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EPIDIOLEX is a brand name for Cannabidiol, supplied as a solution. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: EPIDIOLEX® (cannabidiol oral solution) is indicated for: • use as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 2 years of age and older. 1.1 Pediatrics Pediatrics (<2 years of age): The safety and…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations • EPIDIOLEX is to be administered orally. • EPIDIOLEX is to be titrated according to patient response. Weekly titration is recommended to allow monitoring of individual response and tolerability. • Titration should not be faster than every other day, which was the titration schedule evaluated in clinical trials.
• The weekly titration schedule is based on pharmacokinetic modelling and simulation. Comparable exposures are predicted from both titration schedules through 10 mg/kg/day, but initial (weeks 2-4) lower exposures are predicted beyond this dose range for the weekly titration schedule.
• Dose(s) of existing antiepileptic regimen to remain stable during treatment initiation and titration. • Because of the risk of hepatocellular injury, obtain serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and total bilirubin levels in all EPIDIOLEX® (cannabidiol) Page 5 of 48 patients prior to starting treatment with EPIDIOLEX and at 1 month, 3 months and 6 months post- treatment initiation and then as clinically indicated (see 7 Hepatic/Biliary/Pancreatic).
• Upon changes in EPIDIOLEX dose, this monitoring schedule (1, 3, and 6 months) should be restarted. 2 Discontinuation of EPIDIOLEX). 5 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the ULN should also have treatment discontinued (see 7 Hepatic/Biliary/Pancreatic).
5 mg/kg taken twice daily (5 mg/kg/day). After one week, the dose should be increased to a maintenance dose of 5 mg/kg twice daily (10 mg/kg/day). 5 mg/kg administered twice daily (5 mg/kg/day) up to a maximum recommended dose of 10 mg/kg twice daily (20 mg/kg/day).
For patients in whom a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dose may be increased no more frequently than every other day. Any dose increases above 10 mg/kg/day, up to the maximum recommended daily dose of 20 mg/kg/day, should be made considering individual benefit and risk and with adherence to the full monitoring schedule (see 7 Monitoring and Laboratory Tests).
5 mg/kg taken twice daily (5 mg/kg/day). After one week, the dosage should be increased to 5 mg/kg twice daily (10 mg/kg/day) and the clinical response and tolerability should be assessed. 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 dose may be increased no more frequently than every other day.
1 Adverse Reaction Overview Patients with Dravet Syndrome A total of 221 individual patients were exposed to EPIDIOLEX during the controlled clinical trials of up to 14 weeks duration. 7% in the placebo group. The most commonly observed serious adverse events in patients receiving EPIDIOLEX were status epilepticus, pneumonia and seizure.
2%). The incidence of discontinuation due to transaminase elevations was dose dependent. Risk factors for transaminase elevation include concomitant valproate and clobazam, dose of EPIDIOLEX, and baseline transaminase elevations. The most common adverse reactions that occurred in EPIDIOLEX-treated patients with DS (incidence at least 5% and a difference of ≥2% than placebo) are somnolence and sedation (30%), decreased appetite (24%), diarrhea (22%), pyrexia (20%), fatigue (15%) and vomiting (12%) (see Table 3 for detailed data).
EPIDIOLEX®(cannabidiol) Page 12 of 48 Patients with Lennox-Gastaut Syndrome A total of 235 individual patients were exposed to EPIDIOLEX during the controlled clinical trials of up to 14 weeks duration. 5% in the placebo group. The most commonly observed serious adverse events in patients receiving EPIDIOLEX were status epilepticus, pneumonia and transaminase elevations.
7%). The incidence of discontinuation due to transaminase elevations was dose dependent. Risk factors for transaminase elevation include concomitant valproate and clobazam, dose of EPIDIOLEX, and baseline transaminase elevations. The most common adverse reactions that occurred in EPIDIOLEX-treated patients with LGS (incidence at least 5% and a difference of ≥2% than placebo) are somnolence and sedation (27%), decreased appetite (18%) and diarrhea (15%) (see Table 4 for detailed data).
Patients with Tuberous Sclerosis Complex A total of 148 individual patients were exposed to EPIDIOLEX during a controlled clinical trial of up to 16 weeks duration. 6% in the placebo group. The most commonly observed serious adverse events in patients receiving EPIDIOLEX were transaminase elevations.
General Somnolence and Sedation EPIDIOLEX can cause somnolence and sedation. In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages), the incidence of somnolence and sedation (including lethargy) was 31% in EPIDIOLEX-treated patients (27% and 33% of patients taking EPIDIOLEX 10 or 20 mg/kg/day, respectively), compared with 12% in patients receiving placebo, and was generally dose-related.
The Route of Administration Dosage Form/ Strength/Composition Non-medicinal Ingredients Oral Solution 100 mg/mL Each mL of solution contains 100 mg of cannabidiol. Ethanol anhydrous (10% v/v) Sesame seed oil Strawberry flavouring Sucralose EPIDIOLEX®(cannabidiol) Page 8 of 48 rate was higher in patients on concomitant clobazam (44% in EPIDIOLEX-treated patients taking clobazam compared with 14% in EPIDIOLEX-treated patients not on clobazam).
In the controlled study for TSC, the incidence of somnolence and sedation including lethargy was 19% in EPIDIOLEX-treated patients (25mg/kg/day) compared with 17% of patients on placebo. The rate was higher in patients on concomitant clobazam (33% in EPIDIOLEX-treated patients taking clobazam compared with 14% in EPIDIOLEX-treated patients not on clobazam).
In general, these effects were more common early in treatment and may diminish with continued treatment. Other CNS depressants, including alcohol, can potentiate the somnolence and sedation effect of EPIDIOLEX. 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 EPIDIOLEX to gauge whether it adversely effects their ability to drive or operate machinery (see 7 Driving and Operating Machinery).
2 Recommended Dose and Dosage Adjustment). If prompt withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered and transition to another antiepileptic drug should be made under close medical supervision.
EPIDIOLEX is contraindicated for use in: • patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• patients with transaminase elevations greater than 3 times the upper limit of normal (ULN) and concurrent elevations of bilirubin greater than 2 times the ULN.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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5 mg/kg twice daily has not been studied in patients with TSC. Any dose increases above 10 mg/kg/day, up to the maximum recommended dose of 25 mg/kg/day, should be made considering individual benefit and risk and with adherence to the full monitoring schedule (see 7 Monitoring and Laboratory Tests).
Patients with Hepatic Impairment Dose adjustment is required in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. 3 Special Populations and Conditions. EPIDIOLEX does not require dose adjustment in patients with mild (Child-Pugh A) hepatic impairment.
5 mg/kg twice daily (5 mg/kg/day) Monitoring of liver function should occur at baseline, 1 month, 3 months, and 6 months after initiation of treatment with EPIDIOLEX. , unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with EPIDIOLEX, as appropriate (see 7 General).
Patients with Renal Impairment There is no requirement for dose modification of EPIDIOLEX in patients with any degree of renal impairment. EPIDIOLEX has not been studied in patients with end-stage renal disease or those undergoing dialysis.
Discontinuation of EPIDIOLEX When discontinuing EPIDIOLEX, the dose should be decreased gradually. As with most antiepileptic drugs (AEDs) abrupt discontinuation should be avoided when possible to minimize the risk of increased seizure frequency and status epilepticus (see 7 General).
In clinical trials, EPIDIOLEX discontinuation was achieved by reducing the dose by approximately 10% per day for 10 days. A slower or faster down titration may be required, as clinically indicated. 4 Administration Food affects EPIDIOLEX absorption significantly, thus EPIDIOLEX should be taken consistently with food (preferably with the same type of meal) or consistently […]
In the controlled clinical trial, the adverse events most frequently leading to discontinuation was rash (5%). The most common adverse reactions that occurred in EPIDIOLEX-treated patients with TSC (incidence at least 5% at the recommended dose and a difference of ≥2% greater than placebo) are diarrhea (31%), decreased appetite (20%), pyrexia (18%), vomiting (17%), somnolence (13%), cough (11%), increased liver enzymes (12%), and constipation (11%) (see Table 5 for detailed data).
2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. Dravet Syndrome Clinical Trials In placebo-controlled trials of patients with DS (includes GWPCARE1 [parts A and B] and GWPCARE2), 221 patients received EPIDIOLEX.
Adverse reactions are presented below; the duration of treatment in these trials was up to 14 weeks. Approximately 51% of patients were female, 84% were Caucasian, and the mean age was 9 years (range 2 to 18 years). All patients were taking other AEDs.
EPIDIOLEX® (cannabidiol) Page 13 of 48 Table 3 lists the adverse reactions that were reported in DS patients treated with EPIDIOLEX as adjunctive therapy in the Phase 3 controlled trials.
Table 3:
Treatment Emergent Adverse Events Occurring in ≥5% in EPIDIOLEX-treated patients, and at ≥2% higher frequency than placebo, in Randomized Controlled Trials (GWPCARE1 [parts A and B] and GWPCARE2), in Patients with DS System Organ Class Preferred Term EPIDIOLEX 10 mg/kg/day (n=72) 20 mg/kg/day (n=139) All active (n=221b) Placebo (n=131) N (%) N (%) N (%) N (%) Gastrointestinal Disorders Diarrhea 11 (15) 37 (27) 48 (22) 15 (12) Vomiting 5 (7) 21 (15) 27 (12) 7 (5) General Disorders and Administration Site Conditions Pyrexia 18 (25) 24 (17) 45 (20) 16 (12) Fatigue 5 (7) 28 (20) 33 (15) 11 (8) Infections and Infestations Pneumoniaa 7 (10) 7 (5) 14 (6) 3 (2) Investigations Aspartate aminotransferase increased 3 (4) 11 (8) 14 (6) 0 Alanine aminotransferase increased 3 (4) 9 (7) 12 (5) 0 Gamma-glutamyltransferase increased 4 (6) 8 (6) 12 (5) 3 (2) Metabolism and Nutrition Disorders Decreased appetite 12 (17) 41 (30) 53 (24) 14 (11) Nervous System Disorders Somnolence and Sedation 20 (28) 42 (30) 66 (30) 16 (12) Psychiatric Disorders Irritability 4 (6) 9 (7) 13 (6) 2 (2) a Grouped Terms: Pneumonia: Pneumonia, Pneumonia viral, Aspiration pneumonia b Includes 10 patients randomized to 5 mg/kg/day in GWPCARE1 Part A.
Lennox-Gastaut Syndrome Clinical Trials In placebo-controlled trials of patients with LGS (includes GWPCARE3 and GWEPCARE4), 235 patients received EPIDIOLEX. Adverse reactions are presented below; the duration of treatment in these trials was up to 14 weeks.
Approximately 45% of patients were female, 87% were Caucasian, and the mean age was 15 years (range 2 to 48 years). All patients were taking other AEDs. EPIDIOLEX®(cannabidiol) Page 14 of 48 Table 4 lists the adverse reactions that were reported in […]
Driving and Operating Machinery EPIDIOLEX can cause somnolence and sedation. 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 EPIDIOLEX to gauge whether it adversely affects their ability to drive or operate machinery (see 7 Somnolence and Sedation).
Hepatic/Biliary/Pancreatic Hepatocellular Injury EPIDIOLEX can cause dose-related elevations of liver transaminases (ALT and/or AST). In controlled studies for LGS, DS, and TSC (10, 20, and 25 mg/kg/day dosages), the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 12% in EPIDIOLEX-treated patients compared with <1% in patients on placebo.
5 times ULN). The patients continued their respective treatments and their abnormal liver laboratory tests resolved without intervention. 5 times the ULN or more. Liver enzyme elevations have been observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate.
Concomitant Valproate and Clobazam In clinical trials, the majority of ALT elevations occurred in patients taking concomitant valproate. Concomitant use of clobazam also increased the incidence of transaminase elevations, although to a lesser extent than valproate.
4 Drug-Drug Interactions). Resolution of transaminase elevations occurred with discontinuation of EPIDIOLEX or reduction of EPIDIOLEX 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 EPIDIOLEX, without dose reduction.
Dose ALT elevations greater than 3 times the ULN were reported in 15% of patients taking EPIDIOLEX 20 or 25 mg/kg/day compared with 3% in patients taking EPIDIOLEX 10 mg/kg/day. 5 times the ULN) without an alternative explanation are an important predictor of severe liver injury.
Early identification of elevated liver enzymes may decrease the risk of a serious outcome. 5 times the ULN), should be evaluated prior to initiation of EPIDIOLEX treatment. Prior to starting treatment with EPIDIOLEX obtain serum transaminases and total bilirubin levels.
Serum transaminases and total bilirubin levels should be obtained at 1 month, 3 months and 6 months after initiation of treatment with EPIDIOLEX, and periodically thereafter or as clinically indicated. 4 Drug-Drug Interactions). In patients with identified baseline elevations of liver enzymes or patients who are taking valproate should have serum transaminases and total bilirubin levels obtained at 2 weeks, 1 month, 2 months, 3 months, and 6 months after initiation of treatment with EPIDIOLEX, and periodically thereafter or as clinically indicated.
Upon changes in EPIDIOLEX dose or changes in medicinal products (dose change or additions) that are known to impact the liver, this monitoring schedule should be restarted. , unexplained nausea, vomiting, right upper quadrant pain, fatigue, […]