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.

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

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).

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.

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

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).

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).

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, 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 Very common Somnolencea Nervous system disorders Common Lethargy, Seizure Respiratory, thoracic and mediastinal disorders Common Cough Very common Diarrhoea, Vomiting Gastrointestinal disorders 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.

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

Pharmacotherapeutic group: antiepileptics, other antiepileptics; ATC code: N03AX24 Mechanism of action The precise mechanisms by which cannabidiol exerts its anticonvulsant effects in humans are unknown. Cannabidiol does not exert its anticonvulsant effect through

Absorption Cannabidiol appears rapidly in plasma with a time to maximum plasma concentration of 2.5–5 hours at steady state. Steady-state plasma concentrations are attained within 2-4 days of twice daily dosing based on pre-dose (Ctrough) concentrations. The rapid achievement of steady state is related to the multiphasic elimination profile of the drug in which the terminal elimination represents only a small fraction of the drug’s clearance. In healthy volunteer studies, co-administration of cannabidiol (750 or 1500 mg) with a high-fat/high calorie meal increased the rate and extent of absorption (5-fold increase in Cmax and 4-fold increase in AUC) and reduced the total variability of exposure compared with the fasted state in healthy volunteers. Although the effect is slightly smaller for a low-fat/low-calorie meal, the elevation in exposure is still marked (Cmax by 4-fold, AUC by 3- fold). Furthermore, taking cannabidiol with bovine milk enhanced exposure by approximately 3-fold for Cmax and 2.5-fold for AUC. Taking cannabidiol with alcohol also caused enhanced exposure to cannabidiol, with a 63% greater AUC. In the randomised controlled trials, the timing of dose of cannabidiol with respect to meal times was not restricted. In patients, a high fat meal was also shown to increase the bioavailability of cannabidiol (3-fold). This increase was moderate when the prandial state was not fully known, i.e., 2.2-fold increase of the relative bioavailability. To minimise the variability in the bioavailability of cannabidiol in the individual patient, administration of cannabidiol should be standardised in relation to food intake including a ketogenic diet (high-fat meal) i.e., Epidyolex should be taken consistently with or without food. When taken with food, a similar composition of food should be considered, if possible.. Distribution In vitro, > 94% of cannabidiol and its phase I metabolites were bound to plasma proteins, with preferential binding to human serum albumin. The apparent volume of distribution was high in healthy volunteers at 20,963 L to 42,849 L and greater than total body water, suggesting a wide distribution of cannabidiol. Biotransformation and elimination The half-life of cannabidiol in plasma was 56–61 hours after twice daily dosing for 7 days in healthy volunteers. Metabolism Cannabidiol is extensively metabolised by the liver via CYP450 enzymes and the UGT enzymes. The major CYP450 isoforms responsible for the phase I metabolism of cannabidiol are CYP2C19 and CYP3A4. The UGT isoforms responsible for the phase II conjugation of cannabidiol are UGT1A7, UGT1A9 and UGT2B7. Studies in healthy subjects showed there were no major differences in the plasma exposure to cannabidiol in CYP2C19 intermediate and ultra-rapid metabolisers when compared to extensive metabolisers. The phase I metabolites identified in standard in vitro assays were 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD (a minor circulating metabolite). After multiple dosing with cannabidiol, the 7-OH-CBD metabolite (active in a preclinical model of seizure) circulates in human plasma at lower concentrations than the parent drug cannabidiol (~ 40% of CBD exposure) based on AUC. Excretion The plasma clearance of cannabidiol following a single 1500 mg dose of cannabidiol is about 1,111 L/h. Cannabidiol is predominantly cleared by metabolism in the liver and gut and excreted in faeces, with renal clearance of parent drug being a minor pathway. Cannabidiol does not interact with the major renal and hepatic transporters in a way that is likely to result in relevant drug-drug

Mutagenicity and Carcinogenicity In a carcinogenicity study in mice, oral administration of Epidyolex (0 [water], 0 [vehicle], 30, 100, or 300 mg/kg/day) for 2 years increased the incidence of benign hepatocellular adenomas in male mice at all doses tested and in female mice at the highest dose tested. At the highest dose evaluated, plasma exposures (AUC) in mice were approximately 7 times greater than the anticipated exposure in humans at a dosage of 25 mg/kg/day. A study of the carcinogenic potential of cannabidiol in rats has not been conducted Genotoxicity studies have not detected any mutagenic or clastogenic activity. Reproductive toxicity No adverse reactions were observed on male or female fertility or reproduction performance in rats at doses up to 250 mg/kg/day (approximately 34-fold greater than the maximum recommended human dose (MRHD) at 25 mg/kg/day). The embryo-foetal development (EFD) study performed in rabbits evaluated doses of 50, 80, or 125 mg/kg/day. The dose level of 125 mg/kg/day induced decreased foetal body weights and increased foetal structural variations associated with maternal toxicity. Maternal plasma cannabidiol exposures at the no observed-adverse-effect-level (NOAEL) for embryofoetal developmental toxicity in rabbits were less than that in humans at a dosage of 25 mg/kg/day. In rats, the EFD study evaluated doses of 75, 150, or 250 mg/kg/day. Embryofoetal mortality was observed at the high dose, with no treatment- related effects on implantation loss at the low or mid doses. The NOAEL was associated with maternal plasma exposures (AUC) approximately 9 times greater than the anticipated exposure in humans at a dosage of 25 mg/kg/day. A pre- and post-natal development study was performed in rats at doses of 75, 150, or 250 mg/kg/day. Decreased growth, delayed sexual maturation, behavioural changes (decreased activity), and adverse effects on male reproductive organ development (small testes in adult offspring) and fertility were observed in the offspring at doses = 150 mg/kg/day. The NOAEL was associated with maternal plasma cannabidiol exposures approximately 5 times that in humans at a dosage of 25 mg/kg/day. Juvenile toxicity In juvenile rats, administration of cannabidiol for 10 weeks (subcutaneous doses of 0 or 15 mg/kg on postnatal days [PNDs] 4-6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs 7-77) resulted in increased body weight, delayed male sexual maturation, neurobehavioural effects, increased bone mineral density, and liver hepatocyte vacuolation. A no-effect dose was not established. The lowest dose causing developmental toxicity in juvenile rats (15 mg/kg subcutaneous/100 mg/kg oral) was associated with cannabidiol exposures (AUC) approximately 8 times that in humans at 25 mg/kg/day. In another study, cannabidiol was dosed to juvenile rats from PND 4-21 (as a subcutaneous injection) and from PND 22-50 (as an intravenous injection). A NOAEL of 15 mg/kg/day was established. Abuse Animal abuse-related studies show that cannabidiol does not produce cannabinoid-like behavioural responses, including generalisation to delta-9-tetrahydrocannabinol (THC) in a drug discrimination study. Cannabidiol also does not produce animal self-administration, suggesting it does not produce rewarding effects.

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 bottle is packaged in a carton with two 5 ml and two 1 ml calibrated oral dosing syringes (plunger HDPE and barrel polypropylene) and two bottle adaptors (LDPE). The 5 ml syringes are graduated in 0.1 ml increments and the 1 ml syringes are graduated in 0.05 ml increments.

Nasogastric tubes made of silicone, with a length of more than 50 cm and maximum of 125 cm and a diameter of more than 5 FR and maximum of 12 FR, can be used. Nasogastric tubes made of silicone, being 50 cm or shorter and 5 FR or less in diameter should be avoided. Gastric tubes made of silicone, with a length of 0.8 to 4 cm and a diameter of 12 FR to 24 FR, can be used. Tubes made of polyvinyl chloride and polyurethane should not be used. After administration, the enteral feeding tube should be flushed at least once with room temperature water. If more than one drug is being administered, the tube should be flushed between each drug. It is recommended that the flushing volume is approximately 5 times the priming volume of the tube (with a minimum of 3 ml for the shortest/narrowest tubes to a maximum of 20 ml for the longest/largest tubes). The flushing volume may need to be modified in patients with fluid restrictions. Enteral tubes with ENFit® connections require the use of ENFit compatible syringes and bottle adaptors. To maximise dose accuracy, 1 ml syringes should be used for doses = 1 ml. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Feb. 16, 2026

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