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Safety profile of
EPIDIOLEX® (cannabidiol)

Evaluated in an expansive clinical trial program in LGS, Dravet syndrome, and TSC1-3

MOST COMMON ADVERSE EVENTS (≥10% AND GREATER THAN PLACEBO) OBSERVED DURING THE 14-WEEK TREATMENT PERIOD OF THE 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 ADVERSE EVENTS (≥10% AND GREATER THAN PLACEBO) OBSERVED DURING THE 16-WEEK TREATMENT PERIOD OF THE 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 3 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.

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%

OBTAIN SERUM TRANSAMINASES (ALT AND AST) TOTAL BILIRUBIN LEVELS

Monitoring frequency of Serum Transaminases and Bilirubin in patients 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)

The combined incidence of somnolence and sedation were more common early in treatment and may diminish with continued treatment, See Important Safety Information The combined incidence of somnolence and sedation were more common early in treatment and may diminish with continued treatment, See Important Safety Information TSC clinical trials chart - The combined incidence of somnolence and sedation were more common early in treatment and may diminish with continued treatment, See Important Safety Information
  • 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

  • ASMs, including EPIDIOLEX, increase the risk of suicidal thoughts or behavior
  • Inform patients, caregivers, and families of the risk and advise them 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 ASM or the underlying illness

Withdrawal of ASMs

  • As with most ASMs, 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 of CYP2C19 substrates (eg, clobazam, diazepam, stiripentol), orally administered P-gp substrates, 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 coadministered with EPIDIOLEX

Effect on EPIDIOLEX and 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 and dose adjustment based on tolerability

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 ASMs

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

Valporate

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

Rapid withdrawal of most ASMs 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