Safety profile of EPIDIOLEX® (cannabidiol)
Evaluated in an expansive clinical trial program in LGS, Dravet syndrome, and TSC1
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 (%)
|Nervous System Disorders|
|Fatigue, malaise, asthenia||4||11||12|
|Insomnia, sleep disorder, poor-quality sleep||4||11||5|
MOST COMMON AEs (≥10% AND GREATER THAN PLACEBO) OBSERVED DURING THE 16-WEEK TREATMENT PERIOD OF PHASE 3 CONTROLLED TRIAL FOR TSC (%)
|Nervous System Disorders|
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
- EPIDIOLEX (cannabidiol) oral solution is contraindicated in patients with a history of hypersensitivity to cannabidiol or any ingredients in the product
WARNINGS & PRECAUTIONS
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 treated with 10 and 20 mg/kg/day of EPIDIOLEX and 12% in patients 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
Consider more frequent monitoring of serum transaminases and bilirubin in patients who are taking valproate or who have elevated liver enzymes at baseline with and without valproate
- 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
- 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
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) or others. Dosage adjustment of EPIDIOLEX or other concomitant medications may be necessary
In clinical trials, clobazam and valproate were among the most commonly used concomitant AEDs
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 and liver enzyme elevations.
Coadministration of EPIDIOLEX with valproate increases the incidence of liver enzyme elevation.
In drug interaction studies, there was no effect on valproate exposure.
Dose adjustments should be made by clinicians based on individual patient response and tolerability and physician experience.
Rapid withdrawal of any AED can lead to increased seizure frequency and status epilepticus1
Mammalian target of rapamycin (mTOR) inhibitors and calcineurin inhibitors: No drug interaction studies have been completed, but case reports suggest a potential for elevations of mTOR or calcineurin inhibitors when used with EPIDIOLEX.
- 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.