Epidyolex · 4.8 Undesirable effects · 1

HOS-098561 · has-adverse-reaction-information · PDF-Seite 10

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. 10 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 Very common Haemoglobin decreased disorders Haematocrit decreased Metabolism and nutrition Very common Decreased appetite disorders Psychiatric disorders Common Irritability Aggression Nervous system disorders Very common Somnolencea Common Lethargy Seizure Respiratory, thoracic and Common Cough mediastinal disorders Gastrointestinal disorders Very common Diarrhoea Vomiting Common Nausea Hepatobiliary disorders Common AST increased ALT increased GGT increased Skin and subcutaneous tissue Common Rash disorders Renal and urinary disorders Common Blood creatinine increased General disorders and

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HOS-098557 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with transaminase elevations greater than 3 times the upper limit of normal (ULN) and bilirubin greater than 2 times the ULN (see section 4.4).

HOS-098556 · has-indication-information · PDF-Seite 2

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) for patients 2 years of age and older.

HOS-098559 · has-interaction-information · PDF-Seite 7

CYP3A4 or CYP2C19 inducers The strong CYP3A4/2C19 inducing agent rifampicin (600 mg administered once daily) decreased plasma concentrations of cannabidiol and of 7-hydroxy-cannabidiol (7-OH-CBD; an active metabolite of cannabidiol) by approximately 30% and 60%, respectively. Other strong inducers of CYP3A4 and/or CYP2C19, such as carbamazepine, enzalutamide, mitotane, and St. John’s wort, when administered concomitantly with cannabidiol, may also cause a decrease in the plasma concentrations of cannabidiol and of 7-OH-CBD by a similar amount. These changes may result in a decrease in the effectiveness of cannabidiol. Dose adjustment may be necessary. UGT inhibitors Cannabidiol is a substrate for UGT1A7, UGT1A9 and UGT2B7. No formal drug-drug interaction studies have been conducted with cannabidiol in combination with UGT inhibitors, therefore, caution should be taken when co-administering medicinal products that are known inhibitors of these UGTs. Dose reduction of cannabidiol and/or the inhibitor may be necessary when given in combination. Concomitant AED treatments The pharmacokinetics of cannabidiol are complex and may cause interactions with the patient’s concomitant AED treatments. Cannabidiol and/or concomitant AED treatment should therefore be adjusted during regular medical supervision and the patient should be closely monitored for adverse drug reactions. In addition, monitoring of plasma concentrations should be considered. The potential for drug-drug interactions with other concomitant AEDs has been assessed in healthy volunteers and patients with epilepsy for clobazam, valproate, stiripentol and everolimus. 7 Clobazam When cannabidiol and clobazam are co-administered, bi-directional PK interactions occur. Based on a healthy volunteer study, elevated levels (3- to 4-fold) of N-desmethylclobazam (an active metabolite of clobazam) can occur when combined with cannabidiol, likely mediated by CYP2C19 inhibition, with no effect on clobazam levels. In addition, there was an increased exposure to 7-OH-CBD, for which plasma area under the curve (AUC) increased by 47% (see section 5.2). Increased systemic levels of these active substances may lead to enhanced pharmacological effects and to an increase in adverse drug reactions. Concomitant use of cannabidiol and clobazam increases the incidence of somnolence and sedation compared with placebo (see sections 4.4 and 4.8). Reduction in dose of c

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HOS-098560 · has-pregnancy-information · PDF-Seite 10

Pregnancy There are only limited data from the use of cannabidiol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). As a precautionary measure, cannabidiol should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus. Breast-feeding There are no clinical data on the presence of cannabidiol or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Studies in animals have shown toxicological changes in lactating animals, when the mother was treated with cannabidiol (see section 5.3). There are no human studies on excretion of cannabidiol in breast milk. Given that cannabidiol is highly protein bound and will likely pass freely from plasma into milk, as a precaution, breast-feeding should be discontinued during treatment. Fertility No human data on the effect of cannabidiol on fertility are available. No effect on reproductive ability of male or female rats was noted with an oral dose of up to 150 mg/kg/day cannabidiol (see section 5.3).

HOS-098558 · has-warning-information · PDF-Seite 5

Hepatocellular injury Cannabidiol can cause dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) (see section 4.8). 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. 5 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 th

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