OH-THC, the primary metabolite of THC; similarly, CBD is transformed into 7-OH-CBD. The hepatic cytochrome P450 2C9 isoenzyme catalyses the formation of 11-OH-THC, the primary metabolite, which is further metabolized by the liver and converted into other compounds such as 11-nor-carboxy-D9-THC (THC-COOH), the most abundant human metabolite in plasma and urine. The P450-3A subfamily catalyzes the formation of other minor hydroxylated metabolites. CBD is extensively metabolised and over 33 metabolites have been identified in the urine. The major metabolic pathway is C-7 hydroxylation and oxidation followed by further hydroxylation into the pentyl and propenyl groups. The major oxidized metabolite identified is CBD-7-oic acid containing a hydroxyethyl side chain.
See section 4.5 for information on interaction with other medicinal products and metabolism via the cytochrome P450 enzyme system.
Elimination
From clinical studies conducted with Sativex, a "non-compartmental pharmacokinetic analysis showed a" terminal first-order elimination half-life from plasma of 1.94, 3.72 and 5.25 hours for THC and 5.28, 6, 39 and 9.36 hours for CBD following the administration of 2, 4 and 8 spray applications, respectively.
From information reported in the scientific literature, "elimination of oral cannabinoids from plasma is biphasic with an" initial half-life of approximately four hours and terminal elimination half-lives are within a range of 24 "." 36 hours or longer. Cannabinoids are distributed throughout the body, are highly soluble in lipids and accumulate in adipose tissue. The release of cannabinoids from adipose tissue induces the prolongation of the terminal elimination half-life.
05.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
Reproductive toxicity studies conducted with THC and CBD extracts present in Sativex did not reveal any adverse effects on male or female fertility in terms of the number of mated animals, the number of fertile males and females or mating and fertility indices. There was a decrease in absolute epididymal weights with a no-effect dose level of 25 mg / kg / day (150 mg / m2) for male fertility. In studies in rats, no-effect dose levels for effects on embryo and fetal survival in early pregnancy were approximately 1 mg / kg / day (6 mg / m2), which approximates, or is lower than the maximum dose levels of Sativex that can probably be administered in humans. There is no evidence to support teratogenic activity in rats or rabbits at dose levels far in excess of the maximum dose levels that are likely to be possible. to administer to humans. In a pre- and postnatal development study in rats, pup survival and lactation regimen were compromised at doses of 2 and 4 mg / kg / day (12 and 24 mg / m2, respectively. Data published in the scientific literature have shown negative effects of THC and / or CBD on sperm count and motility.
In animal studies, as can be expected, due to the lipophilic nature of cannabinoids, elevated levels of cannabinoids have been found in breast milk. Administration of repeated dosing results in the concentration of cannabinoids in breast milk (plasma levels 40 - 60 times higher). Doses higher than normal clinical doses may have an effect on the growth rates of nursing infants.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Anhydrous ethanol.
Propylene glycol.
Peppermint oil.
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
2 years.
During use, the stability after first opening is:
5.5 ml bottle: 28 days from the date of opening the package;
10 ml bottle: 42 days from the date of opening the package.
06.4 Special precautions for storage
Store in a refrigerator (2 to 8 ° C).
Once opened and used, the refrigerated storage of the spray container is no longer necessary; however, it must be kept at temperatures no higher than 25 ° C.
Store upright.
06.5 Nature of the immediate packaging and contents of the package
Type I brown glass spray container (10 ml glass bottle covered with amber plastic) equipped with pump dispenser equipped with polypropylene suction tube and elastomer neck with polyethylene cap. The pump dispenser delivers 100 microliters per spray.
Packaging: 5.5 ml and 10 ml.
The 5.5 ml package allows you to dispense up to 48 sprays of 100 microliters each after priming the dispenser.
The 10 ml package allows to dispense up to 90 sprays of 100 microliters each after the priming of the dispenser.
1, 2, 3, 4, 5, 6, 10 or 12 glass spray containers per box.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
GW Pharma Ltd
Porton Down Science Park
Salisbury
Wiltshire
SP4 0JQ, United Kingdom
08.0 MARKETING AUTHORIZATION NUMBER
040548012 - "SPRAY FOR ORAL MUCOSA" 1 NEBULIZER BOTTLE WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548024 - "SPRAY FOR ORAL MUCOSA" 2 NEBULIZER BOTTLES WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548036 - "SPRAY FOR ORAL MUCOSA" 3 NEBULIZER BOTTLES WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548048 - "SPRAY FOR ORAL MUCOSA" 4 NEBULIZER BOTTLES WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548051 - "SPRAY FOR ORAL MUCOSA" 5 NEBULIZER BOTTLES WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548063 - "SPRAY FOR ORAL MUCOSA" 6 NEBULIZER BOTTLES WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548075 - "SPRAY FOR ORAL MUCOSA" 10 NEBULIZER BOTTLES WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548087 - "SPRAY FOR ORAL MUCOSA" 12 NEBULIZER BOTTLES WITH 5.5 ML DOSING PUMP - 48 DISPENSES
040548099 - "SPRAY FOR ORAL MUCOSA" 1 NEBULIZER BOTTLE WITH 10 ML DOSING PUMP - 90 DISPENSES
040548101 - "SPRAY FOR ORAL MUCOSA" 2 NEBULIZER BOTTLES WITH 10 ML DOSING PUMP - 90 DISPENSES
040548113 - "SPRAY FOR ORAL MUCOSA" 3 NEBULIZER BOTTLES WITH 10 ML DOSING PUMP - 90 DISPENSES
040548125 - "SPRAY FOR ORAL MUCOSA" 4 NEBULIZER BOTTLES WITH 10 ML DOSING PUMP - 90 DISPENSES
040548137 - "SPRAY FOR ORAL MUCOSA" 5 NEBULIZER BOTTLES WITH 10 ML DOSING PUMP - 90 DISPENSES
040548149 - "SPRAY FOR ORAL MUCOSA" 6 NEBULIZER BOTTLES WITH 10 ML DOSING PUMP - 90 DISPENSES
040548152 - "SPRAY FOR ORAL MUCOSA" 10 NEBULIZER BOTTLES WITH 10 ML DOSING PUMP - 90 DISPENSES
040548164 - "SPRAY FOR ORAL MUCOSA" 12 NEBULIZER BOTTLES WITH 10 ML DOSING PUMP - 90 DISPENSES
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
April 2013
10.0 DATE OF REVISION OF THE TEXT
06/2014
