CARBAMAZEPINE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution with monitoring. Potential dose reduction and monitor serum concentrations
• Rationale: Carbamazepine and cannabis are both metabolized by CYP3A4. Furthermore cannabis as found to be a weak inhibitor of CYP3A4.  Drugs that inhibit CYP3A4 may decrease carbamazepine metabolism and increase plasma concentrations. Serum carbamazepine concentrations should be monitored closely and a reduction in dose may be necessary.

ETHOSUXIMIDE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution with close monitoring
• Rationale: In vitro studies have shown that cannabis  is a weak  inhibitor of CYP3A4. Close clinical monitoring is advised when administering ethosuximide with cobicistat(CYP3A4 inhibitor) since elevated ethosuximide plasma concentrations may result.

FOSPHENYTOIN AND PHENYTOIN

• Cytochrome P450 enzyme substrate: CYP2C9 and CYP2C19
• Action to be taken: Potential dose reduction. Assess patient clinical status and serum phenytoin concentrations
• Rationale: Cannabis is a weak inhibitor cytochrome P450 isoenzymes and may reduce the metabolism of drugs such as phenytoin. Drugs that have a low therapeutic margin such as phenytoin may have delayed elimination, which can increase serum half-life. The dosage may need to be modified for phenytoin through analysis of serum phenytoin as well as patient clinical status.

PHENOBARBITAL

• Cytochrome P450 enzyme substrate: CYP2C9 and CYP2C19
• Action to be taken: Caution with close monitoring
• Rationale: In vitro studies show that cannabis is a substrate for CYP2C19 as well as weak inhibitor of CYP2C enzymes. Fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Although concomitant use with phenobarbital has not been formally studied, theoretically it can increase plasma concentrations of phenobarbital. Phenobarbital is a drug with a narrow therapeutic range; monitor the therapeutic effect during co-administration of CYP2C9 and CYP2C19 inhibitors.

PRIMIDONE

• Cytochrome P450 enzyme substrate: CYP2C9 and CYP2C19

• Action to be taken: Caution with close monitoring
• Rationale: In vitro studies show that cannabis is a substrate for CYP2C19 as well as weak inhibitor of CYP2C enzymes. Fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Although concomitant use with phenobarbital has not been formally studied, theoretically it can increase plasma concentrations of primidone. Primidone is a drug with a narrow therapeutic range; monitor the therapeutic effect during co-administration of CYP2C9 and CYP2C19 inhibitors.

VALPROIC ACID

• Cytochrome P450 enzyme substrate: CYP2C19 and CYP2C9
  
• Action to be taken: Caution with close monitoring
• Rationale: In vitro studies show that cannabis is a substrate for CYP2C19 as well as weak inhibitor of CYP2C enzymes. Inhibitors of CYP2C19 and CYP2C9 isoenzymes and interactions are possible with valproic acid.Increased valproic acid plasma levels may occur.

References

1. Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
   
2. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.​​
3. Tegretol (carbamazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015 Sep.
4. Nilandron® (nilutamide) package insert. Kansas City, MO: Aventis Pharmaceuticals; 2004 Dec.
5. Fibricor (fenofibric acid) package insert. Philadelphia, PA: Mutual Pharmaceutical Company, Inc.; 2012 Mar.
6. Tybost (cobicistat) package insert. Foster City, CA: Gilead Sciences, Inc; 2016 Jun.
7. Bachmann K, He Y, Sarver JG, et al. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica 2003;33:265-76.