Midazolam Aprepitant

Aprepitant may be affected by paroxetine, CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin), CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine), and oral contraceptives. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Clinically important, potentially hazardous interactions with acetylcysteine, adenosine, aprepitant, aripiprazole, buprenorphine, caffeine, charcoal, clarithromycin, clobazam, dorazepate, clozapine, darunavir, dasatinib, delavirdine, dexamethasone, diltiazem, doxacurium, erythromycin, felodipine, fesoterodine, fosamprenavir, imatinib, influenza vaccines, lacosamide, lapatinib, levetiracetam, lopinavir, methylprednisolone, midazolam, nelfinavir, nilotinib, piracetam, prednisolone, propoxyphene, ritonavir, rivaroxaban, rufinamide, solifenacin, St John s wort, telithromycin, temsirolimus, terbinafine, tolvaptan, troleandomycin, verapamil, voriconazole... 

Clinically important, potentially hazardous interactions with alprazolam, aprepitant, astemizole, atorvastatin, benzodiazepines, carbamazepine, chlordiazepoxide, cilostazol, clonazepam, clorazepate, colchicine, conivaptan, cyclosporine, dabigatran, dasatinib, diazepam, digoxin, dihydroergotamine, disopyramide, ergot alkaloids, fesoterodine, fluoxetine, flurazepam, fluvastatin, HMG-CoA reductase inhibitors, imatinib, ixabepilone, lapatinib, lopinavir, lorazepam, lovastatin, methylprednisolone, methysergide, midazolam, nilotinib, oxazepam, paroxetine, pimozide, pravastatin, prednisone, quazepam, repaglinide, rimonabant, rivaroxaban, sertraline, silodosin, simvastatin, solifenacin, temazepam, temsirolimus, tolvaptan, trabectedin, triazolam, warfarin, zidovudine... 

Clinically important, potentially hazardous interactions with amlodipine, anisindione, anticoagulants, aprepitant, atorvastatin, barbiturates, benzodiazepines, butabarbital, carbamazepine, chlordiazepoxide, clarithromycin, clonazepam, dorazepate, corticosteroids, cyclosporine, dexamethasone, diazepam, dicumarol, erythromycin, ethotoin, felodipine, flurazepam, fluvastatin, fosphenytoin, isradipine, itraconazole, ketoconazole, lorazepam, lovastatin, mephenytoin, mephobarbital, midazolam, nicardipine, nifedipine, nimodipine, nisoldipine, oxazepam, pentobarbital, phenobarbital, pimozide, pravastatin, primidone, quazepam, rifampin, secobarbital, simvastatin, St John s wort, temazepam, warfarin... 

Clinically important, potentially hazardous interactions with amiodarone, amprenavir, anisindione, antacids, anticoagulants, aprepitant, atazanavir, atovaquone, beclomethasone, buprenorphine, corticosteroids, cortisone, cyclosporine, cyproterone, dabigatran, dapsone, darunavir, delavirdine, dexamethasone, dicumarol, digoxin, eszopiclone, flunisolide, fosamprenavir, gadoxetate, gestrinone, halothane, imatinib, isoniazid, itraconazole, ketoconazole, lapatinib, lorcainide, methylprednisolone, midazolam, nelfinavir, nifedipine, oral contraceptives, phenylbutazone, prednisone, protease inhibitors, pyrazinamide, ramelteon, ritonavir, saquinavir, solifenacin, sunitinib, tacrolimus, telithromycin, temsirolimus, tipranavir, tolvaptan, trabectedin, triamcinolone, triazolam, voriconazole, warfarin, zaleplon... 

Clinically important, potentially hazardous interactions with alfentanil, alfuzosin, alprazolam, amiodarone, amprenavir, aprepitant, astemizole, atazanavir, bepridil, buprenorphine, bupropion, carbamazepine, chlordiazepoxide, ciclesonide, clozapine, conivaptan, cyclosporine, cyproterone, dasatinib, diazepam, dihydroergotamine, ergot alkaloids, estazolam, eszopidone, etravirine, ezetimibe, fentanyl, fesoterodine, flecainide, flurazepam, fluticasone, halazepam, ivabradine, ixabepilone, ketoconazole, lapatinib, levothyroxine, meperidine, meptazinol, methysergide, midazolam, nifedipine, nilotinib, oral contraceptives, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quazepam, quinidine, ranolazine, rifabutin, rifampin, rifapentine, rimonabant, rivaroxaban, saquinavir, sildenafil, silodosin, simvastatin, solifenacin, St John s wort, tadalafil, temsirolimus, trabectedin, triazolam, vardenafil, voriconazole, zolpidem... 

Aprepitant inhibits the metabolism of oral midazolam resulting in increased plasma levels. It appears to have less effect on intravenous midazolam. A few days after aprepitant treatment is stopped a transient slight reduction in midazolam plasma levels may occur due to induction of its metabolism. Alprazolam and triazolam are expected to be affected similarly. 

In a randomised study 16 healthy subjeets took either aprepitant 125 mg on day 1 followed by 80 mg daily for 4 days, or 40 mg on day 1 followed by 25 mg daily for 4 days, with a single 2-mg oral dose of midazolam on days 1 and 5. The aprepitant 40/25 mg dosing sehedule had no significant effect on the pharmacokinetics of midazolam. However, the aprepitant 125/80 mg dosing schedule increased the AUC of oral midazolam by 126% and 229% on days 1 and 5, respectively, and increased the maximum plasma levels of midazolam by 46% and 94% on days 1 and 5, respectively. ... 

In a randomised, placebo-controlled study, 24 healthy subjects were given aprepitant 125 mg on day one then 80 mg daily for a further 2 days. A single 2-mg intravenous dose of midazolam was given on days 4,8 and 15. The 3-day aprepitant regimen increased midazolam levels slightly on day 4 (AUC increased by 25% and clearance reduced by 20%), decreased midazolam levels slightly on day 8 (AUC decreased by 19% and clearance increased by 24%) and had almost no effect by day 15, when compared to placebo. ... 

Aprepitant inhibits the cytochrome P450 isoenzyme CYP3A4 by which midazolam is metabolised, resulting in increased midazolam levels. The pharmacokinetic effect on intravenous midazolam indicate the effects of aprepitant on systemic rather than on intestinal CYP3A4 activity. Aprepitant is also a mild inducer of CYP3A4, however the induction is transient, with maximal effect 3 to 5 days after the end of treatment. 

Based on the way midazolam interaets with similarly potent inhibitors of CYP3A4, aprepitant may be expeeted to increased the drowsiness and length of sedation and amnesia in patients given midazolam. Consider re-dueing the midazolam dose in patients given aprepitant and monitor the outeome of eoneurrent use earefully. The manufaeturer notes that the potential effeets of inereased levels of other benzodiazepines metabolised via CYP3A4, sueh as alprazolam and triazolam, should be eonsidered if... 

In the first few days of use, aprepitant 125/80 mg markedly increased levels of midazolam, a probe drug subsfrafe for fhe cyfoehrome P450 isoenzyme CYP3A4. Then, within 2 weeks, a reduction in levels was seen, see Benzodiazepines + Aprepitant , p.721. This effect was not seen with the 40/25 mg dose regimen. Aprepitant is therefore both a dose-dependent inhibitor and an inducer of CYraA4. 

Benzodiazepines midazolam is also metabolized by the isoenzyme CYP3 A4, which when inhibited by high-dose aprepitant will lead to an increase in plasma levels for any given dose. 

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