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 contraindicated 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 | major: apixaban, betrixaban, dabigatran, rivaroxaban moderate: edoxaban, warfarin |
| 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 | major |
| 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 |
| 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 |
| benzodiazepines | COMT inhibitors | may potentiate the CNS effects of either drug | reassess patients for drowsiness or sleepiness throughout treatment | major |
| benzodiazepines | COMT inhibitors | may potentiate the CNS effects of either drug | reassess patients for drowsiness or sleepiness throughout treatment | major |
| benzodiazepines | gabapentin/pregabalin | may cause excessive sedation, somnolence, and respiratory depression | initiate gabapentin at the lowest recommended dose and monitor for symptoms of respiratory depression and sedation | major |
| benzodiazepines | may increase the risk of over sedation, CNS effects, or sleep-related behaviors | use caution when combining melatonin with a benzodiazepine. Avoid use if benzodiazepine is used for sleep. | major | |
| benzodiazepines | opioids | may increase the risk of respiratory depression, hypotension, profound sedation, and death | if concurrent use is necessary, use lowest effective doses and minimum treatment durations | major |
| benzodiazepines | tricyclic antidepressants | increased risk of respiratory depression and sedation | limit dosage and duration of use. Monitor patients for respiratory depression and sedation | major |
| CNS depressant anxiolytics, sedatives, hypnotics, or other sedative CNS depressant drugs | sodium oxybates | concurrent use may result in impaired cognitive and motor skills. Concurrent use may increase sleep duration, result in rapid sleep onset, increase CNS depression, respiratory depression, and coma | do not use concurrently | contraindicated |
| daridorexant | colchicine | colchicine is a P-gp substrate and daridorexant is a P-gp inhibitor | avoid concurrent use due to risk of increased colchicine exposure. Concurrent use is contraindicated in patients with renal or hepatic impairment. Concurrent use is contraindicated in patients using colchicine for cardiovascular risk reduction | major - contraindicated |
| daridorexant | moderate CYP3A4 inhibitors (e.g., butalbital, ciprofloxacin) | potential for increased daridorexant plasma concentrations and enhanced pharmacologic/ adverse effects | Concurrent administration is not recommended | major |
| daridorexant | moderate CYP3A4 inhibitors (e.g., butalbital, ciprofloxacin) | 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 |
| daridorexant | CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) | potential for decreased daridorexant exposure and risk of reduced efficacy | avoid concurrent therapy, if possible | major |
| 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 | moderate - major |
| 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 | major |
| 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 |
| lemborexant | CYP3A inducers | potential for decreased lemborexant exposure and risk of reduced efficacy | monitor patients for decreased efficacy; consider alternate therapy if possible | Major |
| 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 | moderate |
| 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: triazolam major: estazolam |
| 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) | contraindicated: triazolam moderate: estazolam |
| 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 |
| 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 | moderate - contraindicated |
| 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 | moderate - contraindicated |
| 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 | moderate |
| phenobarbital | COMT inhibitors | concomitant use may increase the risk of CNS depression | prescribers should reassess patients for drowsiness or sleepiness regularly | major |
| phenobarbital | CYP2C9 substrates and CYP2C9 inhibitors | phenobarbital induces CYP2C9 and concurrent use may result in decreased efficacy of interacting drugs Concurrent use with drugs that inhibit CYP2C9 may result in increased or prolonged therapeutic effects of phenobarbital | avoid concurrent use of phenobarbital with contraindicated CYP2C9 substrates and inhibitors. More frequent monitoring of therapies may be required with concomitant use of interacting drugs | minor - contraindicated |
| phenobarbital | CYP3A4 substrates | phenobarbital is a strong CYP3A4 inducer and concurrent use may result in decreased efficacy of interacting drugs | avoid concurrent use of phenobarbital with contraindicated CYP3A4 substrates. More frequent monitoring of therapies may be required with concomitant use of interacting drugs | minor - contraindicated |
| phenobarbital | P-glycoprotein (P-gp) substrates | phenobarbital is a strong P-gp inducer and concurrent use may result in decreased efficacy of interacting drugs | use caution when using interacting drugs concurrently or avoid concurrent use. Monitor for decreased efficacy of interacting drugs | major |
| 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 | strong CYP2A1 inhibitors (e.g., ciprofloxacin) | concurrent use may increase exposure to ramelteon and associated adverse effects | use caution if used concomitantly | major |
| 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 |
| ramelteon | viloxazine | ramelteon is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. May increase ramelteon exposure and associated adverse effects | do not use concurrently | contraindicated |
| 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 |
| 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 |
| 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 | major |
| 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 | moderate |
| 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 - contraindicated |
| 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 | moderate - major |
| 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 | minor - contraindicated |
| 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 | moderate |
| 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 | major |
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- # Clinical Pharmacology