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Epidyolex is a brand name for Cannabidiol. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Epidyolex is indicated for use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS), in conjunction with clobazam, for patients 2 years of age and older. Epidyolex is indicated for use as adjunctive therapy of seizures associated with tuberous sclerosis complex (TSC)…
Verbatim from this product's EMA label. Tap a section to expand.
Epidyolex should be initiated and supervised by physicians with experience in the treatment of epilepsy. 5 mg/kg taken twice daily (5 mg/kg/day) for one week. 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). 4). 5 mg/kg taken twice daily (5 mg/kg/day) for one week. After one week, the dose should be increased to a dose of 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). 4). 1 ml increment corresponds to 10 mg cannabidiol) If the calculated dose is 100 mg (1 ml) or less, the smaller 1 ml oral syringe should be used. If the calculated dose is more than 100 mg (1 ml), the larger 5 ml oral syringe should be used.
The calculated dose should be rounded to the nearest graduated increment. 5). Discontinuation If cannabidiol has to be discontinued, the dose should be decreased gradually. In clinical trials, cannabidiol 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, at the discretion of the prescriber. Missed doses In the case of one or more missed doses, the missed doses should not be compensated. Dosing should be resumed at the existing treatment schedule.
In the case of more than 7 days’ missed doses, re-titration to the therapeutic dose should be made. 4 Special populations Elderly Clinical trials of cannabidiol in the treatment of LGS, DS and TSC did not include a sufficient number of patients aged above 55 years to determine whether or not they respond differently from younger patients.
2). 2). There is no experience in patients with end-stage renal disease. It is not known if cannabidiol is dialysable. Hepatic impairment Cannabidiol does not require dose adjustment in patients with mild hepatic impairment (Child-Pugh A).
4). A lower starting dose is recommended in patients with moderate or severe hepatic impairment. The dose titration should be performed as detailed in the table below. 5 mg/kg twice daily (5 mg/kg/day)* *Higher doses of cannabidiol may be considered in patients with severe hepatic impairment where the potential benefits outweigh the risks.
Summary of the safety profile Adverse reactions reported with cannabidiol in the recommended dose range of 10 to 25 mg/kg/day are shown below. The most common adverse reactions are somnolence (23%), decreased appetite (21%), diarrhoea (20%), pyrexia (16%), vomiting (12%) and fatigue (10%).
The most frequent causes of discontinuation were transaminase elevation (2%), somnolence (2%) and decreased appetite (1%). Tabulated list of adverse reactions Adverse reactions reported with cannabidiol in placebo-controlled clinical studies are listed in the table below by System Organ Class and frequency.
The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 11 Table 3: Tabulated list of adverse reactions System Organ Class Frequency Adverse reactions from clinical trials Infections and infestations Common Pneumoniaa Urinary tract infection Blood and lymphatic system disorders Very common Haemoglobin decreased Haematocrit decreased Metabolism and nutrition disorders Very common Decreased appetite Psychiatric disorders Common Irritability Aggression Nervous system disorders Very common Somnolencea Common Lethargy Seizure Respiratory, thoracic and mediastinal disorders Common Cough Gastrointestinal disorders Very common Diarrhoea Vomiting Common Nausea Hepatobiliary disorders Common AST increased ALT increased GGT increased Skin and subcutaneous tissue disorders Common Rash Renal and urinary disorders Common Blood creatinine increased General disorders and administration site conditions Very common Pyrexia Fatigue Investigations Common Weight decreased a Grouped Terms: Pneumonia: Pneumonia, Pneumonia RSV, Pneumonia mycoplasmal, Pneumonia adenoviral, Pneumonia viral, Aspiration pneumonia; Somnolence: Somnolence, Sedation.
4). In controlled studies for LGS, DS (receiving 10 or 20 mg/kg/day) and for TSC (receiving 25 mg/kg/day), the incidence of ALT elevations above 3 times the ULN was 12% in cannabidiol-treated patients compared with < 1% in patients on placebo.
8). The elevations typically occur in the first two months of treatment initiation; however, there were cases observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate. 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. Dose adjustment or discontinuation of valproate or dose adjustment of clobazam should be considered if transaminase elevations occur.
Resolution of transaminase elevations occurred with discontinuation of cannabidiol or reduction of cannabidiol 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 cannabidiol, without dose reduction.
Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevations when taking cannabidiol. In some patients, a synergistic effect of concomitant treatment with valproate upon baseline elevated transaminases resulted in a higher risk of transaminase elevations.
In an uncontrolled study in patients in a different non-epilepsy indication, 2 elderly patients experienced elevations of alkaline phosphatase levels above 2 times the ULN in combination with transaminase elevations. The elevations resolved after discontinuation of cannabidiol.
Monitoring In general, transaminase elevations of greater than 3 times the ULN in the presence of elevated bilirubin without an alternative explanation are an important predictor of severe liver injury. Early identification of elevated transaminase may decrease the risk of a serious outcome.
Patients with elevated baseline transaminase levels above 3 times the ULN, or elevations in bilirubin above 2 times the ULN, should be evaluated prior to initiation of cannabidiol treatment. Prior to starting treatment with cannabidiol, obtain serum transaminases (ALT and AST) and total bilirubin levels.
1. 4).
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Paediatric population With LGS and DS There is no relevant use of cannabidiol in children aged below 6 months. The safety and efficacy of cannabidiol in children aged 6 months to 2 years have not yet been established. No data are available.
With TSC There is no relevant use of cannabidiol in children aged below 1 month. The safety and efficacy of cannabidiol in children aged 1 month to 2 years have not yet been established. 1 but no recommendation on a posology can be […]
Less than 1% of cannabidiol-treated patients had ALT or AST levels greater than 20 times the ULN. There have been cases of transaminase elevations associated with hospitalisation in patients taking cannabidiol. Risk factors for hepatocellular injury Concomitant valproate and clobazam, dose of cannabidiol and baseline transaminase elevations Concomitant valproate and clobazam In cannabidiol-treated patients receiving doses of 10, 20, and 25 mg/kg/day, the incidence of ALT elevations greater than 3 times the ULN was 23% in patients taking both concomitant valproate and clobazam, 19% in patients taking concomitant valproate (without clobazam), 3% in patients taking concomitant clobazam (without valproate), and 3% in patients taking neither medicinal product.
Dose ALT elevations greater than 3 times the ULN were reported in 15% of patients taking cannabidiol 20 or 25 mg/kg/day compared with 3% in patients taking cannabidiol 10 mg/kg/day. 12 The risk of ALT elevations was higher at doses higher than the 25 mg/kg/day in the controlled study in TSC.
1) in patients taking cannabidiol 20 or 25 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 times the ULN was 29% (80% of these were on valproate) when ALT was above the ULN at baseline, compared to 12% (89% of these were on valproate) when ALT was within the normal range at baseline.
A total of 5% of patients (all on valproate) taking cannabidiol 10 mg/kg/day experienced ALT elevations greater than 3 times the ULN when ALT was above the ULN at baseline, compared with 3% of patients (all on valproate) in whom ALT was within the normal range at baseline.
4) with cannabidiol in LGS, DS and TSC, including 29% of cannabidiol-treated patients (30% of patients taking cannabidiol 20 or 25 mg/kg/day and 27% of patients taking cannabidiol 10 mg/kg/day). These adverse reactions were observed at higher incidences at doses above 25 mg/kg/day in the controlled study in TSC.
The rate of somnolence and sedation (including lethargy) was higher in patients on concomitant clobazam (43% in cannabidiol-treated patients taking clobazam, compared with 14% in cannabidiol-treated patients not on clobazam). Seizures In the controlled trial in TSC patients, an increased frequency of adverse events associated with seizure worsening was seen at doses above 25 mg/kg/day.
Although no clear pattern was established, the adverse events reflected increased seizure frequency or intensity, or new seizure types. The frequency of adverse events associated with seizure worsening was 11% for patients taking 25 mg/kg/day cannabidiol and 18% for patients taking cannabidiol doses greater than 25 mg/kg/day, compared to 9% in patients taking placebo.
4). In LGS, DS and TSC patients, the decrease in weight appeared to be dose-related, with 21% of patients on cannabidiol 20 or 25 mg/kg/day experiencing a decrease in weight of ≥ 5%, compared to 7% in patients on cannabidiol 10 mg/kg/day.
In some cases, the decreased weight was reported as an adverse event (see Table 3 above). Decreased appetite and weight loss may result in slightly reduced height gain. Diarrhoea Cannabidiol can cause dose-related diarrhoea. In controlled trials in LGS and DS, the frequency of diarrhoea was 13% in patients receiving 10 mg/kg/day cannabidiol and 21% in patients receiving 20 mg/kg/day cannabidiol, compared to 10% in patients receiving placebo.
In a […]
6 Routine monitoring Serum transaminases and total bilirubin levels should be obtained at 1 month, 3 months, and 6 months after initiation of treatment with cannabidiol, and periodically thereafter or as clinically indicated. Upon changes in cannabidiol dose above 10 mg/kg/day or changes in medicinal products (dose change or additions) that are known to impact the liver, this monitoring schedule should be restarted.
Intensified monitoring Patients with identified baseline elevations of ALT or AST and 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 cannabidiol, and periodically thereafter or as clinically indicated.
Upon changes in cannabidiol dose above 10 mg/kg/day or changes in medicinal products (dose change or additions) that are known to impact the liver, this monitoring schedule should be restarted. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, serum transaminases and total bilirubin should be promptly measured and treatment with cannabidiol should be interrupted or discontinued, as appropriate.
Cannabidiol should be discontinued in any patients with elevations of transaminase levels greater than 3 times the ULN and bilirubin levels greater than 2 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the ULN should also have treatment discontinued.
Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes. 5). Somnolence and sedation Cannabidiol can cause somnolence and sedation, which occur more commonly early in treatment and may diminish with continued treatment.
8). Other CNS depressants, including alcohol, can potentiate the somnolence and sedation effect. Increased seizure frequency As with other AEDs, a clinically relevant increase in seizure frequency may occur during treatment with cannabidiol, which may require adjustment in dose of cannabidiol and/or concomitant AEDs, or discontinuation of cannabidiol, should the benefit-risk be negative.
In the phase 3 clinical trials investigating LGS, DS and TSC, the observed frequency of status epilepticus was similar between the cannabidiol and placebo groups. Suicidal behaviour and ideation Suicidal behaviour and ideation have been reported in patients treated with AEDs in several indications.
A meta-analysis of randomised placebo-controlled trials with AEDs has shown a small increased risk of suicidal behaviour and ideation. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for cannabidiol.
Patients should be monitored for signs of suicidal behaviour and ideation and appropriate treatment should be considered. Patients and caregivers of patients should be advised to seek medical advice should any signs of suicidal behaviour and ideation emerge.
8). In LGS, DS and TSC patients, this appeared to be dose-related. In some cases, decreased weight was reported as an adverse event. Decreased appetite and weight loss may result in slightly reduced height gain. Continuous 7 weight loss/absence of weight gain should be periodically checked to evaluate if cannabidiol treatment should be continued.
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