ALPRAZOLAM
CLONAZEPAM
DIAZEPAM
LORAZEPAM
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Caution with close monitoring of side effects
- Rationale: Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 to two major metabolites in the plasma. Compounds that are potent inhibitors of CYP3A would be expected to increase plasma
alprazolam concentrations.CYP3A inducers would be expected to decrease alprazolam concentrations and this has been
observed in vivo. Cannabis is a substrate and weak inhibitor of CYP3A4 and thus may increase serum concentration of alprazolam. Furthermore both alprazolam and cannabis have the ability to depress CNS, therefore concomitant administration should be used in caution as additive CNS effects may impair ability to drive and use machines and increase risk off falls.
CLONAZEPAM
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Caution with close monitoring of side effects (changes in psychomotor performance and sedation)
- Rationale: Clonazepam is a substrate of CYP3A4. In theory, co-administration of clonazepam and a potent CYP3A4 inhibitor, such as fluvoxamine, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity. On the other hand, fluoxetine, a CYP3A4 inhibitor, does not affect the pharmacokinetics of clonazepam. Monitor patients closely for excessive clonazepam-related side effects, including changes in psychomotor performance and sedation.
DIAZEPAM
- Cytochrome P450 enzyme substrate: CYP2C19 and CYP3A4
- Action to be taken: Caution with close monitoring of side effects
- Rationale: Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4.10 Diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes. While diazepam clearance may be inhibited, diazepam pharmacodynamics are not always affected. Fluoxetine inhibits both metabolic pathways for diazepam, however the effect on diazepam pharmacodynamics is unclear. Other drugs that may inhibit diazepam metabolism include: amiodarone, anti-retroviral protease inhibitors, cimetidine, clarithromycin, dalfopristin; quinupristin, delavirdine, diltiazem, disulfiram, erythromycin, fluconazole, fluvoxamine, imatinib, STI-571, itraconazole, ketoconazole, IV miconazole, nefazodone, nicardipine, ranolazine, troleandomycin, verapamil, voriconazole, zafirlukast, and zileuton. This list is not inclusive of all agents that may inhibit diazepam metabolism. Itraconazole has been shown to alter diazepam pharmacokinetics, but not diazepam pharmacodynamics. Ciprofloxacin also inhibits diazepam clearance, although diazepam pharmacodynamics do not appear to be affected. Probenecid may also inhibit the hepatic metabolism of benzodiazepines. Patients receiving diazepam should be monitored for signs of an exaggerated response if any of the above drugs are used concomitantly.
LORAZEPAM
- Action to be taken: Caution with close monitoring of side effects
- Rationale: The 3-hydroxybenzodiazepines such as lorazepam, oxazepam and temazepam undergo Phase II conjugation reactions and are therefore devoid of CYP450 interactions. However both Lorazepam and cannabis can depress the CNS,therefore concomitant administration should be used in caution as additive CNS effects may impair ability to drive and use machines and increase risk off falls.
References
- Xanax (alprazolam) package insert. Pfizer NY, NY 2017
- 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.
- 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.
- English BA, Dortch M, Ereshefsky L, Jhee S. CLINICALLY SIGNIFICANT PSYCHOTROPIC DRUG-DRUG INTERACTIONS IN THE PRIMARY CARE SETTING. Current psychiatry reports. 2012;14(4):376-390. doi:10.1007/s11920-012-0284-9.
- Klonopin (clonazepam) package insert. South San Francisco, CA; Genetech, Inc.; 2016
- Kamali F, Thomas SH, Edwards C. The influence of steady-state ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of diazepam in healthy volunteers. Eur J Clin Pharmacol 1993;44:365—7.0