Safety profile of EPIDIOLEX^®
(cannabidiol)

Evaluated in an expansive clinical trial program in LGS, Dravet syndrome, and TSC

MOST COMMON AEs (≥10% AND GREATER THAN PLACEBO) OBSERVED DURING THE 14-WEEK TREATMENT PERIOD OF PHASE 3 CONTROLLED TRIALS FOR LGS AND DRAVET SYNDROME (%)

	Placebo (n=227)	EPIDIOLEX 10 mg/kg/day (n=75)	EPIDIOLEX 20 mg/kg/day (n=238)
Hepatic Disorders
Transaminases elevated	3	8	16
Gastrointestinal Disorders
Decreased appetite	5	16	22
Diarrhea	9	9	20
Nervous System Disorders
Somnolence	8	23	25
Fatigue, malaise, asthenia	4	11	12
Insomnia, sleep disorder, poor-quality sleep	4	11	5
Infections
Infection, all	31	41	40
Other
Rash	3	7	13

MOST COMMON AEs (≥10% AND GREATER THAN PLACEBO) OBSERVED DURING THE 16-WEEK TREATMENT PERIOD OF PHASE 3 CONTROLLED TRIAL FOR TSC (%)

	Placebo (n=76)	EPIDIOLEX 25 mg/kg/day (n=75)
Hepatic Disorders
Transaminases elevated	0	25
Gastrointestinal Disorders
Diarrhea	25	31
Decreased appetite	12	20
Vomiting	9	17
Nervous System Disorders
Somnolence	9	13
Other
Pyrexia	8	19

In all three indications, EPIDIOLEX was found to have a consistent safety profile in children and adults

Hematologic abnormalities, decreased weight, and increased creatinine levels were also observed
In the LGS and Dravet syndrome studies, the rate of discontinuation for any adverse reaction was 2.7% for patients taking EPIDIOLEX 10 mg/kg/day, 11.8% for patients taking EPIDIOLEX 20 mg/kg/day, and 1.3% for patients on placebo. In the TSC study, the rate of discontinuation for any adverse event was 3% for patients treated with placebo, and 11% with EPIDIOLEX 25 mg/kg/day
The most frequent causes of discontinuation were transaminase elevations, somnolence, sedation, and lethargy in the LGS and Dravet syndrome studies and rash in the TSC study

Pneumonia was observed more frequently with concomitant use of EPIDIOLEX and clobazam

DISCOVER EFFICACY DATA

Contraindication: hypersensitivity

EPIDIOLEX (cannabidiol) oral solution is contraindicated in patients with a history of hypersensitivity to cannabidiol or any ingredients in the product

WARNINGS & PRECAUTIONS

Hepatocellular injury

EPIDIOLEX can cause dose-related transaminase elevations

In controlled studies, the incidence of ALT elevations (>3x the upper limit of normal [ULN]) was 13% in patients with LGS and Dravet syndrome treated with 10 and 20 mg/kg/day of EPIDIOLEX and 12% in patients with TSC treated with 25 mg/kg/day of EPIDIOLEX and 1% with placebo. Less than 1% of EPIDIOLEX-treated patients had ALT or AST 20x the ULN

Concomitant use of valproate and elevated transaminase levels at baseline increase this risk

INCIDENCE OF ALT ELEVATIONS >3x ULN IN PATIENTS TREATED WITH EPIDIOLEX

	EPIDIOLEX + clobazam and valproate	EPIDIOLEX + valproate (without clobazam)	EPIDIOLEX + clobazam (without valproate)	EPIDIOLEX (without clobazam or valproate)
LGS & Dravet syndrome clinical trials	30%	21%	4%	3%
TSC clinical trial	20%	25%	0%	6%

	LGS & Dravet syndrome clinical trials	TSC clinical trial
EPIDIOLEX + clobazam and valproate	30%	20%
EPIDIOLEX + valproate (without clobazam)	21%	25%
EPIDIOLEX + clobazam (without valproate)	4%	0%
EPIDIOLEX (without clobazam or valproate)	3%	6%

Monitoring Frequency of Serum Transaminases and Bilirubin in Patients

Consider more frequent monitoring of serum transaminases and bilirubin in patients who are taking valproate or who have elevated liver enzymes at baseline

Monitor within 1 month following changes in EPIDIOLEX dosage and addition of or changes in medications that are known to impact the liver
Consider discontinuation or dose reduction of EPIDIOLEX or concomitant medications known to affect the liver (eg, valproate or clobazam) if liver enzyme elevations occur (transaminase levels >3x the ULN and bilirubin levels >2x the ULN, or sustained transaminase elevations >5x the ULN)

Somnolence and sedation

COMBINED INCIDENCE OF SOMNOLENCE AND SEDATION (INCLUDING LETHARGY)

		LGS & Dravet syndrome clinical trials	TSC clinical trial
OVERALL	PLACEBO overall	11%	17%
OVERALL	EPIDIOLEX overall	32%	19%

BY DOSE	EPIDIOLEX 10 mg/kg/day	27%
	EPIDIOLEX 20 mg/kg/day	34%
	EPIDIOLEX 25 mg/kg/day		19%

USE OF CLOBAZAM	EPIDIOLEX without clobazam	16%	14%
	EPIDIOLEX with concomitant clobazam	46%	33%

		LGS & Dravet syndrome clinical trials
OVERALL	PLACEBO overall	11%
OVERALL	EPIDIOLEX overall	32%

BY DOSE	EPIDIOLEX 10 mg/kg/day	27%
	EPIDIOLEX 20 mg/kg/day	34%
	EPIDIOLEX 25 mg/kg/day

USE OF CLOBAZAM	EPIDIOLEX without clobazam	16%
	EPIDIOLEX with concomitant clobazam	46%

		TSC clinical trial
OVERALL	PLACEBO overall	17%
OVERALL	EPIDIOLEX overall	19%

BY DOSE	EPIDIOLEX 10 mg/kg/day
	EPIDIOLEX 20 mg/kg/day
	EPIDIOLEX 25 mg/kg/day	19%

USE OF CLOBAZAM	EPIDIOLEX without clobazam	14%
	EPIDIOLEX with concomitant clobazam	33%

In general, these effects were more common early in treatment and may diminish with continued treatment
Other CNS depressants, including alcohol, could potentiate the somnolence and sedation effect of EPIDIOLEX
Monitor for somnolence and sedation and advise patients not to drive or operate machinery until they have gained sufficient experience on EPIDIOLEX

Suicidal behavior and ideation

Antiepileptic drugs (AEDs), including EPIDIOLEX, increase the risk of suicidal thoughts or behavior
Inform patients, caregivers, and families of the risk and advise to monitor and report any signs of depression, suicidal thoughts or behavior, or unusual changes in mood or behavior
If these symptoms occur, consider if they are related to the AED or the underlying illness

Withdrawal of antiepileptic drugs

As with most AEDs, EPIDIOLEX should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus

Drug interactions

Considerations for patients on multiple therapies:

Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations
EPIDIOLEX may affect exposure to CYP2C19 substrates (eg, clobazam, diazepam, stiripentol) or other substrates. Dosage adjustment of EPIDIOLEX or other concomitant medications may be necessary
Increases in exposure of sensitive CYP1A2 substrates (eg, caffeine, theophylline, or tizanidine) may be observed when co-administered with EPIDIOLEX

Effect on EPIDIOLEX

Dose adjustment based on tolerability

Strong inducer of CYP3A4 and CYP2C19

Consider up to a 2-fold dose increase of EPIDIOLEX

EPIDIOLEX effect on other substrates

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

Consider dose reduction of the substrate

Substrates of CYP2B6

Consider adjusting dosage of the substrate

Orally administered substrates of P-gp

Consider dose reduction of the substrate and monitor theraputic levels; recommend lower starting dose of everolimus

In clinical trials, clobazam and valproate were among the most commonly used concomitant AEDs

CLOBAZAM
EPIDIOLEX produces a 3-fold increase in plasma concentrations of the active metabolite of clobazam, with no effect on clobazam levels. This may increase the risk of clobazam-related adverse reactions, including somnolence/sedation, liver enzyme elevations, and pneumonia.

Consider a reduction of dosage of clobazam if known clobazam adverse reactions occur.

VALPROATE
Coadministration of EPIDIOLEX with valproate increases the incidence of liver enzyme elevation.

In drug interaction studies, there was no clinically relevant effect on valproate exposure.

Dose adjustments should be made by clinicians based on individual patient response and tolerability and physician experience.

Rapid withdrawal of most AEDs can lead to increased seizure frequency and status epilepticus

Pregnancy

EPIDIOLEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage women who are taking EPIDIOLEX during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry

Please refer to the EPIDIOLEX full Prescribing Information for additional important information.

The EPIDIOLEX dosing calculator can help when adjusting dosage based on your patient’s weight

CALCULATE DOSE

Safety profile of EPIDIOLEX^®
(cannabidiol)