Cannabidiol Other names: CBD

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 drugs that are known inhibitors of these UGTs. Dose reduction of cannabidiol and/or the inhibitor may be necessary when given in combination.

In vitro data suggest that cannabidiol is a reversible inhibitor of UGT1A9 and UGT2B7 activity at clinically relevant concentrations. The metabolite 7-carboxy-cannabidiol (7-COOH-CBD) is also an inhibitor of UGT1A1, UGT1A4 and UGT1A6-mediated activity in vitro. Dose reduction of the substrates may be necessary when cannabidiol is administered concomitantly with substrates of these UGTs.

In vivo data from steady-state dosing with cannabidiol (750 mg twice daily) when co-administered with a single dose of caffeine (200 mg), a sensitive CYP1A2 substrate, showed increased caffeine exposure by 15% for C_max and 95% for AUC compared to when caffeine was administered alone. These data indicate that cannabidiol is a weak inhibitor of CYP1A2. Similar modest increases in exposure may be observed with other sensitive CYP1A2 substrates (e.g., theophylline or tizanidine). The clinical importance of these findings has not been studied. The patient should be closely monitored for adverse drug reactions.

In vitro data predict drug-drug interactions with CYP2B6 substrates (e.g., bupropion, efavirenz), uridine 5' diphospho-glucuronosyltransferase 1A9 (UGT1A9) (e.g., diflunisal, propofol, fenofibrate), and UGT2B7 (e.g., gemfibrozil, morphine, lorazepam) when co-administered with cannabidiol. Co-administration of cannabidiol is also predicted to cause clinically significant interactions with CYP2C8 (repaglinide) and CYP2C9 (e.g., warfarin) substrates.

In vitro data have demonstrated that cannabidiol inhibits CYP2C19, which may cause increased plasma concentrations of medicines that are metabolised by this isoenzyme such as clobazam and omeprazole. Dose reduction should be considered for concomitant medicinal products that are sensitive CYP2C19 substrates or that have a narrow therapeutic index.

Because of potential inhibition of enzyme activity, dose reduction of substrates of UGT1A9, UGT2B7, CYP2C8, and CYP2C9 should be considered, as clinically appropriate, if adverse reactions are experienced when administered concomitantly with cannabidiol. Because of potential for both induction and inhibition of enzyme activity, dose adjustment of substrates of CYP1A2 and CYP2B6 should be considered, as clinically appropriate.

The strong CYP3A4/2C9 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, 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.

Coadministration of cannabidiol with orally administered everolimus, a P-gp and CYP3A4 substrate, results in an approximately 2.5-fold increase in mean C and AUC of everolimus. When initiating cannabidiol 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 cannabidiol, 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 cannabidiol. Therapeutic drug monitoring and dose reduction of other P-gp substrates should be considered when given orally and concurrently with cannabidiol.

There is no experience in patients with end-stage renal disease. It is not known if cannabidiol is dialysable.

Caution should be used in patients with moderate (Child-Pugh B) or severe hepatic impairment (Child-Pugh C). 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.

Dose adjustments in patients with moderate or severe hepatic impairment:

^* Higher doses of cannabidiol may be considered in patients with severe hepatic impairment where the potential benefits outweigh the risks.

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 and stiripentol. Although no formal drug-drug interaction studies have been performed for other AEDs, phenytoin and lamotrigine are addressed based on in vitro data.

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%. 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. Reduction in dose of clobazam should be considered if somnolence or sedation are experienced when clobazam is co-administered with cannabidiol.

Lamotrigine is a substrate for UGT enzymes including UGT2B7 which is inhibited by cannabidiol in vitro. There have not been any clinical studies formally investigating this interaction. Lamotrigine levels may be elevated when it is co-administered with cannabidiol.

Exposure to phenytoin may be increased when it is co-administered with cannabidiol, as phenytoin is largely metabolised via CYP2C9, which is inhibited by cannabidiol in vitro. There have not been any clinical studies formally investigating this interaction. Phenytoin has a narrow therapeutic index, so combining cannabidiol with phenytoin should be initiated with caution and if tolerability issues arise, dose reduction of phenytoin should be considered.

When cannabidiol was combined with stiripentol in a healthy volunteer trial there was an increase in stiripentol levels of 28% for maximum measured plasma concentration (C_max) and 55% for AUC. In patients, however, the effect was smaller, with an increase in stiripentol levels of 17% in C_max and 30% in AUC. The clinical importance of these results has not been studied. The patient should be closely monitored for adverse drug reactions.

Concomitant use of cannabidiol and valproate increases the incidence of transaminase enzyme elevations. The mechanism of this interaction remains unknown. If clinically significant increases of transaminases occur, cannabidiol and/or concomitant valproate should be reduced or discontinued in all patients until a recovery of transaminase elevations are observed. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic medicinal products and cannabidiol.

Concomitant use of cannabidiol and valproate increases the incidence of diarrhoea and events of decreased appetite. The mechanism of this interaction is unknown.

There are only limited data from the use of cannabidiol in pregnant women. Studies in animals have shown reproductive toxicity.

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.

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.

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.

Cannabidiol has major influence on the ability to drive and operate machines because it may cause somnolence and sedation. Patients should be advised not to drive or operate machinery until they have gained sufficient experience to gauge whether it adversely affects their abilities.

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, decreased appetite, diarrhoea, pyrexia, fatigue, and vomiting.

The most frequent cause of discontinuations was transaminase elevation.

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.

Tabulated list of adverse reactions:

^a Grouped Terms: Pneumonia: Pneumonia, Pneumonia RSV, Pneumonia mycoplasmal, Pneumonia adenoviral, Pneumonia viral, Aspiration pneumonia; Somnolence: Somnolence, Sedation.

Description of selected adverse reactions

Hepatocellular injury

Cannabidiol can cause dose-related elevations of ALT and AST.

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.

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 drug.

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.

The risk of ALT elevations was higher at dosages higher than the 25 mg/kg/day in the controlled study in TSC.

Baseline transaminase elevations:

In controlled trials 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.

Somnolence and sedation

Somnolence and sedation (including lethargy) events have been observed in controlled trials 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 dosages 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.

Decreased weight

Cannabidiol can cause weight loss or decreased weight gain. 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 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 controlled trial in TSC, the frequency of diarrhoea was 31% in patients receiving 25 mg/kg/day cannabidiol and 56% in patients receiving doses greater than 25 mg/kg/day cannabidiol, compared to 25% in patients receiving placebo.

In the clinical trials, the first onset of diarrhoea was typically in the first 6 weeks of treatment with cannabidiol. The median duration of diarrhoea was 8 days. The diarrhoea led to cannabidiol dose reduction in 10% of patients, temporary dose interruption in 1% of patients and permanent discontinuation in 2% of patients.

Haematologic abnormalities

Cannabidiol can cause decreases in haemoglobin and haematocrit. In LGS, DS and TSC patients, the mean decrease in haemoglobin from baseline to end of treatment was −0.36 g/dL in cannabidiol-treated patients receiving 10, 20, or 25 mg/kg/day. A corresponding decrease in haematocrit was also observed, with a mean change of −1.3% in cannabidiol-treated patients.

Twenty-seven percent (27%) of cannabidiol-treated patients with LGS and DS and 38% of cannabidiol-treated patients (25 mg/kg/day) with TSC developed a new laboratory-defined anaemia during the course of the study (defined as a normal haemoglobin concentration at baseline, with a reported value less than the lower limit of normal at a subsequent time point).

Increases in creatinine

Cannabidiol can cause elevations in serum creatinine. The mechanism has not yet been determined. In controlled studies in healthy adults and in patients with LGS, DS and TSC, an increase in serum creatinine of approximately 10% was observed within 2 weeks of starting cannabidiol. The increase was reversible in healthy adults. Reversibility was not assessed in studies in LGS, DS or TSC.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.