4.1. 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 (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)

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.

Discontinuation

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 for 10 days. A slower or faster down titration may be required, as clinically indicated, at the discretion of the prescriber.

Missed doses

In the case of one or more missed doses, the missed doses should not be compensated. Dosing should be 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.

Special populations

Elderly

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

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other concurrent therapy (see sections 4.4 under hepatocellular injury and 5.2).

Renal impairment

Cannabidiol can be administered to patients with mild, moderate, or severe renal impairment without dose adjustment (see section 5.2). There is no experience in patients with end‑stage renal disease. It is not known if cannabidiol is dialysable.

Hepatic impairment

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). A lower starting dose is recommended in patients with moderate or severe hepatic impairment. The dose titration should be performed as detailed in the table below.

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

Hepatic Impairment

Starting Dose

For LGS, DS and TSC

Maintenance Dose

For LGS and DS

Second Week

For TSC

Maximal Recommended Dose

For LGS and DS

Maximal Recommended Dose

For TSC

Moderate

1.25 mg/kg twice daily

(2.5 mg/kg/day)

2.5 mg/kg twice daily

(5 mg/kg/day)

5 mg/kg twice daily

(10 mg/kg/day)

6.25 mg/kg twice daily

(12.5 mg/kg/day)

Severe

0.5 mg/kg twice daily

(1 mg/kg/day)

1 mg/kg twice daily

(2 mg/kg/day)

2 mg/kg twice daily

(4 mg/kg/day)*

2.5 mg/kg twice daily

(5 mg/kg/day)*

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

Paediatric population

With LGS and DS

There is no relevant use of cannabidiol in children aged below 6 months. The safety and efficacy of cannabidiol 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 of cannabidiol in children aged 1 month to 2 years have not yet been established. Currently available data in patients aged 1 to 2 years are described in section 5.1 but no recommendation on a posology can be made.

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 medicinal product(s) to manage potential drug interactions (see sections 4.4 and 4.5).

Method of administration

Oral use

Food may increase cannabidiol levels and therefore it should be taken consistently either with or without food, including the ketogenic diet. When taken with food, a similar composition of food should be considered, if possible (see section 5.2).

Oral administration is recommended; however, when necessary, nasogastric and gastrostomy tubes may be acceptable routes for enteral administration.

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

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

Common

Lethargy, Seizure

Respiratory, thoracic and mediastinal disorders

Common

Cough

Gastrointestinal disorders

Very common

Diarrhoea, Vomiting

Common

Nausea

Hepatobiliary disorders

Common

AST increased, ALT increased, GGT increased

Skin and subcutaneous tissue disorders

Common

Rash

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.

Pneumonia

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 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.