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.
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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
Hepatic 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
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)
- 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 adverse reactions, including somnolence/sedation, pneumonia, and elevation of liver enzymes and/or ammonia.
Consider a dosage reduction or discontinuation of clobazam and/or valproate if known adverse reactions occur.
Valproate
Coadministration of EPIDIOLEX with valproate increases the risk of elevated liver enzymes and/or ammonia. 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 EPIDIOLEX Pregnancy Surveillance Program and the North American Antiepileptic Drug (NAAED) Pregnancy Registry
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LGS data
EPIDIOLEX significantly reduced drop/total seizure frequency in patients living with LGS
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Dravet syndrome data
EPIDIOLEX significantly reduced convulsive seizures in patients living with Dravet syndrome
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TSC data
EPIDIOLEX reduced the frequency of TSC-associated seizures
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