Epidyolex - summary of medicine characteristics

Summary of medicine characteristics - Epidyolex

1. NAME OF THE MEDICINAL PRODUCT

Epidyolex 100 mg/ml oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 100 mg cannabidiol.

Excipients with known effect

Each ml of solution contains:

79 mg anhydrous ethanol

736 mg refined sesame oil

0.0003 mg benzyl alcohol

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral solution

Clear, colourless to yellow solution

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Epidyolex is indicated for use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS), in conjunction with clobazam, for patients 2 years of age and older.

Epidyolex is indicated for use as adjunctive therapy of seizures associated with tuberous sclerosis complex (TSC) for patients 2 years of age and older.

4.2 Posology and method of administration

Epidyolex should be initiated and supervised by physicians with experience in the treatment of epilepsy.

Posology

For LGS and DS

The recommended starting dose of cannabidiol is 2.5 mg/kg taken twice daily (5 mg/kg/day) for one week. After one week, the dose should be increased to a maintenance dose of 5 mg/kg twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, each dose can be further increased in weekly increments of 2.5 mg/kg administered twice daily (5 mg/kg/day) up to a maximum recommended dose of 10 mg/kg twice daily (20 mg/kg/day).

Any dose increases above 10 mg/kg/day, up to the maximum recommended dose of 20 mg/kg/day, should be made considering individual benefit and risk and with adherence to the full monitoring schedule (see section 4.4).

For TSC

The recommended starting dose of cannabidiol is 2.5 mg/kg taken twice daily (5 mg/kg/day) for one week. After one week, the dose should be increased to a dose of 5 mg/kg twice daily (10 mg/kg/day) and the clinical response and tolerability should be assessed. Based on individual clinical response and tolerability, each dose can be further increased in weekly increments of 2.5 mg/kg administered twice daily (5 mg/kg/day) up to a maximum recommended dose of 12.5 mg/kg twice daily (25 mg/kg/day).

Any dose increases above 10 mg/kg/day, up to the maximum recommended dose of 25 mg/kg/day, should be made considering individual benefit and risk and with adherence to the full monitoring schedule (see section 4.4).

The dosage recommendations for LGS, DS and TSC are summarised in the following table:

Table 1: Dosage recommendations

	LGS and DS	TSC
Starting dose – first week	2.5 mg/kg taken twice daily (5 mg/kg/day)
Second week	Maintenance dose 5 mg/kg twice daily (10 mg/kg/day)	5 mg/kg twice daily (10 mg/kg/day)
Further titration as applicable (incremental steps)	weekly increments of 2.5 mg/kg administered twice daily
Further titration as applicable (incremental steps)	(5 mg/	kg/day)
Maximal recommended dose	10 mg/kg twice daily (20 mg/kg/day)	12.5 mg/kg twice daily (25 mg/kg/day)

Each Epidyolex carton is supplied with:

– Two 1 ml syringes graduated in 0.05 ml increments (each 0.05 ml increment corresponds to 5 mg cannabidiol)
– Two 5 ml syringes graduated in 0.1 ml increments (each 0.1 ml increment corresponds to 10 mg cannabidiol)

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with transaminase elevations greater than 3 times the upper limit of normal (ULN) and bilirubin greater than 2 times the ULN (see section 4.4).

4.4 Special warnings and precautions for use

Hepatocellular injury

Cannabidiol can cause dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) (see section 4.8). The elevations typically occur in the first two months of treatment initiation; however, there were cases observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate.

In clinical trials, the majority of ALT elevations occurred in patients taking concomitant valproate. Concomitant use of clobazam also increased the incidence of transaminase elevations, although to a lesser extent than valproate. Dose adjustment or discontinuation of valproate or dose adjustment of clobazam should be considered if transaminase elevations occur.

Resolution of transaminase elevations occurred with discontinuation of cannabidiol or reduction of cannabidiol and/or concomitant valproate in about two-thirds of the cases. In about one-third of the cases, transaminase elevations resolved during continued treatment with cannabidiol, without dose reduction.

Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevations when taking cannabidiol. In some patients, a synergistic effect of concomitant treatment with valproate upon baseline elevated transaminases resulted in a higher risk of transaminase elevations.

In an uncontrolled study in patients in a different non-epilepsy indication, 2 elderly patients experienced elevations of alkaline phosphatase levels above 2 times the ULN in combination with transaminase elevations. The elevations resolved after discontinuation of cannabidiol.

Monitoring

In general, transaminase elevations of greater than 3 times the ULN in the presence of elevated bilirubin without an alternative explanation are an important predictor of severe liver injury. Early identification of elevated transaminase may decrease the risk of a serious outcome. Patients with elevated baseline transaminase levels above 3 times the ULN, or elevations in bilirubin above 2 times the ULN, should be evaluated prior to initiation of cannabidiol treatment.

Prior to starting treatment with cannabidiol, obtain serum transaminases (ALT and AST) and total bilirubin levels.

Routine Monitoring:

Serum transaminases and total bilirubin levels should be obtained at 1 month, 3 months, and 6 months after initiation of treatment with cannabidiol, and periodically thereafter or as clinically indicated.

Upon changes in cannabidiol dose above 10 mg/kg/day or changes in medicinal products (dose change or additions) that are known to impact the liver, this monitoring schedule should be restarted.

Intensified Monitoring :

Patients with identified baseline elevations of ALT or AST and patients who are taking valproate should have serum transaminases and total bilirubin levels obtained at 2 weeks, 1 month, 2 months, 3 months, and 6 months after initiation of treatment with cannabidiol, and periodically thereafter or as clinically indicated. Upon changes in cannabidiol dose above 10 mg/kg/day or changes in medicinal products (dose change or additions) that are known to impact the liver, this monitoring schedule should be restarted.

If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, serum transaminases and total bilirubin should be promptly measured and treatment with cannabidiol should be interrupted or discontinued, as appropriate. Cannabidiol should be discontinued in any patients with elevations of transaminase levels greater than 3 times the ULN and bilirubin levels greater than 2 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the ULN should also have treatment discontinued. Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes. Dose adjustment of any co-administered medicinal product that is known to affect the liver should be considered (e.g., valproate and clobazam) (see section 4.5).

Somnolence and sedation

Cannabidiol can cause somnolence and sedation, which occur more commonly early in treatment and may diminish with continued treatment. The occurrence was higher for those patients on concomitant clobazam (see sections 4.5 and 4.8). Other CNS depressants, including alcohol, can potentiate the somnolence and sedation effect.

Increased seizure frequency

As with other AEDs, a clinically relevant increase in seizure frequency may occur during treatment with cannabidiol, which may require adjustment in dose of cannabidiol and/or concomitant AEDs, or discontinuation of cannabidiol, should the benefit-risk be negative. In the phase 3 clinical trials investigating LGS, DS and TSC, the observed frequency of status epilepticus was similar between the cannabidiol and placebo groups.

Suicidal behaviour and ideation

Suicidal behaviour and ideation have been reported in patients treated with AEDs in several indications. A meta-analysis of randomised placebo-controlled trials with AEDs has shown a small increased risk of suicidal behaviour and ideation. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for cannabidiol.

Patients should be monitored for signs of suicidal behaviour and ideation and appropriate treatment should be considered. Patients and caregivers of patients should be advised to seek medical advice should any signs of suicidal behaviour and ideation emerge.

Decreased weight

Cannabidiol can cause weight loss or decreased weight gain (see section 4.8). In LGS, DS and TSC patients, this appeared to be dose-related. In some cases, decreased weight was reported as an adverse event (see Table 3). Decreased appetite and weight loss may result in slightly reduced height gain.

Continuous weight loss/absence of weight gain should be periodically checked to evaluate if cannabidiol treatment should be continued.

Sesame oil in the formulation

This medicinal product contains refined sesame oil which may rarely cause severe allergic reactions.

Benzyl alcohol in the formulation

This medicinal product contains 0.0003 mg/ml benzyl alcohol corresponding to 0.0026 mg per maximal Epidyolex dose (Epidyolex 12.5 mg/kg per dose (TSC) for an adult weighing 70 kg). Benzyl alcohol may cause allergic reactions.

Populations not studied

Patients with clinically significant cardiovascular impairment were not included in the TSC clinical development programme.

4.5 Interaction with other medicinal products and other forms of interaction

CYP3A4 or CYP2C19 inducers

The strong CYP3A4/2C19 inducing agent rifampicin (600 mg administered once daily) decreased plasma concentrations of cannabidiol and of 7-hydroxy-cannabidiol (7-OH-CBD; an active metabolite of cannabidiol) by approximately 30% and 60%, respectively. Other strong inducers of CYP3A4 and/or CYP2C19, such as carbamazepine, enzalutamide, mitotane, St. John’s wort, when administered concomitantly with cannabidiol, may also cause a decrease in the plasma concentrations of cannabidiol and of 7-OH-CBD by a similar amount. These changes may result in a decrease in the effectiveness of cannabidiol. Dose adjustment may be necessary.

UGT inhibitors

Cannabidiol is a substrate for UGT1A7, UGT1A9 and UGT2B7. No formal drug-drug interaction studies have been conducted with cannabidiol in combination with UGT inhibitors, therefore caution should be taken when co-administering drugs that are known inhibitors of these UGTs. Dose reduction of cannabidiol and/or the inhibitor may be necessary when given in combination.

Concomitant AED treatments

The pharmacokinetics of cannabidiol are complex and may cause interactions with the patient’s concomitant AED treatments. cannabidiol and/or concomitant AED treatment should therefore be adjusted during regular medical supervision and the patient should be closely monitored for adverse drug reactions. In addition, monitoring of plasma concentrations should be considered.

The potential for drug-drug interactions with other concomitant AEDs has been assessed in healthy volunteers and patients with epilepsy for clobazam, valproate, stiripentol and everolimus. Although no formal drug-drug interaction studies have been performed for other AEDs, phenytoin and lamotrigine are addressed based on in vitro data.

Clobazam

When cannabidiol and clobazam are co-administered, bi-directional PK interactions occur. Based on a healthy volunteer study, elevated levels (3– to 4-fold) of N-desmethylclobazam (an active metabolite of clobazam) can occur when combined with cannabidiol, likely mediated by CYP2C19 inhibition, with no effect on clobazam levels. In addition, there was an increased exposure to 7-OH-CBD, for which plasma area under the curve (AUC) increased by 47% (see section 5.2). Increased systemic levels of these active substances may lead to enhanced pharmacological effects and to an increase in adverse drug reactions. Concomitant use of cannabidiol and clobazam increases the incidence of somnolence and sedation compared with placebo (see sections 4.4 and 4.8). Reduction in dose of clobazam should be considered if somnolence or sedation are experienced when clobazam is co-administered with cannabidiol.

Valproate

Concomitant use of cannabidiol and valproate increases the incidence of transaminase enzyme elevations (see section 4.4). The mechanism of this interaction remains unknown. If clinically significant increases of transaminases occur, cannabidiol and/or concomitant valproate should be reduced or discontinued in all patients until a recovery of transaminase elevations are observed (see section 4.4). Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic medicinal products and cannabidiol (see section 4.4).

Concomitant use of cannabidiol and valproate increases the incidence of diarrhoea and events of decreased appetite. The mechanism of this interaction is unknown.

Stiripentol

When cannabidiol was combined with stiripentol in a healthy volunteer trial there was an increase in stiripentol levels of 28% for maximum measured plasma concentration (Cmax) and 55% for AUC. In patients, however, the effect was smaller, with an increase in stiripentol levels of 17% in Cmax and 30% in AUC. The clinical importance of these results has not been studied. The patient should be closely monitored for adverse drug reactions.

Phenytoin

Exposure to phenytoin may be increased when it is co-administered with cannabidiol, as phenytoin is largely metabolised via CYP2C9, which is inhibited by cannabidiol in vitro. There have not been any clinical studies formally investigating this interaction. Phenytoin has a narrow therapeutic index, so combining cannabidiol with phenytoin should be initiated with caution and if tolerability issues arise, dose reduction of phenytoin should be considered.

Lamotrigine

Lamotrigine is a substrate for UGT enzymes including UGT2B7 which is inhibited by cannabidiol in vitro. There have not been any clinical studies formally investigating this interaction. Lamotrigine levels may be elevated when it is co-administered with cannabidiol.

Everolimus

Coadministration of cannabidiol (12.5 mg/kg twice daily) with the P-gp and CYP3A4 substrate everolimus (5 mg) in a healthy volunteer study led to an increase in everolimus exposure of approximately 2.5-fold for both Cmax and AUC. The mechanism for this interaction is believed to be inhibition of intestinal P-gp efflux, leading to increased bioavailability of everolimus, because cannabidiol did not affect midazolam exposure in another interaction study. The half-life of everolimus was not affected, confirming the lack of systemic inhibitory effects of cannabidiol on P-gp and CYP3A4 activity. When initiating cannabidiol in patients taking everolimus, monitor therapeutic drug levels of everolimus and adjust the dosage accordingly. When initiating everolimus in patients taking a stable dosage of cannabidiol, a lower starting dose of everolimus is recommended, with therapeutic drug monitoring.

Potential for cannabidiol to affect other medicinal products

CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A9, and UGT2B7 Substrates

In vivo data from steady-state dosing with cannabidiol (750 mg twice daily) when co-administered with a single dose of caffeine (200 mg), a sensitive CYP1A2 substrate, showed increased caffeine exposure by 15% for Cmax and 95% for AUC compared to when caffeine was administered alone. These data indicate that cannabidiol is a weak inhibitor of CYP1A2. Similar modest increases in exposure may be observed with other sensitive CYP1A2 substrates (e.g., theophylline or tizanidine). The clinical importance of these findings has not been studied. The patient should be closely monitored for adverse drug reactions.

In vitro data predict drug-drug interactions with CYP2B6 substrates (e.g., bupropion, efavirenz), uridine 5' diphospho-glucuronosyltransferase 1A9 (UGT1A9) (e.g., diflunisal, propofol, fenofibrate), and UGT2B7 (e.g., gemfibrozil, morphine, lorazepam) when co-administered with cannabidiol.

Co-administration of cannabidiol is also predicted to cause clinically significant interactions with CYP2C8 (repaglinide) and CYP2C9 (e.g., warfarin) substrates.

In vitro data have demonstrated that cannabidiol inhibits CYP2C19, which may cause increased plasma concentrations of medicines that are metabolised by this isoenzyme such as clobazam and omeprazole. Dose reduction should be considered for concomitant medicinal products that are sensitive CYP2C19 substrates or that have a narrow therapeutic index.

Because of potential inhibition of enzyme activity, dose reduction of substrates of UGT1A9, UGT2B7, CYP2C8, and CYP2C9 should be considered, as clinically appropriate, if adverse reactions are experienced when administered concomitantly with cannabidiol. Because of potential for both induction and inhibition of enzyme activity, dose adjustment of substrates of CYP1A2 and CYP2B6 should be considered, as clinically appropriate.

In vitro assessment of interaction with UGT enzymes

In vitro data suggest that cannabidiol is a reversible inhibitor of UGT1A9 and UGT2B7 activity at clinically relevant concentrations. The metabolite 7-carboxy-cannabidiol (7-COOH-CBD) is also an inhibitor of UGT1A1, UGT1A4 and UGT1A6-mediated activity in vitro. Dose reduction of the substrates may be necessary when cannabidiol is administered concomitantly with substrates of these UGTs.

Sensitive P-gp substrates given orally

Coadministration of cannabidiol with orally administered everolimus, a P-gp and CYP3A4 substrate, has increased everolimus bioavailability likely due to inhibition of intestinal P-gp efflux of everolimus. Increases in exposure of other orally administered sensitive P-gp substrates (e.g., sirolimus, tacrolimus, digoxin) may occur on coadministration with cannabidiol. Therapeutic drug monitoring and dose reduction of other P-gp substrates should be considered when given orally and concurrently with cannabidiol.

Ethanol in the formulation

Each ml of Epidyolex contains 79 mg of ethanol, equivalent to 10% v/v anhydrous ethanol, i.e., up to 691.3 mg ethanol/ per maximal single Epidyolex dose (12.5 mg/kg) for an adult weighing 70 kg (9.9 mg ethanol/ kg). For an adult weighing 70 kg, this is equivalent to 17 ml of beer, or 7 ml of wine per dose.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are only limited data from the use of cannabidiol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

As a precautionary measure, cannabidiol should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus.

Breast-feeding

There are no clinical data on the presence of cannabidiol or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.

Studies in animals have shown toxicological changes in lactating animals, when the mother was treated with cannabidiol (see section 5.3).

There are no human studies on excretion of cannabidiol in breast milk. Given that cannabidiol is highly protein bound and will likely pass freely from plasma into milk, as a precaution, breast-feeding should be discontinued during treatment.

Fertility

No human data on the effect of cannabidiol on fertility are available.

No effect on reproductive ability of male or female rats was noted with an oral dose of up to 150 mg/kg/day cannabidiol (see section 5.3).

4.7 Effects on ability to drive and use machines

Cannabidiol has major influence on the ability to drive and operate machines because it may cause somnolence and sedation (see section 4.4). Patients should be advised not to drive or operate machinery until they have gained sufficient experience-to gauge whether it adversely affects their abilities (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions reported with cannabidiol in the recommended dose range of 10 to 25 mg/kg/day are shown below.

The most common adverse reactions are somnolence, decreased appetite, diarrhoea, pyrexia, fatigue, and vomiting.

The most frequent cause of discontinuations was transaminase elevation.

Tabulated list of adverse reactions

Adverse reactions reported with cannabidiol in placebo-controlled clinical studies are listed in the table below by System Organ Class and frequency.

The frequencies are defined as follows: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3: Tabulated list of adverse reactions

System Organ Class	Frequency	Adverse reactions from clinical trials
Infections and infestations	Common	Pneumoniaa, Urinary tract infection
Metabolism and nutrition disorders	Very common	Decreased appetite
Psychiatric disorders	Common	Irritability, Aggression
Nervous system disorders	Very common	Somnolencea
Nervous system disorders	Common	Lethargy, Seizure
Respiratory, thoracic and mediastinal disorders	Common	Cough
Gastrointestinal disorders	Very common	Diarrhoea, Vomiting
Gastrointestinal disorders	Common	Nausea
Hepatobiliary disorders	Common	AST increased, ALT increased, GGT increased
Skin and subcutaneous tissue disorders	Common	Rash

System Organ Class	Frequency	Adverse reactions from clinical trials
General disorders and administration site conditions	Very common	Pyrexia, Fatigue
Investigations	Common	Weight decreased

a Grouped Terms: Pneumonia: Pneumonia, Pneumonia RSV, Pneumonia mycoplasmal, Pneumonia adenoviral, Pneumonia viral, Aspiration pneumonia; Somnolence: Somnolence, Sedation.

Description of selected adverse reactions

Hepatocellular injury

Cannabidiol can cause dose-related elevations of ALT and AST (see section 4.4).

In controlled studies for LGS, DS (receiving 10 or 20 mg/kg/day) and for TSC (receiving 25 mg/kg/day), the incidence of ALT elevations above 3 times the ULN was 12% in cannabidiol-treated patients compared with < 1% in patients on placebo.

Less than 1% of cannabidiol -treated patients had ALT or AST levels greater than 20 times the ULN. There have been cases of transaminase elevations associated with hospitalisation in patients taking cannabidiol.

Risk Factors for Hepatocellular injury

Concomitant Valproate and Clobazam, Dose of cannabidiol and Baseline Transaminase Elevations

Concomitant Valproate and Clobazam

In cannabidiol-treated patients receiving doses of 10, 20, and 25 mg/kg/day, the incidence of ALT elevations greater than 3 times the ULN was 23% in patients taking both concomitant valproate and clobazam, 19% in patients taking concomitant valproate (without clobazam), 3% in patients taking concomitant clobazam (without valproate), and 3% in patients taking neither drug.

Dose

ALT elevations greater than 3 times the ULN were reported in 15% of patients taking cannabidiol 20 or 25 mg/kg/day compared with 3% in patients taking cannabidiol 10 mg/kg/day.

The risk of ALT elevations was higher at dosages higher than the 25 mg/kg/day in the controlled study in TSC.

Baseline transaminase elevations

In controlled trials (see section 5.1) in patients taking cannabidiol 20 or 25 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 times the ULN was 29% (80% of these were on valproate) when ALT was above the ULN at baseline, compared to 12% (89% of these were on valproate) when ALT was within the normal range at baseline. A total of 5% of patients (all on valproate) taking cannabidiol 10 mg/kg/day experienced ALT elevations greater than 3 times the ULN when ALT was above the ULN at baseline, compared with 3% of patients (all on valproate) in whom ALT was within the normal range at baseline.

Somnolence and sedation

Somnolence and sedation (including lethargy) events have been observed in controlled trials (see section 4.4) with cannabidiol in LGS, DS and TSC, including 29% of cannabidiol-treated patients (30% of patients taking cannabidiol 20 or 25 mg/kg/day and 27% of patients taking cannabidiol 10 mg/kg/day). These adverse reactions were observed at higher incidences at dosages above 25 mg/kg/day in the controlled study in TSC. The rate of somnolence and sedation (including lethargy) was higher in patients on concomitant clobazam (43% in cannabidiol-treated patients taking clobazam, compared with 14% in cannabidiol-treated patients not on clobazam).

Seizures

In the controlled trial in TSC patients, an increased frequency of adverse events associated with seizure worsening was seen at doses above 25 mg/kg/day. Although no clear pattern was established, the adverse events reflected increased seizure frequency or intensity, or new seizure types. The frequency of adverse events associated with seizure worsening was 11% for patients taking

25 mg/kg/day cannabidiol and 18% for patients taking cannabidiol doses greater than 25 mg/kg/day, compared to 9% in patients taking placebo.

Decreased weight

Cannabidiol can cause weight loss or decreased weight gain (see section 4.4). In LGS, DS and TSC patients, the decrease in weight appeared to be dose-related, with 21% of patients on cannabidiol 20 or 25 mg/kg/day experiencing a decrease in weight of > 5%, compared to 7% in patients on cannabidiol 10 mg/kg/day. In some cases, the decreased weight was reported as an adverse event (see Table 3 above). Decreased appetite and weight loss may result in slightly reduced height gain.

Diarrhoea

Cannabidiol can cause dose-related diarrhoea. In controlled trials in LGS and DS, the frequency of diarrhoea was 13% in patients receiving 10 mg/kg/day cannabidiol and 21% in patients receiving 20 mg/kg/day cannabidiol, compared to 10% in patients receiving placebo. In a controlled trial in TSC, the frequency of diarrhoea was 31% in patients receiving 25 mg/kg/day cannabidiol and 56% in patients receiving doses greater than 25 mg/kg/day cannabidiol, compared to 25% in patients receiving placebo.

In the clinical trials, the first onset of diarrhoea was typically in the first 6 weeks of treatment with cannabidiol. The median duration of diarrhoea was 8 days. The diarrhoea led to cannabidiol dose reduction in 10% of patients, temporary dose interruption in 1% of patients and permanent discontinuation in 2% of patients.

Haematologic abnormalities

Cannabidiol can cause decreases in haemoglobin and haematocrit. In LGS, DS and TSC patients, the mean decrease in haemoglobin from baseline to end of treatment was –0.36 g/dL in cannabidiol-treated patients receiving 10, 20, or 25 mg/kg/day. A corresponding decrease in haematocrit was also observed, with a mean change of –1.3% in cannabidiol-treated patients.

Twenty-seven percent (27%) of cannabidiol-treated patients with LGS and DS and 38% of cannabidiol-treated patients (25 mg/kg/day) with TSC developed a new laboratory-defined anaemia during the course of the study (defined as a normal haemoglobin concentration at baseline, with a reported value less than the lower limit of normal at a subsequent time point).

Increases in creatinine

Cannabidiol can cause elevations in serum creatinine. The mechanism has not yet been determined. In controlled studies in healthy adults and in patients with LGS, DS and TSC, an increase in serum creatinine of approximately 10% was observed within 2 weeks of starting cannabidiol. The increase was reversible in healthy adults. Reversibility was not assessed in studies in LGS, DS or TSC.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. listed in

4.9 Overdose

Symptoms

Experience with doses higher than the recommended therapeutic dose is limited. Mild diarrhoea and somnolence have been reported in healthy adult subjects taking a single dose of 6000 mg; this equates to a dose of over 85 mg/kg for a 70 kg adult. These adverse reactions resolved upon study completion.

Management of overdose

In the event of overdose the patient should be observed and appropriate symptomatic treatment given, including monitoring of vital signs.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics; ATC code: N03AX24

Mechanism of action

The precise mechanisms by which cannabidiol exerts its anticonvulsant effects in humans are unknown. Cannabidiol does not exert its anticonvulsant effect through interaction with cannabinoid receptors. Cannabidiol reduces neuronal hyper-excitability through modulation of intracellular calcium via G protein-coupled receptor 55 (GPR55) and transient receptor potential vanilloid 1 (TRPV-1) channels, as well as modulation of adenosine-mediated signalling through inhibition of adenosine cellular uptake via the equilibrative nucleoside transporter 1 (ENT-1).

Pharmacodynamic effects

In patients, there is a potential additive anticonvulsant effect from the bi-directional pharmacokinetic interaction between cannabidiol and clobazam, which leads to increases in circulating levels of their respective active metabolites, 7-OH-CBD (approximately 1.5-fold) and N-CLB (approximately 3-fold) (see sections 4.5, 5.1 and 5.2).

Clinical efficacy

Adjunctive therapy in patients with Lennox-Gastaut syndrome (LGS)

The efficacy of cannabidiol for the adjunctive therapy of seizures associated with Lennox-Gastaut syndrome (LGS) was evaluated in two randomised, double-blind, placebo-controlled, parallel-group studies (GWPCARE3 and GWPCARE4). Each study consisted of a 4-week baseline period, a 2-week titration period and a 12-week maintenance period. Mean age of the study population was 15 years and 94% were taking 2 or more concomitant AEDs (cAEDs) during the trial. The most commonly used cAEDs (> 25% of patients) in both trials were valproate, clobazam, lamotrigine, levetiracetam, and rufinamide. Approximately 50% of the patients were taking concomitant clobazam. Of the patients that were not taking clobazam, the majority had previously taken and subsequently discontinued clobazam treatment.

The primary endpoint was the percentage change from baseline in drop seizures per 28 days over the treatment period for the cannabidiol group compared to placebo. Drop seizures were defined as atonic, tonic, or tonic-clonic seizures that led or could have led to a fall or injury. Key secondary endpoints were the proportion of patients with at least a 50% reduction in drop seizure frequency, the percentage change from baseline in total seizure frequency, and Subject/Caregiver Global Impression of Change at the last visit.

Subgroup analyses were conducted on multiple factors, including cAEDs. Results of the subgroup analysis of patients treated with clobazam compared to patients treated without clobazam, indicated that there is residual statistical uncertainty regarding the treatment effect of cannabidiol in patients not taking clobazam. In this population, efficacy has not been established.

Table 4 summarises the primary endpoint of percent reduction from baseline in drop seizures, and the key secondary measure of proportion of patients with at least a 50% reduction in drop seizure frequency, as well as results of the subgroup analysis for these outcome measures in patients treated with concomitant clobazam.

Table 4: Primary and > 50% responder key secondary outcome measures and subgroup analysis in LGS studies

		Overall	N	Subgroup With Clobazam	N
DROP SEIZU	RES PER 28 DAYS
Percentage Reduction from Baselinea
GWPCARE3	Placebo 10 mg/kg/day 20 mg/kg/day	17.2% 37.2% 41.9%	76 73 76	22.7% 45.6% 64.3%	37 37 36
GWPCARE4	Placebo 20 mg/kg/day	21.8% 43.9%	85 86	30.7% 62.4%	42 42
Difference or	’ercent Reduction Compared with Placebo (95% CI), p-valueb
GWPCARE3	10 mg/kg/day 20 mg/kg/day	19.2 (7.7, 31.2) p = 0.0016 21.6 (6.7, 34.8) p = 0.0047		29.6% (2.4%, 49.2%) p = 0.0355c 53.8% (35.7%, 66.8%) p< 0.0001c
GWPCARE4	20 mg/kg/day	17.2 (4.1, 30.3) p = 0.0135		45.7% (27.0%, 59.6%) p< 0.0001c
> 50% REDUCTION IN DROP SEIZURES (RESPOND]			ER ANALYSIS)
Percentage of > 50% Responders, p-valued
GWPCARE3	Placebo 10 mg/kg/day 20 mg/kg/day	14.5% 35.6% p = 0.0030 39.5% p = 0.0006	76 73 76	21.6% 40.5% p = 0.0584c 55.6% p = 0.0021c	37 37 36
GWPCARE4	Placebo 20 mg/kg/day	23.5% 44.2% p = 0.0043	85 86	28.6% 54.8% p = 0.0140c	42 42

CI=95% confidence interval.

a Data for the overall population are presented as median percent reduction from baseline. Data for the with clobazam subgroup are presented as percent reduction from baseline estimated from a negative binomial regression analysis.

b Overall data are presented as estimated median difference and p-value from a Wilcoxon rank-sum test. Data for the with clobazam subgroup are estimated from a negative binomial regression analysis. c Nominal p-value.

d The Overall p-value is based on a Cochran-Mantel-Haenszel test; the nominal p-values for the with clobazam subgroup are based on logistic regression analysis.

Additional secondary outcome measures in the subgroup of patients treated with concomitant clobazam

Cannabidiol was associated with an increase in the percentage of subjects experiencing a greater than or equal to 75% reduction in drop seizure frequency during the treatment period in each trial (11% 10 mg/kg/day cannabidiol, 31% to 36% 20 mg/kg/day cannabidiol, 3% to 7% placebo).

In each trial, patients receiving cannabidiol experienced a greater median percentage reduction in total seizures compared with placebo (53% 10 mg/kg/day, 64% to 66% 20 mg/kg/day, 25% for each placebo group; p = 0.0025 for 10 mg/kg/day and p< 0.0001 for each 20 mg/kg/day group vs. placebo).

Greater improvements in overall condition, as measured by Global Impression of Change scores at the last visit, were reported by caregivers and patients with both doses of cannabidiol (76% on 10 mg/kg/day, 80% for each group on 20 mg/kg/day, 31% to 46% on placebo; p = 0.0005 for 10 mg/kg/day and p< 0.0001 and 0.0003 for 20 mg/kg/day vs. placebo).

Compared with placebo, cannabidiol was associated with an increase in the number of drop seizure-free days during the treatment period in each trial, equivalent to 3.3 days per 28 days (10 mg/kg/day) and 5.5 to 7.6 days per 28 days (20 mg/kg/day).

Adjunctive therapy in patients with Dravet syndrome

The efficacy of cannabidiol for the adjunctive therapy of seizures associated with Dravet syndrome (DS) was evaluated in two randomised, double-blind, placebo-controlled, parallel-group studies (GWPCARE2 and GWPCARE1). Each study consisted of a 4-week baseline period, a 2-week titration period and a 12-week maintenance period. Mean age of the study population was 9 years and 94% were taking 2 or more cAEDs during the trial. The most commonly used cAEDs (> 25% of patients) in both trials were valproate, clobazam, stiripentol, and levetiracetam. Approximately 65% of the patients were taking concomitant clobazam. Of the patients that were not taking clobazam, the majority had previously taken and subsequently discontinued clobazam treatment.

The primary endpoint was the change in convulsive seizure frequency during the treatment period (Day 1 to the end of the evaluable period) compared to baseline (GWPCARE2), and the percentage change from baseline in convulsive seizures per 28 days over the treatment period (GWPCARE1) for the cannabidiol groups compared to placebo. Convulsive seizures were defined as atonic, tonic, clonic, and tonic-clonic seizures. Key secondary endpoints for GWPCARE2 were the proportion of patients with at least a 50% reduction in convulsive seizure frequency, the change in total seizure frequency, and Caregiver Global Impression of Change at the last visit. The key secondary endpoint for GWPCARE1 was the proportion of patients with at least a 50% reduction in convulsive seizure frequency.

Table 5 summarises the primary endpoint of percent reduction from baseline in convulsive seizures, and the key secondary measure of proportion of patients with at least a 50% reduction in convulsive seizure frequency, as well as results of the subgroup analysis for these outcome measures in patients treated with concomitant clobazam.

Table 5 : Primary and > 50% responder key secondary outcome measures and subgroup analysis in DS studies

		Overall	N	Subgroup With Clobazam	N
CONVULSIVE SEIZ1	URES PER 28 DAYS
Percentage Reduction from Baselinea
GWPCARE2	Placebo 10 mg/kg/day 20 mg/kg/day	26.9% 48.7% 45.7%	65 66 67	37.6% 60.9% 56.8%	41 45 40
GWPCARE1	Placebo 20 mg/kg/day	13.3% 38.9%	59 61	18.9% 53.6%	38 40
Difference or Percent Reduction Compared with Placebo (95% CI),				p-valueb
GWPCARE2	10 mg/kg/day 20 mg/kg/day	29.8% (8.4%, 46.2%) p = 0.0095 25.7% (2.9%, 43.2%) p = 0.0299		37.4% (13.9%, 54.5%) p = 0.0042c 30.8% (3.6%, 50.4%) p = 0.0297c
GWPCARE1	20 mg/kg/day	22.8 (5.4, 41.1) p = 0.0123		42.8% (17.4%, 60.4%) p = 0.0032c
> 50% REDUCTION IN CONVULSIVE SEIZURES (RESPONDER				t ANALYSIS)
Percentage of > 50% Responders, p-valued
GWPCARE2	Placebo 10 mg/kg/day 20 mg/kg/day	26.2% 43.9% p = 0.0332 49.3% p = 0.0069	65 66 67	36.6% 55.6% p = 0.0623c 62.5% p = 0.0130c	41 45 40
GWPCARE1	Placebo 20 mg/kg/day	27.1% 42.6% p = 0.0784	59 61	23.7% 47.5% p = 0.0382c	38 40

CI=95% confidence interval.

a For study GWPCARE1, overall data are presented as median percent reduction from baseline. Data for study GWPCARE2 and the with clobazam subgroup are presented as percent reduction from baseline estimated from a negative binomial regression analysis.

b For study GWPCARE1, overall data are presented as estimated median difference and p-value from a Wilcoxon rank-sum test. Data for study GWPCARE2 and the with clobazam subgroup are estimated from a negative binomial regression analysis.

c Nominal p-value.

d The Overall p-value is based on a Cochran-Mantel-Haenszel test; the nominal p-value for the with clobazam subgroup is based on logistic regression analysis.

Additional secondary outcome measures in the subgroup of patients treated with concomitant clobazam

Cannabidiol was associated with an increase in the percentage of subjects experiencing a greater than or equal to 75% reduction in convulsive seizure frequency during the treatment period in each trial (36% 10 mg/kg/day cannabidiol, 25% for each 20 mg/kg/day cannabidiol group, 10% to 13% placebo).

In each trial, patients receiving cannabidiol experienced a greater percentage reduction in total seizures compared with placebo (66% 10 mg/kg/day, 54% to 58% 20 mg/kg/day, 27% to 41% placebo;

p = 0.0003 for 10 mg/kg/day and p = 0.0341 and 0.0211 for 20 mg/kg/day vs. placebo).

Greater improvements in overall condition, as measured by Global Impression of Change scores at the last visit, were reported by caregivers and patients with both doses of cannabidiol (73% on

10 mg/kg/day, 62% to 77% on 20 mg/kg/day, 30% to 41% on placebo; p = 0.0009 for 10 mg/kg/day and p = 0.0018 and 0.0136 for 20 mg/kg/day vs. placebo).

Compared with placebo, cannabidiol was associated with an increase in the number of convulsive seizure-free days during the treatment period in each trial, equivalent to 2.7 days per 28 days (10 mg/kg/day) and 1.3 to 2.2 days per 28 days (20 mg/kg/day).

Adult population

The DS population in studies GWPCARE2 and GWPCARE1 was predominantly paediatric patients, with only 5 adult patients who were 18 years old (1.6%), and therefore limited efficacy and safety data were obtained in the adult DS population.

Dose response

Given that there was no consistent dose response between 10 mg/kg/day and 20 mg/kg/day in the LGS and DS studies, cannabidiol should be titrated initially to the recommended maintenance dose of 10 mg/kg/day (see Section 4.2). In individual patients titration up to a maximum dose of 20 mg/kg/day may be considered, based on the benefit-risk (see Section 4.2).

Open-label data

Across both randomised LGS studies, 99.5% of patients (N = 366) who completed the studies were enrolled into the long-term open-label extension (OLE) study (GWPCARE5). In the subgroup of LGS patients treated with concomitant clobazam for 37 to 48 weeks (N = 168), the median percentage reduction from baseline in drop seizure frequency was 71% during Week 1–12 (N = 168), which was maintained through to Week 37–48, with a median percentage reduction from baseline in drop seizure frequency of 62%.

Across both randomised DS studies, 97.7% of patients (N = 315) who completed the studies were enrolled into GWPCARE5. In the subgroup of DS patients treated with concomitant clobazam for 37 to 48 weeks (N = 148), the median percentage reduction from baseline in convulsive seizure frequency was 64% during Week 1–12 (N = 148, which was maintained through to Week 37–48, with a median percentage reduction from baseline in convulsive seizure frequency of 58%.

Adjunctive therapy in patients with tuberous sclerosis complex (TSC)

The efficacy of cannabidiol (25 and 50 mg/kg/day) for the adjunctive therapy of seizures associated with TSC was evaluated in a randomised, double-blind, placebo-controlled, parallel-group study (GWPCARE6). The study consisted of a 4-week baseline period, a 4-week titration period and a 12-week maintenance period (16-week treatment and primary evaluation period).

Mean age of the study population was 14 years and all patients but one were taking one or more concomitant AEDs (cAEDs) during the study. The most commonly used cAEDs (> 25% of patients) were valproate (45%), vigabatrin (33%), levetiracetam (29%), and clobazam (27%).

The primary endpoint was the change in number of TSC-associated seizures during the treatment period (maintenance and titration) compared to baseline for the cannabidiol group compared to placebo. TSC-associated seizures were defined as focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and generalized seizures (tonic-clonic, tonic, clonic or atonic seizures). Key secondary endpoints were the proportion of patients with at least a 50% reduction in TSC-associated seizure frequency, Subject/Caregiver Global Impression of Change at the last visit and the percentage change from baseline in total seizure frequency.

Cannabidiol 50 mg/kg/day was shown to have a similar level of seizure reduction as 25 mg/kg/day. However, this dose was associated with an increased rate of adverse reactions compared to the 25 mg/kg/day and therefore the maximum recommended dose is 25 mg/kg/day.

Table 6 summarises the primary endpoint of percent reduction from baseline in TSC-associated seizures, and the key secondary measure of proportion of patients with at least a 50% reduction in TSC-associated seizure frequency for the maximum recommended dose of 25 mg/kg/day.

Table 6 : Primary and > 50% responder key secondary outcome measures in the TSC study (overall patient population)

	Study GWPCARE6
	Cannabidiol 25 mg/kg/day (n = 75)	Placebo (n = 76)
Primary endpoint - Percentage reduction in TSC-associated seizure frequency “
TSC-associated seizures % Reduction from Baseline	48.6%	26.5%
Percent Reduction Compared with Placebo 95% CI P-value	30.1% 13.9%, 43.3% 0.0009
Key Secondary endpoint – > 50% REDUCTION IN TSC-associated seizures (RESPONDER ANALYSIS)
Percentage of patients with a > 50% reduction	36%	22.4%
P-value b	0.0692

CI = 95% confidence interval.

a Data for study GWPCARE6 are presented as percent reduction from baseline estimated from a negative binomial regression analysis.

b The Overall p value is based on a Cochran Mantel Haenszel test.

Subgroup analyses with and without clobazam treatment

In the GWPCARE6 study, 22.7% of TSC patients in the 25 mg/kg/day group and 32.9% in the placebo group were taking concomitant clobazam. Results of subgroup analysis by clobazam use showed additive anticonvulsant effects of cannabidiol in the presence of clobazam.

In the subgroup of patients treated with concomitant clobazam, patients receiving cannabidiol 25 mg/kg/day experienced a 61.1% reduction from baseline in TSC-associated seizure frequency compared to a 27.1 % reduction in the placebo group, based on a negative binomial regression analysis. Compared with placebo, cannabidiol was associated with a 46.6% reduction (nominal p = 0.0025) in TSC-associated seizures (95% CI: 20.0%, 64.4%).

In the subgroup of patients treated without concomitant clobazam, patients receiving cannabidiol 25 mg/kg/day experienced a 44.4 % reduction from baseline in TSC-associated seizure frequency compared to a 26.2% reduction in the placebo group; based on a negative binomial regression analysis. Compared with placebo, cannabidiol was associated with a 24.7% reduction (nominal p = 0.0242) in TSC-associated seizures (95% CI: 3.7%, 41.1%).

Additional secondary outcome measures for cannabidiol 25 mg/kg/day (overall patient population)

Cannabidiol was associated with an increase in the percentage of subjects (16.0%) experiencing a greater than or equal to 75% reduction in TSC-associated seizure frequency during the treatment period compared with the placebo group (0%).

Patients receiving cannabidiol experienced a greater percentage reduction in total seizures (48.1%) compared with placebo (26.9%).

Global Impression of Change scores at the last visit, were reported by caregivers and patients. 68.6% of patients in the cannabidiol group vs. 39.5% in the placebo group experienced an improvement.

Compared with placebo, cannabidiol was associated with an increase in the number of TSC-associated seizure free days during the treatment period, equivalent to 2.82 days per 28 days.

The effect of cannabidiol on infantile/epileptic spasms associated with TSC has not been fully assessed.

Open-label data

Of the 201 patients who completed the GWPCARE6 study, 99.0% (199 patients) were enrolled into the OLE study. In the OLE the median percentage reduction from baseline in TSC-associated seizure frequency was 61% during Week 1–12 (N = 199), which was maintained through to Week 37–48, with a median percentage reduction from baseline in TSC-associated seizure frequency of 68%.

Abuse

In a human abuse potential study, acute administration of cannabidiol to non-dependent adult recreational drug users at therapeutic and supratherapeutic doses produced small responses on positive subjective measures such as Drug Liking and Take Drug Again. Compared to dronabinol (synthetic THC) and alprazolam, cannabidiol has low abuse potential.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with cannabidiol in one or more subsets of the paediatric population in treatment of seizures associated with DS, LGS and TSC. (See section 4.2 for information on paediatric use).

The GWPCARE6 study, conducted in patients with TSC, included 8 children between 1 and 2 years of age across all treatment groups. Although data are limited, the observed treatment effect and tolerability were similar to that seen in patients of 2 years of age and older, however, efficacy, safety and pharmacokinetics in children < 2 years of age have not been established (see section 4.2).

5.2 Pharmacokinetic properties

Absorption

Cannabidiol appears rapidly in plasma with a time to maximum plasma concentration of 2.5–5 hours at steady state.

Steady-state plasma concentrations are attained within 2–4 days of twice daily dosing based on pre-dose (Ctrough) concentrations. The rapid achievement of steady state is related to the multiphasic elimination profile of the drug in which the terminal elimination represents only a small fraction of the drug’s clearance.

In healthy volunteer studies, co-administration of cannabidiol (750 or 1500 mg) with a high-fat/high calorie meal increased the rate and extent of absorption (5-fold increase in Cmax and 4-fold increase in AUC) and reduced the total variability of exposure compared with the fasted state in healthy volunteers. Although the effect is slightly smaller for a low-fat/low-calorie meal, the elevation in exposure is still marked (Cmax by 4-fold, AUC by 3-fold). Furthermore, taking cannabidiol with bovine milk enhanced exposure by approximately 3-fold for Cmax and 2.5-fold for AUC. Taking cannabidiol with alcohol also caused enhanced exposure to cannabidiol, with a 63% greater AUC.

In the randomised controlled trials, the timing of dose of cannabidiol with respect to meal times was not restricted. In patients, a high fat meal was also shown to increase the bioavailability of cannabidiol (3-fold). This increase was moderate when the prandial state was not fully known, i.e., 2.2-fold increase of the relative bioavailability.

To minimise the variability in the bioavailability of cannabidiol in the individual patient, administration of cannabidiol should be standardised in relation to food intake including a ketogenic diet (high-fat meal) i.e., Epidyolex should be taken consistently with or without food. When taken with food, a similar composition of food should be considered, if possible.

Distribution

In vitro , > 94% of cannabidiol and its phase I metabolites were bound to plasma proteins, with preferential binding to human serum albumin.

The apparent volume of distribution after oral dosing was high in healthy volunteers at 20,963 L to 42,849 L and greater than total body water, suggesting a wide distribution of cannabidiol.

Biotransformation and elimination

The half-life of cannabidiol in plasma was 56–61 hours after twice daily dosing for 7 days in healthy volunteers.

Metabolism

Cannabidiol is extensively metabolised by the liver via CYP450 enzymes and the UGT enzymes. The major CYP450 isoforms responsible for the phase I metabolism of cannabidiol are CYP2C19 and CYP3A4. The UGT isoforms responsible for the phase II conjugation of cannabidiol are UGT1A7, UGT1A9 and UGT2B7.

Studies in healthy subjects showed there were no major differences in the plasma exposure to cannabidiol in CYP2C19 intermediate and ultra-rapid metabolisers when compared to extensive metabolisers.

The phase I metabolites identified in standard in vitro assays were 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD (a minor circulating metabolite).

After multiple dosing with cannabidiol, the 7-OH-CBD metabolite (active in a preclinical model of seizure) circulates in human plasma at lower concentrations than the parent drug cannabidiol (~ 40% of CBD exposure) based on AUC.

Excretion

The plasma clearance of cannabidiol following a single 1500 mg dose of cannabidiol is about

1,111 L/h. Cannabidiol is predominantly cleared by metabolism in the liver and gut and excreted in faeces, with renal clearance of parent drug being a minor pathway.

Cannabidiol does not interact with the major renal and hepatic transporters in a way that is likely to result in relevant drug-drug interactions.

Linearity

The Cmax and AUC of cannabidiol are close to dose-proportional over the therapeutic dose range (10–25 mg/kg/day). After single dosing, exposure over the range 750–6000 mg increases in a less than dose-proportional manner, indicating that absorption of cannabidiol may be saturable. Multiple dosing in TSC patients also indicated that absorption is saturable at doses above 25 mg/kg/day.

Pharmacokinetics in special patient groups

Effect of age, weight, sex, race

Population pharmacokinetic analyses demonstrated that there were no clinically relevant effects of age, body weight, sex, or race on exposure to cannabidiol.

Elderly

Pharmacokinetics of cannabidiol have not been studied in subjects > 74 years of age.

Paediatric patients

Pharmacokinetics of cannabidiol have not been studied in paediatric patients < 2 years of age.

A small number of patients < 2 years with treatment-resistant epilepsy (including TSC, LGS and DS) have been exposed to cannabidiol in clinical trials and in an expanded access programme.

Renal impairment

No effects on the Cmax or AUC of cannabidiol were observed following administration of a single dose of cannabidiol 200 mg in subjects with mild, moderate, or severe renal impairment when compared to patients with normal renal function. Patients with end-stage renal disease were not studied.

Hepatic impairment

No effects on cannabidiol or metabolite exposures were observed following administration of a single dose of cannabidiol 200 mg in subjects with mild hepatic impairment.

Subjects with moderate and severe hepatic impairment showed higher plasma concentrations of cannabidiol (approximately 2.5–5.2-fold higher AUC compared to healthy subjects with normal hepatic function). Cannabidiol should be used with caution in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment. The dose titration should be performed as detailed in section 4.2.

Pharmacokinetic/pharmacodynamic relationship(s)

In LGS

In patients with LGS, population pharmacokinetic pharmacodynamic (PK/PD) modelling indicated the presence of an exposure efficacy relationship for the likelihood of achieving a > 50% reduction in drop seizure frequency across the cannabidiol dose range tested (0 [placebo], 10 and 20 mg/kg/day). There was a significant positive correlation between the derived AUC of cannabidiol and the probability of a > 50% response. The responder rate analysis also showed a correlation in the exposure-response relationship for the active metabolite of cannabidiol (7-OH-CBD). PK/PD analysis also demonstrated that systemic exposures to cannabidiol were correlated with some adverse events namely elevated ALT, AST, diarrhoea, fatigue, GGT, loss of appetite, rash, and somnolence (see section 4.8).

Clobazam (separate analysis) was a significant covariate which caused the probability of GGT to increase, loss of appetite to decrease, and somnolence to increase.

In TSC

In TSC patients there is no exposure-response relationship based on efficacy endpoints, as the doses evaluated are at the high end of the dose-response relationship. However, an exposure-response relationship was determined for the 7-OH-CBD metabolite in relation to AST elevation. No other PK/PD relationships with safety endpoints were identified for CBD or its metabolites.

Drug interaction studies

In vitro assessment of drug interactions

Cannabidiol is a substrate for CYP3A4, CYP2C19, UGT1A7, UGT1A9 and UGT2B7.

In vitro data suggest that cannabidiol is an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A9 and UGT2B7 activity at clinically relevant concentrations. The metabolite 7-carboxy-cannabidiol (7-COOH-CBD) is an inhibitor of UGT1A1, UGT1A4 and UGT1A6-mediated activity, in vitro at clinically relevant concentrations (see also section 4.5).

Cannabidiol induces CYP1A2 and CYP2B6 mRNA expression in vitro at clinically relevant concentrations. An in vivo study with caffeine showed that cannabidiol did not induce CYP1A2 in vivo.

Cannabidiol and the metabolite 7-OH-CBD do not interact with the major renal or hepatic uptake transporters and therefore are unlikely to result in relevant drug-drug interactions: OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1B1and OATP1B3. Cannabidiol is not a substrate for or an inhibitor of the brain uptake transporters OATP1A2 and OATP2B1. In vitro, cannabidiol and 7-OH-CBD are not substrates for or inhibitors of efflux transports P-gp/MDR1, BCRP or BSEP. In vivo data with everolimus show that cannabidiol can affect P-gp-mediated efflux of a P-gp substrate in the intestine (see section 4.5) but cannabidiol did not inhibit or induce CYP3A4 based on an in vivo midazolam study. The metabolite 7-COOH-CBD is a P-gp/MDR1 substrate and has the potential to inhibit BCRP, OATP1B3, and OAT3.

In vivo assessment of drug interactions

Drug interaction studies with AEDs

Potential interactions between cannabidiol (750 mg twice daily in healthy volunteers and 20 mg/kg/day in patients) and other AEDs were investigated in drug-drug interaction studies in healthy volunteers and in patients and in a population pharmacokinetic analysis of plasma drug concentrations from placebo-controlled studies in the treatment of patients with LGS.

The combination of cannabidiol with clobazam caused an elevation in exposure to the active metabolite N-desmethylclobazam, with no effect on clobazam levels. Although exposure to cannabidiol was not notably affected by clobazam use, the levels of an active metabolite, 7-OH-CBD, were elevated by this combination. Therefore, dose adjustments of cannabidiol or clobazam may be required.

Coadministration of cannabidiol and everolimus led to an increase in everolimus exposure. Therefore, dose adjustments and therapeutic drug monitoring of everolimus may be required when everolimus and cannabidiol are concomitantly used.

The in vivo interactions forclobazam, everolimus and other concomitant AEDs are summarised in the table below.

Table 7: Drug interactions between cannabidiol and concomitant antiepileptic drugs

Concomitant AED	Influence of AED on cannabidiol	Influence of cannabidiol on AED
Clobazam	No effect on cannabidiol levels. Interaction resulting in an increase in exposure of the active metabolite 7-OH-CBD in HV* studies. a	No effect on clobazam levels. Interaction resulting in approximately 3-fold increase in N-desmethylclobazam metabolite exposure. b
Valproate	No effect on CBD or its metabolites.	No effect on valproic acid exposure or exposure to the putative hepatotoxic metabolite 2-propyl-4-pentenoic acid (4-ene-VPA).
Stiripentol	No effect on cannabidiol levels. Interaction resulting in a decrease (approximately 30%) in Cmax and AUC of the active metabolite 7-OH-CBD in trials conducted in HV* and patients with epilepsy.	Interaction resulting in an approximate 28% increase in Cmax and 55% increase in AUC in a HV* study and increases of 17% in Cmax and 30% increases in AUC in patients.
Everolimus	The effect of everolimus on cannabidiol has not been assessed.	Coadministration of cannabidiol (12.5 mg/kg twice daily) with everolimus (5 mg) resulting in an approximate 2.5-fold increase in everolimus exposure for both Cmax and AUC in a HV* study.
a average increases of 4	17% in AUC and 73% in Cmax.

b based on Cmax and AUC.

*HV = Healthy Volunteer.

5.3 Preclinical safety data

Mutagenicity and Carcinogenicity

In a carcinogenicity study in mice, oral administration of Epidyolex (0 [water], 0 [vehicle], 30, 100, or 300 mg/kg/day) for 2 years increased the incidence of benign hepatocellular adenomas in male mice at all doses tested and in female mice at the highest dose tested. At the highest dose evaluated, plasma exposures (AUC) in mice were approximately 7 times greater than the anticipated exposure in humans at a dosage of 25 mg/kg/day.

A study of the carcinogenic potential of cannabidiol in rats has not been conducted

Genotoxicity studies have not detected any mutagenic or clastogenic activity.

Reproductive toxicity

No adverse reactions were observed on male or female fertility or reproduction performance in rats at doses up to 250 mg/kg/day (approximately 34-fold greater than the maximum recommended human dose (MRHD) at 25 mg/kg/day).

The embryo-foetal development (EFD) study performed in rabbits evaluated doses of 50, 80, or 125 mg/kg/day. The dose level of 125 mg/kg/day induced decreased foetal body weights and increased foetal structural variations associated with maternal toxicity. Maternal plasma cannabidiol exposures at the no observed-adverse-effect-level (NOAEL) for embryofoetal developmental toxicity in rabbits were less than that in humans at a dosage of 25 mg/kg/day.

In rats, the EFD study evaluated doses of 75, 150, or 250 mg/kg/day. Embryofoetal mortality was observed at the high dose, with no treatment-related effects on implantation loss at the low or mid doses. The NOAEL was associated with maternal plasma exposures (AUC) approximately 9 times greater than the anticipated exposure in humans at a dosage of 25 mg/kg/day.

A pre- and post-natal development study was performed in rats at doses of 75, 150, or 250 mg/kg/day. Decreased growth, delayed sexual maturation, behavioural changes (decreased activity), and adverse effects on male reproductive organ development (small testes in adult offspring) and fertility were observed in the offspring at doses > 150 mg/kg/day. The NOAEL was associated with maternal plasma cannabidiol exposures approximately 5 times that in humans at a dosage of 25 mg/kg/day.

Juvenile toxicity

In juvenile rats, administration of cannabidiol for 10 weeks (subcutaneous doses of 0 or 15 mg/kg on postnatal days [PNDs] 4–6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs 7–77) resulted in increased body weight, delayed male sexual maturation, neurobehavioural effects, increased bone mineral density, and liver hepatocyte vacuolation. A no-effect dose was not established. The lowest dose causing developmental toxicity in juvenile rats (15 mg/kg subcutaneous/100 mg/kg oral) was associated with cannabidiol exposures (AUC) approximately 8 times that in humans at 25 mg/kg/day.

In another study, cannabidiol was dosed to juvenile rats from PND 4–21 (as a subcutaneous injection) and from PND 22–50 (as an intravenous injection). A NOAEL of 15 mg/kg/day was established.

Abuse

Animal abuse-related studies show that cannabidiol does not produce cannabinoid-like behavioural responses, including generalisation to delta-9-tetrahydrocannabinol (THC) in a drug discrimination study. Cannabidiol also does not produce animal self-administration, suggesting it does not produce rewarding effects.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Refined sesame oil

Anhydrous ethanol Sucralose (E955) Strawberry flavour (including benzyl alcohol)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

Use within 12 weeks after first opening the bottle.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Amber glass bottle (type III) with a child-resistant and tamper-evident screw cap (polypropylene). The bottle is packaged in a carton with two 5 ml and two 1 ml calibrated oral dosing syringes (plunger HDPE and barrel polypropylene) and two bottle adaptors (LDPE). The 5 ml syringes are graduated in 0.1 ml increments and the 1 ml syringes are graduated in 0.05 ml increments.

6.6 Special precautions for disposal and other handling

Nasogastric tubes made of silicone, with a length of more than 50 cm and maximum of 125 cm and a diameter of more than 5 FR and maximum of 12 FR, can be used. Nasogastric tubes made of silicone, being 50 cm or shorter and 5 FR or less in diameter should be avoided. Gastric tubes made of silicone, with a length of 0.8 to 4 cm and a diameter of 12 FR to 24 FR, can be used. Tubes made of polyvinyl chloride and polyurethane should not be used.

After administration, the enteral feeding tube should be flushed at least once with room temperature water. If more than one drug is being administered, the tube should be flushed between each drug. It is recommended that the flushing volume is approximately 5 times the priming volume of the tube (with a minimum of 3 ml for the shortest/narrowest tubes to a maximum of 20 ml for the longest/largest tubes). The flushing volume may need to be modified in patients with fluid restrictions.

Enteral tubes with ENFit® connections require the use of ENFit compatible syringes and bottle adaptors. To maximise dose accuracy, 1 ml syringes should be used for doses < 1 ml.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

GW Pharma (International) B.V.,

Databankweg 26

3821AL Amersfoort,

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1389/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 September 2019