4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for sedative/hypnotics are summarized in Table 7. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level# |
|---|---|---|---|---|
| barbiturates (BARB) | anticoagulants | BARB induction of apixaban, rivaroxaban, and warfarin metabolic clearance (CYP3A4) with potential for decreased anticoagulant clinical effects | avoid combination, if possible; closely monitor international normalized ratio (INR) when BARB therapy added, discontinued, or changed to warfarin; addition of warfarin to chronic BARB regimen more tolerable | apixaban, rivaroxaban: major, warfarin: moderate (Micromedex) apixaban, rivaroxaban: 2-major, warfarin: 3-moderate (CP) |
| barbiturates | cyclosporine | BARB induction of cyclosporine metabolic clearance (CYP3A4) with potential for reduced cyclosporine clinical effects | avoid concurrent therapy, if possible; if combination necessary, monitor for cyclosporine immunosuppressive efficacy; monitor cyclosporine serum concentrations when BARB therapy added, discontinued, or changed | Moderate (Micromedex), 2-major (CP) |
| barbiturates | oral contraceptives (OC) | BARB induction of estrogen/ progestin hepatic metabolic clearance with potential for decreased OC clinical effects and risk of contraceptive failure | OCs with higher ethinyl estradiol dosages (e.g., 50 mcg) to increase contraceptive efficacy may be necessary; second contraceptive method recommended to prevent unwanted pregnancy | Major (Micromedex), 3-moderate (CP) |
| barbiturates | voriconazole | BARB induction, especially long-acting BARBs (phenobarbital), of voriconazole metabolic clearance (CYP3A4) with potential for decreased voriconazole clinical effects | voriconazole contraindicated for use with long-acting BARBs; use cautiously with short-acting BARBs and monitor clinical effects | contraindicated (DrugReax), 1-contraindicated (CP) |
| daridorexant | strong CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors, macrolides) | potential for increased daridorexant plasma concentrations and enhanced pharmacologic/ adverse effects | Concurrent administration is not recommended | major (Micromedex), 2-major (CP) |
| daridorexant | moderate CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors, macrolides) | potential for increased daridorexant plasma concentrations and enhanced pharmacologic/adverse effects | if used concomitantly, the dose of daridorexant should not exceed 25 mg once per night | major (Micromedex), 2-major (CP) |
| daridorexant | CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) | potential for decreased daridorexant exposure and risk of reduced efficacy | avoid concurrent therapy, if possible | major (Micromedex), 2-major (CP) |
| doxepin | drugs metabolized by CYP2D6 (e.g., phenothiazines, delavirdine) | potential for increased doxepin serum levels and enhanced pharmacologic/ adverse effects due to competition for CYP2D6 metabolic pathway | concurrent administration is not recommended; monitor patients for enhanced doxepin effects; adjust doses as necessary | Major (Micromedex), 2-major (CP) |
| eszopiclone | CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) | induction of eszopiclone metabolic clearance (CYP3A4) with potential for decreased eszopiclone clinical effects | monitor patients for decreased eszopiclone efficacy; consider hypnotic agent not metabolized by CYP3A4 | 3-moderate (CP) |
| eszopiclone | CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors, macrolides) | potential for increased eszopiclone serum concentrations and enhanced pharmacologic/adverse effects | monitor patients for enhanced eszopiclone effects; adjust doses as necessary | Major (Micromedex), 3-moderate (CP) |
| lemborexant | CYP3A inducers | potential for decreased lemborexant exposure and risk of reduced efficacy | monitor patients for decreased efficacy; consider alternate therapy if possible | Major (Micromedex), 2- major (CP) |
| oxidatively metabolized benzodiazepines (BZDs) (e.g., estazolam, triazolam) | imidazole antifungals (e.g., itraconazole, ketoconazole) | potential for increased serum concentrations and enhanced pharmacologic/ adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as imidazole antifungals inhibit CYP3A4 | adjunctive therapy with imidazole antifungals and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | contraindicated (DrugReax), 2-major, 3-moderate (CP) |
| oxidatively metabolized BZDs (e.g., estazolam, triazolam) | macrolides | potential for increased serum concentrations and enhanced pharmacologic/ adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as macrolides inhibit CYP3A4 | adjunctive therapy with macrolides and oxidatively metabolized BZD not recommended; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative; azithromycin may be macrolide alternative (not metabolized by CYP3A4) | major (Micromedex), triazolam: 1-contraindicated; estazolam: 3-moderate (CP) |
| oxidatively metabolized benzodiazepines (e.g., estazolam, triazolam) | nefazodone | potential for increased serum concentrations and enhanced pharmacologic/ adverse effects (e.g., prolonged sedation, excessive hypnotic effects) in oxidatively metabolized BZDs (metabolized by CYP3A4) as nefazodone potently inhibits CYP3A4 | adjunctive therapy with nefazodone and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative; monitor for signs of BZD intoxication and adjust doses if needed | contraindicated (triazolam), moderate (estazolam) (Micromedex), 1-contraindicated (triazolam), 3-moderate (estazolam) (CP) |
| oxidatively metabolized BZDs (e.g., estazolam, triazolam) | non-nucleotide reverse transcriptase (NNRT) inhibitors | potential for altered serum concentrations and pharmacologic effects in oxidatively metabolized BZDs (metabolized by CYP3A4); delavirdine, efavirenz inhibit CYP3A4 and magnify oxidative BZD pharmacologic/ adverse effects, while nevirapine induces oxidative BZD metabolism and diminishes pharmacologic effects | adjunctive therapy with NNRT inhibitors and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | contraindicated (DrugReax), 1-contraindicated, 3-moderate (CP) |
| oxidatively metabolized BZDs (e.g., estazolam, triazolam) | protease inhibitors | potential for increased serum concentrations and enhanced pharmacologic/ adverse effects (e.g., severe sedation, respiratory depression) in oxidatively metabolized BZDs (metabolized by CYP3A4) as protease inhibitors inhibit CYP3A4 | adjunctive therapy with protease inhibitors and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | triazolam: contraindicated, estazolam: moderate (Micromedex), triazolam: 1-contraindicated, estazolam: 3-moderate (CP) |
| oxidatively metabolized BZDs (e.g., estazolam, triazolam) | triazole antifungals (e.g., fluconazole, voriconazole) | potential for increased serum concentrations and enhanced pharmacologic/ adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as triazole antifungals inhibit CYP3A4 | adjunctive therapy with triazole antifungals and oxidatively metabolized BZD not recommended; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | major (DrugReax), 3-moderate (CP) |
| ramelteon | antifungal agents (triazoles or imidazoles) | potential for increased ramelteon serum concentrations and increased clinical/adverse effects due to CYP2C9 inhibition by triazole antifungals (e.g., fluconazole, voriconazole) or CYP3A4 inhibition by imidazole antifungals (e.g., itraconazole, ketoconazole) | cautiously administer therapy concurrently; monitor for enhanced ramelteon pharmacologic/adverse effects | moderate (DrugReax), 3-moderate (CP) |
| ramelteon | fluvoxamine | fluvoxamine inhibition of ramelteon metabolism (CYP1A2) and potential for increased ramelteon serum concentrations and increased clinical/adverse effects | avoid concurrent administration; other selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine) may be safer alternatives to fluvoxamine | contraindicated (DrugReax), 1-contraindicated (CP) |
| ramelteon | strong CYP1A2 inducers (e.g., rifampin, rifabutin) | induction of ramelteon metabolic clearance (CYP1A2) with potential for decreased ramelteon clinical effects | monitor for decreased ramelteon effectiveness | minor (DrugReax), 3-moderate (CP) |
| sedative/hypnotics | sodium oxybate (Xyrem®) | adjunctive administration may result in additive central nervous system (CNS) depression | concurrent administration contraindicated | Contraindicated, major (Micromedex) 1-contraindicated (CP) |
| suvorexant | CNS depressants | adjunctive administration may result in additive CNS depression, cognitive/ behavioral changes, and complex sleep behaviors | combined administration not recommended; if necessary, monitor for residual CNS depressant effects | major (DrugReax), 3-moderate (CP) |
| suvorexant | strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) | potential for increased suvorexant serum levels and increased pharmacologic/ adverse effects and toxicity as suvorexant is CYP3A4 substrate | combined administration not recommended | major (Micromedex), 2-major (CP) |
| suvorexant | moderate CYP3A4 inhibitors (e.g., fluconazole, aprepitant, ciprofloxacin) | potential for increased suvorexant serum levels and increased pharmacologic/ adverse effects as suvorexant is CYP3A4 substrate | administer together cautiously, observing for increased adverse effects; suvorexant dose should be reduced to 5 mg/day, but may be increased to maximum of 10 mg/day to maintain efficacy | moderate (DrugReax), 2-major (CP) |
| suvorexant | CYP3A4 inducers (e.g., carbamazepine, rifampin) | combined administration may result in reduced suvorexant serum levels and decreased efficacy as suvorexant is CYP3A4 substrate | monitor for decreased suvorexant efficacy and adjust dosages as needed | 3-moderate (CP) |
| TCAs (e.g., doxepin) | monoamine oxidase inhibitors (MAOIs) | increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, restless, shivering) due to serotonin metabolism inhibition by monoamine oxidase | allow 14 days after MAOI discontinuation before initiating other antidepressant therapy; wait 5 weeks after discontinuing fluoxetine before initiating MAOIs | major (Micromedex), 1-contraindicated (CP) |
| TCAs (e.g., doxepin) | drugs other than MAOIs with serotonergic activity (e.g., tramadol, sumatriptan, nefazodone, trazodone) | increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, restless, shivering, hypertonia, tremor) due to additive serotonergic effects | use cautiously together; if adjunctive administration necessary, monitor for signs and symptoms of serotonin syndrome | major (DrugReax), 2-major, 3-moderate (CP) |
| TCAs (e.g., doxepin) | drugs that prolong QT interval | increased risk of somnolence, bradycardia, and serious cardiotoxicity (QT prolongation, Torsades de pointes) due to potential additive effects on QT interval | avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary | contraindicated, major (Micromedex), 1-contraindicated, 2-major (CP) |
| zolpidem | CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors) | potential for increased zolpidem serum concentrations and enhanced pharmacologic/ adverse effects (e.g., severe sedation, respiratory depression) with concurrent administration of CYP3A4 inhibitors, as zolpidem is metabolized by CYP3A4 | monitor patients for enhanced zolpidem effects; adjust doses as necessary | major (Micromedex), 3-moderate (CP) |
| zolpidem | CYP3A4 inducers (e.g., carbamazepine, rifampin) | induction of zolpidem metabolic clearance (CYP3A4) with potential for decreased zolpidem clinical effects | monitor for decreased zolpidem effectiveness | moderate (DrugReax), 2-major (CP) |
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- # Clinical Pharmacology