Epidiolex

/ Neopharm Ltd, Israel

Assessments Prior to Initiation:
Because of the risk of hepatocellular injury, obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment with this medicinal product.
Dosing for Seizures Associated with Lennox-Gastaut Syndrome or Dravet Syndrome:
The starting dosage is 2.5 mg/kg by mouth twice daily (5 mg/kg/day).
After 1 week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day).
Patients who are tolerating the 5 mg/kg twice-daily dose and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day), in weekly increments of 2.5 mg/kg twice daily (5 mg/kg/day), as tolerated.
For patients in whom a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day. Administration of the 20 mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions.
Dosing for Seizures Associated with Tuberous Sclerosis Complex:
The starting dosage is 2.5 mg/kg by mouth twice daily (5 mg/kg/day).
Increase the dose in weekly increments of 2.5 mg/kg twice daily (5 mg/kg/day), as tolerated, to a recommended maintenance dosage of 12.5 mg/kg twice daily (25 mg/kg/day). For patients in whom a more rapid titration to 25 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day.
See prescribing information for full details.

Use as adjunctive therapy of seizures associated with Lennox-Gastaut
syndrome (LGS) or Dravet syndrome (DS) for patients 2 years of age and older.
Use as adjunctive therapy of seizures associated with tuberous sclerosis
complex (TSC) in patients 1 year of age and older.

History of hypersensitivity to cannabidiol or any of the ingredients in the product.

Hepatocellular Injury:
This medicinal product can cause dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages) and TSC (25 mg/kg/day), the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 13% (10 and 20 mg/kg/day dosages) and 12% (25 mg/kg/day dosage) in treated patients compared with 1% in patients on placebo. Less than 1% of treated patients had ALT or AST levels greater than 20 times the ULN. There were cases of transaminase elevations associated with hospitalization in patients taking this drug. In clinical trials, serum transaminase elevations typically occurred in the first 2 months of treatment initiation; however, there were some cases observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate. Resolution of transaminase elevations occurred with discontinuation or reduction of this drug 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 this drug, without dose reduction.
Somnolence and Sedation:
This medicinal product can cause somnolence and sedation. In controlled studies. Controlled studies showed the rate was higher in patients on concomitant clobazam. 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 this drug. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on this medicinal product to gauge whether it adversely affects their ability to drive or operate machinery.
This medicine can affect a patient’s ability to drive cycle or use any tools or machines safely.Therefore according to the Israeli transport regulations and the narcotics ordinance, driving is forbidden during the use with this drug.
Suicidal Behavior and Ideation:
Antiepileptic drugs (AEDs), including this drug, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Hypersensitivity Reactions:
This medicinal product can cause hypersensitivity reactions. Some subjects in the clinical trials had pruritus, erythema, and angioedema requiring treatment, including corticosteroids and antihistamines. Patients with known or suspected hypersensitivity to any ingredients of this drug were excluded from the clinical trials. If a patient develops hypersensitivity reactions after treatment with this drug, the drug should be discontinued. This medicinal product is contraindicated in patients with a prior hypersensitivity reaction to cannabidiol or any of the ingredients in the product, which includes sesame seed oil.
Withdrawal of Antiepileptic Drugs (AEDs):
As with most antiepileptic drugs, this drug should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
See prescribing information for full details.

The most common adverse reactions that occurred in treated patients with Lennox-Gastaut Syndrome or Dravet Syndrome were somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections.
The most common adverse reactions that occurred in treated patients with Tuberous Sclerosis Complex were diarrhea; transaminase elevations; decreased appetite; somnolence; pyrexia; and vomiting.
See prescribing information for full details.

Effect of Other Drugs on EPIDIOLEX:
Strong CYP3A4 or CYP2C19 Inducers: Coadministration with a strong CYP3A4 and CYP2C19 inducer (rifampin 600 mg once daily) decreased cannabidiol and 7-OH-CBD plasma concentrations by approximately 32% and 63%. The impact of such changes on efficacy of this medicinal product are not known. Consider an increase in this drug dosage (based on clinical response and tolerability) up to 2-fold, when coadministered with a strong CYP3A4 and/or CYP2C19 inducer.
Effect of EPIDIOLEX on Other Drugs:
UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 Substrates: Cannabidiol is a weak inhibitor of CYP1A2. Increases in exposure of sensitive CYP1A2 substrates (e.g., caffeine, theophylline, or tizanidine) may be observed when coadministered with cannabidiol.
In vitro data predict drug-drug interactions with CYP2B6 substrates (e.g., bupropion, efavirenz), uridine 5′-diphospho-glucuronosyltransferase 1A9 (UGT1A9) substrates (e.g., diflunisal, propofol, fenofibrate), and UGT2B7 substrates (e.g., gemfibrozil, lamotrigine, morphine, lorazepam) when coadministered with this drug. Coadministration is also predicted to cause clinically significant interactions
with CYP2C8 and CYP2C9 (e.g., phenytoin) substrates. Because of potential inhibition of enzyme activity, consider a reduction in dosage of substrates of UGT1A9, UGT2B7, CYP1A2, CYP2C8, and CYP2C9, as clinically appropriate, if adverse reactions are experienced when administered concomitantly with this drug.
Because of the potential for both induction and inhibition of enzyme activity, consider adjusting dosage of substrates of CYP2B6, as clinically appropriate.
Sensitive CYP2C19 Substrates:
In vivo data show that coadministration increases plasma concentrations of drugs that are metabolized by (i.e., are substrates of) CYP2C19 (e.g., diazepam) and may increase the risk of adverse reactions with these substrates. Consider a reduction in dosage of sensitive CYP2C19 substrates, as clinically appropriate, when coadministered with this drug.
Clobazam: Coadministration produces a 3-fold increase in plasma concentrations of
N-desmethylclobazam, the active metabolite of clobazam (a substrate of CYP2C19), with no effect on clobazam levels. The increase in N-desmethylclobazam may increase the risk of clobazam-related adverse reactions. Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when coadministered with this drug.
Stiripentol: Concomitant use of this drug and stiripentol causes an elevation in exposure to stiripentol. The mechanism of this interaction has not been determined. The clinical relevance of this effect is unknown, but patients should be monitored for stiripentol-related adverse drug reactions.
Sensitive P-gp Substrates Given Orally:
Coadministration of this drug with orally administered everolimus, a P-gp and CYP3A4 substrate, results in an approximately 2.5-fold increase in mean Cmax and AUC of everolimus. When initiating this drug in patients taking everolimus, monitor therapeutic drug levels of everolimus and adjust the dosage accordingly. When initiating everolimus in patients taking a stable dosage of this drug, a lower starting dose of everolimus is recommended, with therapeutic drug monitoring.
Increases in exposure of other orally administered P-gp substrates (e.g., sirolimus, tacrolimus, digoxin) may be observed on coadministration with this drug. Therapeutic drug monitoring and dose reduction of other P-gp substrates should be considered when given orally and concurrently with this drug.
Concomitant Use with Valproate:
Concomitant use with valproate increases the incidence of liver enzyme elevations. If such elevations occur, discontinuation or reduction of this drug and/or concomitant valproate should be considered. Insufficient data are available to assess the risk of concomitant administration with other hepatotoxic drugs.
CNS Depressants and Alcohol:
Concomitant use with other CNS depressants (including alcohol) may increase the risk of sedation and somnolence.

Pregnancy:
There are no adequate data on the developmental risks associated with the use of this drug in pregnant women. Administration of cannabidiol to pregnant animals produced evidence of developmental toxicity (increased embryofetal mortality in rats and decreased fetal body weights in rabbits; decreased growth, delayed sexual maturation, long-term neurobehavioral changes, and adverse effects on the reproductive system in rat offspring) at maternal plasma exposures similar to (rabbit) or greater than (rat) that in humans at therapeutic doses. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. The background risks of major birth defects and miscarriage for the indicated populations are unknown. See prescribing information for full details.
Lactation:
There are no data on the presence of cannabidiol or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for this drug and any potential adverse effects on the breastfed infant from cannabidiol or from the underlying maternal condition.

Store in an upright position.
It is recommended to store at room temperature. Do not freeze.
Keep the cap tightly closed.
Use within 12 weeks of first opening the bottle, then discard any remainder.
There are no special storage conditions after opening the product. It is recommended to store in room temperature.