EPIDYOLEX 100mg / ml oral solution medication leaflet

Epidyolex 100 mg/ml oral solution

Each ml of oral solution contains 100 mg cannabidiol.

Each ml of solution contains:

79 mg anhydrous ethanol736 mg refined sesame oil0.0003 mg benzyl alcohol

For the full list of excipients, see section 6.1.

Oral solution

Clear, colourless to yellow solution

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

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

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

For LGS and DS

The recommended starting dose of cannabidiol is 2.5 mg/kg taken twice daily (5 mg/kg/day) for oneweek. 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 furtherincreased in weekly increments of 2.5 mg/kg administered twice daily (5 mg/kg/day) up to amaximum 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 monitoringschedule (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 oneweek. 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 andtolerability, each dose can be further increased in weekly increments of 2.5 mg/kg administered twicedaily (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 monitoringschedule (see section 4.4).

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

Table 1: Dose recommendations

LGS and DS TSC

Starting dose - first week 2.5 mg/kg taken twice daily (5 mg/kg/day)

Second week Maintenance dose5 mg/kg twice daily 5 mg/kg twice daily(10 mg/kg/day) (10 mg/kg/day)

Further titration as applicable weekly increments of 2.5 mg/kg administered twice daily(incremental steps) (5 mg/kg/day)

Maximal recommended dose 10 mg/kg twice daily 12.5 mg/kg twice daily(20 mg/kg/day) (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 mgcannabidiol)

- Two 5 ml syringes graduated in 0.1 ml increments (each 0.1 ml increment corresponds to 10 mgcannabidiol)

If the calculated dose is 100 mg (1 ml) or less, the smaller 1 ml oral syringe should be used.

If the calculated dose is more than 100 mg (1 ml), the larger 5 ml oral syringe should be used.

The calculated dose should be rounded to the nearest graduated increment.

Dose adjustments of other medicinal products used in combination with cannabidiol

A physician experienced in treating patients who are on concomitant antiepileptic drugs (AEDs)should evaluate the need for dose adjustments of cannabidiol or of the concomitant medicinalproduct(s) to manage potential drug interactions (see sections 4.4 and 4.5).

If cannabidiol has to be discontinued, the dose should be decreased gradually. In clinical trials,cannabidiol discontinuation was achieved by reducing the dose by approximately 10% per day for10 days. A slower or faster down titration may be required, as clinically indicated, at the discretion ofthe prescriber.

In the case of one or more missed doses, the missed doses should not be compensated. Dosing shouldbe resumed at the existing treatment schedule. In the case of more than 7 days’ missed doses,re-titration to the therapeutic dose should be made.

Clinical trials of cannabidiol in the treatment of LGS, DS and TSC did not include a sufficient numberof patients aged above 55 years to determine whether or not they respond differently from youngerpatients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end ofthe dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, andof concomitant disease or other concurrent therapy (see sections 4.4 under hepatocellular injury and5.2).

Cannabidiol can be administered to patients with mild, moderate, or severe renal impairment withoutdose adjustment (see section 5.2). There is no experience in patients with end-stage renal disease. It isnot known if cannabidiol is dialysable.

Cannabidiol does not require dose adjustment in patients with mild hepatic impairment(Child-Pugh A).

Caution should be used in patients with moderate (Child-Pugh B) or severe hepatic impairment(Child-Pugh C) (see sections 4.3 and 4.4). A lower starting dose is recommended in patients withmoderate or severe hepatic impairment. The dose titration should be performed as detailed in the tablebelow.

Table 2: Dose adjustments in patients with moderate or severe hepatic impairment

Hepatic Starting dose Maintenance Second week Maximal Maximalimpairment For LGS, DS dose For TSC recommended recommendedand TSC For LGS and dose dose

DS For LGS and For TSC

DS

Moderate 1.25 mg/kg 2.5 mg/kg 5 mg/kg 6.25 mg/kgtwice daily twice daily twice daily twice daily(2.5 mg/kg/day) (5 mg/kg/day) (10 mg/kg/day) (12.5 mg/kg/day)0.5 mg/kg 1 mg/kg 2 mg/kg 2.5 mg/kg

Severe twice daily twice daily twice daily twice daily(1 mg/kg/day) (2 mg/kg/day) (4 mg/kg/day)* (5 mg/kg/day)*

*Higher doses of cannabidiol may be considered in patients with severe hepatic impairment where thepotential benefits outweigh the risks.

With LGS and DS

There is no relevant use of cannabidiol in children aged below 6 months. The safety and efficacy ofcannabidiol in children aged 6 months to 2 years have not yet been established. No data are available.

With TSC

There is no relevant use of cannabidiol in children aged below 1 month. The safety and efficacy ofcannabidiol in children aged 1 month to 2 years have not yet been established. Currently available datain patients aged 1 to 2 years are described in section 5.1 but no recommendation on a posology can bemade.

Oral use

Food may increase cannabidiol levels and therefore it should be taken consistently either with orwithout food, including the ketogenic diet. When taken with food, a similar composition of foodshould be considered, if possible (see section 5.2).

Oral administration is recommended; however, when necessary, nasogastric and gastrostomy tubesmay be acceptable methods for enteral administration.

For further information on the use of feeding tubes see section 6.6.

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) andbilirubin greater than 2 times the ULN (see section 4.4).

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 firsttwo months of treatment initiation; however, there were cases observed up to 18 months after initiationof 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 alesser extent than valproate. Dose adjustment or discontinuation of valproate or dose adjustment ofclobazam should be considered if transaminase elevations occur.

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

Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevationswhen taking cannabidiol. In some patients, a synergistic effect of concomitant treatment withvalproate 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 patientsexperienced elevations of alkaline phosphatase levels above 2 times the ULN in combination withtransaminase elevations. The elevations resolved after discontinuation of cannabidiol.

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

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

Routine monitoring

Serum transaminases and total bilirubin levels should be obtained at 1 month, 3 months, and 6 monthsafter 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 changeor 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 valproateshould 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 asclinically indicated. Upon changes in cannabidiol dose above 10 mg/kg/day or changes in medicinalproducts (dose change or additions) that are known to impact the liver, this monitoring scheduleshould be restarted.

If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, serumtransaminases and total bilirubin should be promptly measured and treatment with cannabidiol shouldbe interrupted or discontinued, as appropriate. Cannabidiol should be discontinued in any patients withelevations of transaminase levels greater than 3 times the ULN and bilirubin levels greater than2 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the ULNshould also have treatment discontinued. Patients with prolonged elevations of serum transaminasesshould be evaluated for other possible causes. Dose adjustment of any co-administered medicinalproduct that is known to affect the liver should be considered (e.g., valproate and clobazam) (seesection 4.5).

Somnolence and sedation

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

Increased seizure frequency

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

Suicidal behaviour and ideation

Suicidal behaviour and ideation have been reported in patients treated with AEDs in severalindications. A meta-analysis of randomised placebo-controlled trials with AEDs has shown a smallincreased risk of suicidal behaviour and ideation. The mechanism of this risk is not known, and theavailable 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 treatmentshould be considered. Patients and caregivers of patients should be advised to seek medical adviceshould 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 TSCpatients, this appeared to be dose-related. In some cases, decreased weight was reported as an adverseevent. Decreased appetite and weight loss may result in slightly reduced height gain. Continuousweight loss/absence of weight gain should be periodically checked to evaluate if cannabidiol treatmentshould be continued.

Sesame oil

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

Benzyl alcohol

This medicinal product contains 0.0003 mg/ml benzyl alcohol corresponding to 0.0026 mg permaximal Epidyolex dose (Epidyolex 12.5 mg/kg per dose (TSC) for an adult weighing 70 kg).

Benzyl alcohol may cause allergic reactions.

High volumes should be used with caution and only if necessary, especially in subjects with liver orkidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

Each ml of Epidyolex contains 79 mg of ethanol, equivalent to 10% v/v anhydrous ethanol, i.e., up to691.3 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 wineper dose.

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

CYP3A4 or CYP2C19 inducers

The strong CYP3A4/2C19 inducing agent rifampicin (600 mg administered once daily) decreasedplasma concentrations of cannabidiol and of 7-hydroxy-cannabidiol (7-OH-CBD; an active metaboliteof cannabidiol) by approximately 30% and 60%, respectively. Other strong inducers of CYP3A4and/or CYP2C19, such as carbamazepine, enzalutamide, mitotane, St. John’s wort, when administeredconcomitantly with cannabidiol, may also cause a decrease in the plasma concentrations ofcannabidiol and of 7-OH-CBD by a similar amount. These changes may result in a decrease in theeffectiveness of cannabidiol. Dose adjustment may be necessary.

UGT inhibitors

Cannabidiol is a substrate for UGT1A7, UGT1A9 and UGT2B7. No formal drug-drug interactionstudies have been conducted with cannabidiol in combination with UGT inhibitors, therefore cautionshould be taken when co-administering medicinal products 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’sconcomitant AED treatments. Cannabidiol and/or concomitant AED treatment should therefore beadjusted during regular medical supervision and the patient should be closely monitored for adversedrug reactions. In addition, monitoring of plasma concentrations should be considered.

The potential for drug-drug interactions with other concomitant AEDs has been assessed in healthyvolunteers and patients with epilepsy for clobazam, valproate, stiripentol and everolimus. Although noformal drug-drug interaction studies have been performed for other AEDs, phenytoin and lamotrigineare addressed based on in vitro data.

Clobazam

When cannabidiol and clobazam are co-administered, bi-directional PK interactions occur. Based on ahealthy volunteer study, elevated levels (3- to 4-fold) of N-desmethylclobazam (an active metaboliteof 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, forwhich plasma area under the curve (AUC) increased by 47% (see section 5.2). Increased systemiclevels of these active substances may lead to enhanced pharmacological effects and to an increase inadverse drug reactions. Concomitant use of cannabidiol and clobazam increases the incidence ofsomnolence and sedation compared with placebo (see sections 4.4 and 4.8). Reduction in dose ofclobazam should be considered if somnolence or sedation are experienced when clobazam isco-administered with cannabidiol.

Valproate

Concomitant use of cannabidiol and valproate increases the incidence of transaminase enzymeelevations (see section 4.8. The mechanism of this interaction remains unknown. If clinicallysignificant increases of transaminases occur, cannabidiol and/or concomitant valproate should bereduced or discontinued in all patients until a recovery of transaminase elevations are observed.

Insufficient data are available to assess the risk of concomitant administration of other hepatotoxicmedicinal products and cannabidiol (see section 4.4).

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

Stiripentol

When cannabidiol was combined with stiripentol in a healthy volunteer trial there was an increase instiripentol levels of 28% for maximum measured plasma concentration (Cmax) and 55% for AUC. Inpatients, 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 closelymonitored for adverse drug reactions.

Exposure to phenytoin may be increased when it is co-administered with cannabidiol, as phenytoin islargely metabolised via CYP2C9, which is inhibited by cannabidiol in vitro. There have not been anyclinical studies formally investigating this interaction. Phenytoin has a narrow therapeutic index, socombining 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 invitro. There have not been any clinical studies formally investigating this interaction. Lamotriginelevels may be elevated when it is co-administered with cannabidiol.

Coadministration of cannabidiol (12.5 mg/kg twice daily) with the P-gp and CYP3A4 substrateeverolimus (5 mg) in a healthy volunteer study led to an increase in everolimus exposure ofapproximately 2.5-fold for both Cmax and AUC. The mechanism for this interaction is believed to beinhibition of intestinal P-gp efflux, leading to increased bioavailability of everolimus, becausecannabidiol did not affect midazolam exposure in another interaction study. The half-life ofeverolimus was not affected, confirming the lack of systemic inhibitory effects of cannabidiol on P-gpand CYP3A4 activity. When initiating cannabidiol in patients taking everolimus, monitor therapeuticdrug levels of everolimus and adjust the dose accordingly. When initiating everolimus in patientstaking a stable dose of cannabidiol, a lower starting dose of everolimus is recommended, withtherapeutic 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-administeredwith a single dose of caffeine (200 mg), a sensitive CYP1A2 substrate, showed increased caffeineexposure 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 inexposure 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 closelymonitored 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 increasedplasma concentrations of medicines that are metabolised by this isoenzyme such as clobazam andomeprazole. Dose reduction should be considered for concomitant medicinal products that aresensitive 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 areexperienced when administered concomitantly with cannabidiol. Because of potential for bothinduction and inhibition of enzyme activity, dose adjustment of substrates of CYP1A2 and CYP2B6should 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 atclinically relevant concentrations. The metabolite 7-carboxy-cannabidiol (7-COOH-CBD) is also aninhibitor of UGT1A1, UGT1A4 and UGT1A6-mediated activity in vitro. Dose reduction of thesubstrates 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 ofeverolimus. Increases in exposure of other orally administered sensitive P-gp substrates (e.g.,sirolimus, tacrolimus, digoxin) may occur on coadministration with cannabidiol. Therapeutic drugmonitoring and dose reduction of other P-gp substrates should be considered when given orally andconcurrently with cannabidiol.

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

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

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

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

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

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 to150 mg/kg/day cannabidiol (see section 5.3).

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

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

The most common adverse reactions are somnolence (23%), decreased appetite (21%), diarrhoea(20%), pyrexia (16%), vomiting (12%) and fatigue (10%).

The most frequent cause of discontinuations was transaminase elevation (2%), somnolence (2%) anddecreased appetite (1%).

Adverse reactions reported with cannabidiol in placebo-controlled clinical studies are listed in thetable 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 presentedin 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

Blood and lymphatic system Very common Haemoglobin decreaseddisorders Haematocrit decreased

Metabolism and nutrition Very common Decreased appetitedisorders

System Organ Class Frequency Adverse reactions from clinical trials

Psychiatric disorders Common Irritability

Aggression

Nervous system disorders Very common Somnolencea

Common Lethargy

Respiratory, thoracic and Common Coughmediastinal disorders

Gastrointestinal disorders Very common Diarrhoea

Common Nausea

Hepatobiliary disorders Common AST increased

ALT increased

GGT increased

Skin and subcutaneous tissue Common Rashdisorders

Renal and urinary disorders Common Blood creatinine increased

General disorders and Very common Pyrexiaadministration site conditions Fatigue

Investigations Common Weight decreaseda Grouped Terms: Pneumonia: Pneumonia, Pneumonia RSV, Pneumonia mycoplasmal, Pneumoniaadenoviral, Pneumonia viral, Aspiration pneumonia; Somnolence: Somnolence, Sedation.

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 (receiving25 mg/kg/day), the incidence of ALT elevations above 3 times the ULN was 12% incannabidiol-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 takingcannabidiol.

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 ALTelevations greater than 3 times the ULN was 23% in patients taking both concomitant valproate andclobazam, 19% in patients taking concomitant valproate (without clobazam), 3% in patients takingconcomitant clobazam (without valproate), and 3% in patients taking neither medicinal product.

Dose

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

The risk of ALT elevations was higher at doses 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 frequencyof treatment-emergent ALT elevations greater than 3 times the ULN was 29% (80% of these were onvalproate) when ALT was above the ULN at baseline, compared to 12% (89% of these were onvalproate) when ALT was within the normal range at baseline. A total of 5% of patients (all onvalproate) taking cannabidiol 10 mg/kg/day experienced ALT elevations greater than 3 times the ULNwhen 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 (seesection 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 cannabidiol10 mg/kg/day). These adverse reactions were observed at higher incidences at doses above25 mg/kg/day in the controlled study in TSC. The rate of somnolence and sedation (includinglethargy) was higher in patients on concomitant clobazam (43% in cannabidiol-treated patients takingclobazam, compared with 14% in cannabidiol-treated patients not on clobazam).

In the controlled trial in TSC patients, an increased frequency of adverse events associated withseizure 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. Thefrequency of adverse events associated with seizure worsening was 11% for patients taking25 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 TSCpatients, the decrease in weight appeared to be dose-related, with 21% of patients on cannabidiol 20 or25 mg/kg/day experiencing a decrease in weight of ≥ 5%, compared to 7% in patients on cannabidiol10 mg/kg/day. In some cases, the decreased weight was reported as an adverse event (see Table 3above). Decreased appetite and weight loss may result in slightly reduced height gain.

Cannabidiol can cause dose-related diarrhoea. In controlled trials in LGS and DS, the frequency ofdiarrhoea was 13% in patients receiving 10 mg/kg/day cannabidiol and 21% in patients receiving20 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% inpatients receiving doses greater than 25 mg/kg/day cannabidiol, compared to 25% in patients receivingplacebo.

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

Haematologic abnormalities

Cannabidiol can cause decreases in haemoglobin and haematocrit. In LGS, DS and TSC patients, themean decrease in haemoglobin from baseline to end of treatment was −0.36 g/dL incannabidiol-treated patients receiving 10, 20, or 25 mg/kg/day. A corresponding decrease inhaematocrit 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% ofcannabidiol-treated patients (25 mg/kg/day) with TSC developed a new laboratory-defined anaemiaduring the course of the study (defined as a normal haemoglobin concentration at baseline, with areported 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. Incontrolled studies in healthy adults and in patients with LGS, DS and TSC, an increase in serumcreatinine of approximately 10% was observed within 2 weeks of starting cannabidiol. The increasewas reversible in healthy adults. Reversibility was not assessed in studies in LGS, DS or TSC.

Pneumonia events have been observed in controlled trials with cannabidiol in patients with LGS, DS,or TSC, including 6% of cannabidiol-treated patients compared with 1% of patients receiving placebo.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system.listed in Appendix V.

Experience with doses higher than the recommended therapeutic dose is limited. Mild diarrhoea andsomnolence have been reported in healthy adult subjects taking a single dose of 6 000 mg; this equatesto a dose of over 85 mg/kg for a 70 kg adult. These adverse reactions resolved upon study completion.

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

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

The precise mechanisms by which cannabidiol exerts its anticonvulsant effects in humans areunknown. Cannabidiol does not exert its anticonvulsant effect through interaction with cannabinoidreceptors. Cannabidiol reduces neuronal hyper-excitability through modulation of intracellular calciumvia 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 adenosinecellular uptake via the equilibrative nucleoside transporter 1 (ENT-1).

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

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

The efficacy of cannabidiol for the adjunctive therapy of seizures associated with Lennox-Gastautsyndrome (LGS) was evaluated in two randomised, double-blind, placebo-controlled, parallel-groupstudies (GWPCARE3 and GWPCARE4). Each study consisted of a 4-week baseline period, a 2-weektitration period and a 12-week maintenance period. Mean age of the study population was 15 years and94% were taking 2 or more concomitant AEDs (cAEDs) during the trial. The most commonly usedcAEDs (> 25% of patients) in both trials were valproate, clobazam, lamotrigine, levetiracetam, andrufinamide. Approximately 50% of the patients were taking concomitant clobazam. Of the patientsthat were not taking clobazam, the majority had previously taken and subsequently discontinuedclobazam treatment.

The primary endpoint was the percentage change from baseline in drop seizures per 28 days over thetreatment 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 endpointswere the proportion of patients with at least a 50% reduction in drop seizure frequency, the percentagechange from baseline in total seizure frequency, and Subject/Caregiver Global Impression of Changeat the last visit.

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

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

Table 4: Primary and ≥ 50% responder key secondary outcome measures and subgroup analysisin LGS studies

Subgroup

Overall N with Nclobazam

DROP SEIZURES PER 28 DAYS

Percentage reduction from baselinea

GWPCARE3 Placebo 17.2% 76 22.7% 3710 mg/kg/day 37.2% 73 45.6% 3720 mg/kg/day 41.9% 76 64.3% 36

GWPCARE4 Placebo 21.8% 85 30.7% 4220 mg/kg/day 43.9% 86 62.4% 42

Difference or percent reduction compared with placebo (95% CI), p-valueb

GWPCARE3 10 mg/kg/day 19.2 29.6%(7.7, 31.2) (2.4%, 49.2%)p = 0.0016 p = 0.0355c20 mg/kg/day 21.6 53.8%(6.7, 34.8) (35.7%, 66.8%)p = 0.0047 p< 0.0001c

GWPCARE4 20 mg/kg/day 17.2 45.7%(4.1, 30.3) (27.0%, 59.6%)p = 0.0135 p< 0.0001c≥ 50% REDUCTION IN DROP SEIZURES (RESPONDER ANALYSIS)

Percentage of ≥ 50% responders, p-valued

GWPCARE3 Placebo 14.5% 76 21.6% 3710 mg/kg/day 35.6% 73 40.5% 37p = 0.0030 p = 0.0584c20 mg/kg/day 39.5% 76 55.6% 36p = 0.0006 p = 0.0021c

GWPCARE4 Placebo 23.5% 85 28.6% 4220 mg/kg/day 44.2% 86 54.8% 42p = 0.0043 p = 0.0140c

CI=95% confidence interval.a Data for the overall population are presented as median percent reduction from baseline. Data for thewith clobazam subgroup are presented as percent reduction from baseline estimated from a negativebinomial regression analysis.b Overall data are presented as estimated median difference and p-value from a Wilcoxon rank-sumtest. 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 withclobazam subgroup are based on logistic regression analysis.

Additional secondary outcome measures in the subgroup of patients treated with concomitantclobazam

Cannabidiol was associated with an increase in the percentage of subjects experiencing a greater thanor 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 totalseizures compared with placebo (53% 10 mg/kg/day, 64% to 66% 20 mg/kg/day, 25% for eachplacebo 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 thelast visit, were reported by caregivers and patients with both doses of cannabidiol (76% on10 mg/kg/day, 80% for each group on 20 mg/kg/day, 31% to 46% on placebo; p = 0.0005 for10 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 dropseizure-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 titrationperiod 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) inboth trials were valproate, clobazam, stiripentol, and levetiracetam. Approximately 65% of the patientswere taking concomitant clobazam. Of the patients that were not taking clobazam, the majority hadpreviously 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 percentagechange from baseline in convulsive seizures per 28 days over the treatment period (GWPCARE1) forthe 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 patientswith 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 seizurefrequency.

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

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 convulsiveseizure frequency, as well as results of the subgroup analysis for these outcome measures in patientstreated with concomitant clobazam.

Table 5: Primary and ≥ 50% responder key secondary outcome measures and subgroup analysisin DS studies

Subgroup

Overall N with Nclobazam

CONVULSIVE SEIZURES PER 28 DAYS

Percentage reduction from baselinea

GWPCARE2 Placebo 26.9% 65 37.6% 4110 mg/kg/day 48.7% 66 60.9% 4520 mg/kg/day 45.7% 67 56.8% 40

GWPCARE1 Placebo 13.3% 59 18.9% 3820 mg/kg/day 38.9% 61 53.6% 40

Difference or percent reduction compared with placebo (95% CI), p-valueb

GWPCARE2 10 mg/kg/day 29.8% 37.4%(8.4%, 46.2%) (13.9%, 54.5%)p = 0.0095 p = 0.0042c20 mg/kg/day 25.7% 30.8%(2.9%, 43.2%) (3.6%, 50.4%)p = 0.0299 p = 0.0297c

GWPCARE1 20 mg/kg/day 22.8 42.8%(5.4, 41.1) (17.4%, 60.4%)p = 0.0123 p = 0.0032c≥ 50% REDUCTION IN CONVULSIVE SEIZURES (RESPONDER ANALYSIS)

Percentage of ≥ 50% responders, p-valued

GWPCARE2 Placebo 26.2% 65 36.6% 4110 mg/kg/day 43.9% 66 55.6% 45p = 0.0332 p = 0.0623c20 mg/kg/day 49.3% 67 62.5% 40p = 0.0069 p = 0.0130c

GWPCARE1 Placebo 27.1% 59 23.7% 3820 mg/kg/day 42.6% 61 47.5% 40p = 0.0784 p = 0.0382c

CI=95% confidence interval.a For study GWPCARE1, overall data are presented as median percent reduction from baseline. Datafor study GWPCARE2 and the with clobazam subgroup are presented as percent reduction frombaseline estimated from a negative binomial regression analysis.b For study GWPCARE1, overall data are presented as estimated median difference and p-value froma Wilcoxon rank-sum test. Data for study GWPCARE2 and the with clobazam subgroup are estimatedfrom 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 withclobazam subgroup is based on logistic regression analysis.

Additional secondary outcome measures in the subgroup of patients treated with concomitantclobazam

Cannabidiol was associated with an increase in the percentage of subjects experiencing a greater thanor 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 seizurescompared 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 thelast visit, were reported by caregivers and patients with both doses of cannabidiol (73% on10 mg/kg/day, 62% to 77% on 20 mg/kg/day, 30% to 41% on placebo; p = 0.0009 for 10 mg/kg/dayand 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 convulsiveseizure-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 datawere 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 LGSand DS studies, cannabidiol should be titrated initially to the recommended maintenance dose of10 mg/kg/day (see section 4.2). In individual patients titration up to a maximum dose of 20 mg/kg/daymay 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 wereenrolled into the long-term open-label extension (OLE) study (GWPCARE5). In the subgroup of LGSpatients treated with concomitant clobazam for 37 to 48 weeks (N = 168), the median percentagereduction from baseline in drop seizure frequency was 71% during Week 1-12 (N = 168), which wasmaintained through to Week 37-48, with a median percentage reduction from baseline in drop seizurefrequency of 62%.

Across both randomised DS studies, 97.7% of patients (N = 315) who completed the studies wereenrolled into GWPCARE5. In the subgroup of DS patients treated with concomitant clobazam for37 to 48 weeks (N = 148), the median percentage reduction from baseline in convulsive seizurefrequency was 64% during Week 1-12 (N = 148, which was maintained through to Week 37-48, witha 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 associatedwith 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 a12-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 moreconcomitant 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 treatmentperiod (maintenance and titration) compared to baseline for the cannabidiol group compared toplacebo. TSC-associated seizures were defined as focal motor seizures without impairment ofconsciousness or awareness; focal seizures with impairment of consciousness or awareness; focalseizures 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 leasta 50% reduction in TSC-associated seizure frequency, Subject/Caregiver Global Impression of Changeat 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 the25 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-associatedseizures, 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 Placebo(n = 75) (n = 76)

Primary endpoint -percentage reduction in TSC-associated seizure frequencya

TSC-associated seizures% reduction from baseline 48.6% 26.5%

Percent reduction compared withplacebo30.1%95% CI 13.9%, 43.3%

P-value 0.0009

Key secondary endpoint - ≥ 50% REDUCTION IN TSC-associated seizures (RESPONDER

ANALYSIS)

Percentage of patients with a ≥ 50% 36% 22.4%reduction

P-value b 0.0692

CI = 95% confidence interval.a Data for study GWPCARE6 are presented as percent reduction from baseline estimated from anegative 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 placebogroup were taking concomitant clobazam. Results of subgroup analysis by clobazam use showedadditive anticonvulsant effects of cannabidiol in the presence of clobazam.

In the subgroup of patients treated with concomitant clobazam, patients receiving cannabidiol25 mg/kg/day experienced a 61.1% reduction from baseline in TSC-associated seizure frequencycompared to a 27.1 % reduction in the placebo group, based on a negative binomial regressionanalysis. Compared with placebo, cannabidiol was associated with a 46.6% reduction (nominalp = 0.0025) in TSC-associated seizures (95% CI: 20.0%, 64.4%).

In the subgroup of patients treated without concomitant clobazam, patients receiving cannabidiol25 mg/kg/day experienced a 44.4 % reduction from baseline in TSC-associated seizure frequencycompared to a 26.2% reduction in the placebo group; based on a negative binomial regressionanalysis. Compared with placebo, cannabidiol was associated with a 24.7% reduction (nominalp = 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 agreater than or equal to 75% reduction in TSC-associated seizure frequency during the treatmentperiod 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-associatedseizure 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 fullyassessed.

Open-label data

Of the 201 patients who completed the GWPCARE6 study, 99.0% (199 patients) were enrolled intothe OLE study. The median modal dose was 25 mg/kg/day and median treatment period was 90 weeks(range: 2.6-209 weeks). In the OLE the median percentage reduction from baseline in TSC-associatedseizure frequency was 54% during Week 1-12 (N = 199), which was maintained through to Week 85-96 (N = 98), with a median percentage reduction from baseline in TSC-associated seizure frequency of75%.

Abuse

In a human abuse potential study, acute administration of cannabidiol to non-dependent adultrecreational drug users at therapeutic and supratherapeutic doses produced small responses on positivesubjective measures such as Drug Liking and Take Drug Again. Compared to dronabinol (synthetic

THC) and alprazolam, cannabidiol has low abuse potential.

The European Medicines Agency has deferred the obligation to submit the results of studies withcannabidiol in one or more subsets of the paediatric population in treatment of seizures associated with

LGS, DS 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 ofage across all treatment groups. Although data are limited, the observed treatment effect andtolerability were similar to that seen in patients of 2 years of age and older, however, efficacy, safetyand pharmacokinetics in children < 2 years of age have not been established (see section 4.2).

Cannabidiol appears rapidly in plasma with a time to maximum plasma concentration of 2.5-5 hoursat steady state.

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

In healthy volunteer studies, co-administration of cannabidiol (750 or 1 500 mg) with a high-fat/highcalorie 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 healthyvolunteers. Although the effect is slightly smaller for a low-fat/low-calorie meal, the elevation inexposure is still marked (Cmax by 4-fold, AUC by 3-fold). Furthermore, taking cannabidiol with bovinemilk enhanced exposure by approximately 3-fold for Cmax and 2.5-fold for AUC. Taking cannabidiolwith 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 wasnot 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-foldincrease 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 ketogenicdiet (high-fat meal) i.e., Epidyolex should be taken consistently with or without food. When takenwith food, a similar composition of food should be considered, if possible.

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

The apparent volume of distribution after oral dosing was high in healthy volunteers at 20 963 L to42 849 L and greater than total body water, suggesting a wide distribution of cannabidiol.

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

Cannabidiol is extensively metabolised by the liver via CYP450 enzymes and the UGT enzymes. Themajor 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 tocannabidiol in CYP2C19 intermediate and ultra-rapid metabolisers when compared to extensivemetabolisers.

The phase I metabolites identified in standard in vitro assays were 7-COOH-CBD, 7-OH-CBD, and6-OH-CBD (a minor circulating metabolite).

After multiple dosing with cannabidiol, the 7-OH-CBD metabolite (active in a preclinical model ofseizure) 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 1 500 mg dose of cannabidiol is about1 111 L/h. Cannabidiol is predominantly cleared by metabolism in the liver and gut and excreted infaeces, 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 toresult in relevant drug-drug interactions.

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 750-6 000 mg increases in a less thandose-proportional manner, indicating that absorption of cannabidiol may be saturable. Multiple dosingin TSC patients also indicated that absorption is saturable at doses above 25 mg/kg/day.

Effect of age, weight, sex, race

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

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

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.

No effects on the Cmax or AUC of cannabidiol were observed following administration of a single doseof cannabidiol 200 mg in subjects with mild (CLcr 50 to 80 ml/min), moderate (CLcr 30 to< 50 ml/min), or severe (CLcr < 30 ml/min) renal impairment when compared to patients with normalrenal function (CLcr > 80 ml/min). Patients with end-stage renal disease were not studied.

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

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

In LGS

In patients with LGS, population pharmacokinetic pharmacodynamic (PK/PD) modelling indicated thepresence of an exposure efficacy relationship for the likelihood of achieving a ≥ 50% reduction in dropseizure frequency across the cannabidiol dose range tested (0 [placebo], 10 and 20 mg/kg/day). Therewas 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-responserelationship for the active metabolite of cannabidiol (7-OH-CBD). PK/PD analysis also demonstratedthat 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 toincrease, 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 dosesevaluated are at the high end of the dose-response relationship. However, an exposure-responserelationship 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.

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 metabolite7-carboxy-cannabidiol (7-COOH-CBD) is an inhibitor of UGT1A1, UGT1A4 and UGT1A6-mediatedactivity, in vitro at clinically relevant concentrations (see also section 4.5).

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

Cannabidiol and the metabolite 7-OH-CBD do not interact with the major renal or hepatic uptaketransporters 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 aninhibitor of the brain uptake transporters OATP1A2 and OATP2B1. In vitro, cannabidiol and7-OH-CBD are not substrates for or inhibitors of efflux transports P-gp/MDR1, BCRP or BSEP. Invivo data with everolimus show that cannabidiol can affect P-gp-mediated efflux of a P-gp substrate inthe intestine (see section 4.5) but cannabidiol did not inhibit or induce CYP3A4 based on an in vivomidazolam study. The metabolite 7-COOH-CBD is a P-gp/MDR1 substrate and has the potential toinhibit 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 and20 mg/kg/day in patients) and other AEDs were investigated in drug-drug interaction studies inhealthy volunteers and in patients and in a population pharmacokinetic analysis of plasma drugconcentrations from placebo-controlled studies in the treatment of patients with LGS.

The combination of cannabidiol with clobazam caused an elevation in exposure to the activemetabolite N-desmethylclobazam, with no effect on clobazam levels. Although exposure tocannabidiol 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 berequired.

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 everolimusand cannabidiol are concomitantly used.

The in vivo interactions for clobazam, everolimus and other concomitant AEDs are summarised in thetable 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. No effect on clobazam levels.

Interaction resulting in an increase Interaction resulting in approximatelyin exposure of the active 3-fold increase inmetabolite 7-OH-CBD in HV* N-desmethylclobazam metabolitestudies. a exposure. b

Valproate No effect on CBD or its No effect on valproic acid exposure ormetabolites. exposure to the putative hepatotoxicmetabolite 2-propyl-4-pentenoic acid(4-ene-VPA).

Stiripentol No effect on cannabidiol levels. Interaction resulting in an approximate

Interaction resulting in a decrease 28% increase in Cmax and 55% increase(approximately 30%) in Cmax and in AUC in a HV* study and increases of

AUC of the active metabolite 17% in Cmax and 30% increases in AUC7-OH-CBD in trials conducted in in patients.

HV* and patients with epilepsy.

Everolimus The effect of everolimus on Coadministration of cannabidiolcannabidiol has not been assessed. (12.5 mg/kg twice daily) witheverolimus (5 mg) resulting in anapproximate 2.5-fold increase ineverolimus exposure for both Cmax and

AUC in a HV* study.

a average increases of 47% in AUC and 73% in Cmax.b based on Cmax and AUC.

*HV = Healthy Volunteer.

In a carcinogenicity study in mice, oral administration of Epidyolex (0 [water], 0 [vehicle], 30, 100, or300 mg/kg/day) for 2 years increased the incidence of benign hepatocellular adenomas in male mice atall doses tested and in female mice at the highest dose tested. At the highest dose evaluated, plasmaexposures (AUC) in mice were approximately 7 times greater than the anticipated exposure in humansat a dose 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.

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

The embryo-foetal development (EFD) study performed in rabbits evaluated doses of 50, 80, or125 mg/kg/day. The dose level of 125 mg/kg/day induced decreased foetal body weights and increasedfoetal structural variations associated with maternal toxicity. Maternal plasma cannabidiol exposuresat the no observed-adverse-effect-level (NOAEL) for embryofoetal developmental toxicity in rabbitswere less than that in humans at a dose of 25 mg/kg/day.

In rats, the EFD study evaluated doses of 75, 150, or 250 mg/kg/day. Embryofoetal mortality wasobserved at the high dose, with no treatment-related effects on implantation loss at the low or middoses. The NOAEL was associated with maternal plasma exposures (AUC) approximately 9 timesgreater than the anticipated exposure in humans at a dose 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 adverseeffects on male reproductive organ development (small testes in adult offspring) and fertility wereobserved in the offspring at doses ≥ 150 mg/kg/day. The NOAEL was associated with maternalplasma cannabidiol exposures approximately 5 times that in humans at a dose of 25 mg/kg/day.

Juvenile toxicity

In juvenile rats, administration of cannabidiol for 10 weeks (subcutaneous doses of 0 or 15 mg/kg onpostnatal days [PNDs] 4-6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs7-77) resulted in increased body weight, delayed male sexual maturation, neurobehavioural effects,increased bone mineral density, and liver hepatocyte vacuolation. A no-effect dose was notestablished. The lowest dose causing developmental toxicity in juvenile rats (15 mg/kgsubcutaneous/100 mg/kg oral) was associated with cannabidiol exposures (AUC) approximately8 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 behaviouralresponses, including generalisation to delta-9-tetrahydrocannabinol (THC) in a drug discriminationstudy. Cannabidiol also does not produce animal self-administration, suggesting it does not producerewarding effects.

Refined sesame oil

Anhydrous ethanol

Sucralose (E955)

Strawberry flavour (including benzyl alcohol)

Not applicable.

2 years.

Use within 12 weeks after first opening the bottle.

This medicinal product does not require any special storage conditions.

Amber glass bottle (type III) with a child-resistant and tamper-evident screw cap (polypropylene).

The following pack sizes are available for Epidyolex 100 mg/ml oral solution:

100 ml (1 × 100 ml bottle) with 2 × 5 ml and 2 × 1 ml calibrated oral dosing syringes (HDPE plungerand Polypropylene barrel) and two bottle adaptors (LDPE).

300 ml (3 × 100 ml bottles) with 2 × 5 ml and 2 × 1 ml calibrated oral dosing syringes (HDPE plungerand Polypropylene barrel) and three bottle adaptors (LDPE).

The 5 ml syringes are graduated in 0.1 ml increments and the 1 ml syringes are graduated in 0.05 mlincrements.

Not all pack sizes may be marketed.

Nasogastric tubes made of silicone, with a length of more than 50 cm and maximum of 125 cm and adiameter 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 polyvinylchloride and polyurethane should not be used.

After administration, the enteral feeding tube should be flushed at least once with room temperaturewater. If more than one medicinal product is being administered, the tube should be flushed betweeneach medicinal product. It is recommended that the flushing volume is approximately 5 times thepriming volume of the tube (with a minimum of 3 ml for the shortest/narrowest tubes to a maximum of20 ml for the longest/largest tubes). The flushing volume may need to be modified in patients withfluid restrictions.

Enteral tubes with ENFit® connections require the use of ENFit compatible syringes and bottleadaptors. 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 localrequirements.

Jazz Pharmaceuticals Ireland Ltd5th Floor

Waterloo Exchange

Waterloo Road

Dublin 4

D04 E5W7

Ireland

EU/1/19/1389/001

EU/1/19/1389/002

Date of first authorisation: 19 September 2019

Date of latest renewal: 26 July 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency, https://www.ema.europa.eu