Interactions : אינטראקציות

7 DRUG INTERACTIONS
7.1 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 EPIDIOLEX is not known [see Clinical Pharmacology (11.3)]. Consider an increase in EPIDIOLEX dosage (based on clinical response and tolerability) up to 2-fold, when coadministered with a strong CYP3A4 and/or CYP2C19 inducer.


7.2 Effect of EPIDIOLEX on Other Drugs
UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 Substrates Cannabidiol is a weak inhibitor of CYP1A2 [see Clinical Pharmacology (11.3)]. 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 EPIDIOLEX. Coadministration of EPIDIOLEX 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 EPIDIOLEX.
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 of EPIDIOLEX 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 [see Clinical Pharmacology (11.3)]. Consider a reduction in dosage of sensitive CYP2C19 substrates, as clinically appropriate, when coadministered with EPIDIOLEX.


Clobazam
Coadministration of EPIDIOLEX 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 [see Clinical Pharmacology (11.3)]. The increase in N-desmethylclobazam may increase the risk of clobazam-related adverse reactions [see Adverse Reactions (6) and Warnings and Precautions (5.1, 5.2)].
Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when coadministered with EPIDIOLEX.


Stiripentol
Concomitant use of EPIDIOLEX and stiripentol causes an elevation in exposure to stiripentol [see Clinical Pharmacology (11.3)]. 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 EPIDIOLEX 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 [see Clinical Pharmacology (11.3)].
When initiating EPIDIOLEX 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 EPIDIOLEX, 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 EPIDIOLEX. Therapeutic drug monitoring and dose reduction of other P-gp substrates should be considered when given orally and concurrently with EPIDIOLEX.
7.3 Concomitant Use of EPIDIOLEX and Valproate
Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions (5.1)]. If such elevations occur, discontinuation or reduction of EPIDIOLEX and/or concomitant valproate should be considered. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs and EPIDIOLEX.
7.4 CNS Depressants and Alcohol
Concomitant use of EPIDIOLEX with other CNS depressants (including alcohol) may increase the risk of sedation and somnolence [see Warnings and Precautions (5.2)].