Triazolam nefazodone

Nefazodone + triazolam —> increased effect of triazolam due to impaired hepatic metabolism. 

Triazolam is distributed quickly because of its high lipophilicity, and thus it has a short duration of effect. Erythromycin, nefazodone, fluvoxamine, and ketoconazole reduce the clearance of triazolam and increase plasma concentrations. 

Coadministration of triazolam and nefazodone causes a significant increase in the plasma level of triazolam a 75% reduction in the initial triazolam dosage is recommended. Avoid the coadministration of triazolam and nefazodone for most... 

Concurrent use with ketoconazole, itraconazole, and nefazodone, medications that significantly impair the oxidative metabolism of triazolam mediated by cytochrome P-450 3A (CYP3A). 

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,... 

Use with caution in older patients with Concurrent treatment with potent CYP 3A4 inhibitors (e.g., nefazodone) leads to increased plasma concentrations of triazolam COPD untreated sleep apnea... 

The use of two or more agents concurrently has the potential for possibly deleterious drug interactions. Thus, as noted in subsequent chapters, the addition or elimination of an agent may significantly alter the activity of the concurrent drug treatment (e.g., carbamazepine lowering haloperidol plasma levels nefazodone increasing the levels of triazolam). 

Nefazodone substantially decreases the clearance rate for triazolam, which results in a 400% increase in triazolam s serum levels (131). Erythromycin can also interfere with the metabolism of triazolam, resulting in decreased clearance and increased plasma levels, possibly causing toxicity. Troleandomycin and other macrolide antibiotics, such as clarithromycin, flurithromycin, josamycin, midecamycin, or roxithromycin, also may inhibit triazolam s metabolism (132). The coadministration of itraconazoie and triazolam can produce a marked elevation of triazolam plasma levels associated with statistically significant impairment of psychomotor tests and a prolongation of other effects (e.g., amnesia, lethargy, and confusion) for hours after awakening ( 133). 

With the important exception of additive effects when combined with other CNS depressants, including alcohol, BZDs interact with very few drugs. Disulfiram (see the section The Alcoholic Patient in Chapter 14) and cimetidine may increase BZD blood levels, and diazepam may increase blood levels of digoxin and phenytoin. Antacids may reduce the clinical effects of clorazepate by hindering its biotransformation to desmethyidiazepam. Coadministration of a BZD and another drug known to induce seizures may possibly increase seizure risk, especially if the BZD is abruptly withdrawn. Furthermore, as noted earlier, important interactions have been reported among nefazodone, erythromycin, troleandomycin, and other macrolide antibiotics, as well as itraconazole. In each case, metabolism is inhibited, and triazolam levels can increase significantly. 

BZD hypnotics such as midazolam and triazolam are primarily metabolized via the P450 3A3/4 microenzyme system. Other BZDs often used as hypnotics, such as diazepam, can also be metabolized by CYP 33/4 and CYP 2C19. Any drugs that act as inhibitors or inducers of these isoenzymes could increase or decrease BZD levels, respectively (350). Thus, ketoconazole, macrolide antibiotics (e.g., erythromycin), SSRIs (e.g., fluoxetine-norfluoxetine and fluvoxamine), and other antidepressants (especially nefazodone) may decrease clearance and increase BZD levels to potentially toxic ranges. Conversely, rifampacin, CBZ, and dexamethasone may increase clearance and decrease BZD levels to potentially subtherapeutic ranges. 

Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it can raise the level and thus exacerbate adverse effects of many 3A4-dependent drugs. For example, triazolam levels are increased by concurrent administration of nefazodone such that a reduction in triazolam dosage by 75% is recommended. Likewise, administration of nefazodone with simvastatin has been associated with 20-fold increase in plasma levels of simvastatin. 

A third important CYP450 enzyme for antidepressants and mood stabilizers is 3A4. Some benzodiazepines (e.g., alprazolam and triazolam) are substrates for 3A4 (Fig. 6—17). Some antidepressants are 3A4 inhibitors, including the SSRIs fluoxetine and fluvoxamine and the antidepressant nefazodone (Fig. 6—18). Administration of a 3A4 substrate with a 3A4 inhibitor will raise the level of the substrate. For example, fluoxetine, fluvoxamine, or nefazodone will raise the levels of alprazolam or triazolam, requiring dose reduction of the benzodiazepine (Fig. 6—18). 

Barbhaiya RH, Shukla UA, Kroboth PD, et al. Coadministration of nefazodone and benzodiazepines II. A pharmacokinetic interaction study with triazolam. J Clin Psychopharmacol 1995 15 320-326. 

A4/3A5 Midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, triazolam Atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin Rifampin, carbamazepine... 

Nefazodone is a weak inhibitor of CYP2D6 but a potent inhibitor of CYP3A4 and it increases plasma concentrations of drugs that are substrates of CYP3A4, such as alprazolam, astemizole, carbamazepine, ciclosporin, cisapride, terfenadine, and triazolam. 

Via CYP450 3A4 inhibition, nefazodone may increase the half-life of alprazolam and triazolam, so their dosing may need to be reduced by half or more... 

CYP450 3A inhibitors such as nefazodone, fluoxetine, and fluvoxamine may decrease clearance of triazolam and raise triazolam levels significantly... 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by hepatic microsomal oxidation and then undergo glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. Drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., erythromycin, nefazodone, fluvoxamine, and ketoconazole) reduce the clearance of triazolam and increase its plasma concentrations."... 

Nefazodone Alprazolam, triazolam Increased blood levels of the second drug doses may need to be decreased... 

Nefazodone increases the plasma levels and effects of alprazolam, midazolam, triazolam and zopiclone, but not lorazepam. 

A study in 12 healthy subjects found that the maximum plasma levels, the half-life and the AUC of a single 250-microgram dose of triazolam were increased 1.7-fold, 4.6-fold, and 4-fold, respectively, by nefazodone 200 mg twice daily. Another study showed that impairment of psychomotor performance and increased sedation occurred when nefazodone was given with triazolam. ... 

Nefazodone appears to inhibit the oxidative metabolism of alprazolam, midazolam, triazolam and zopiclone by the cytochrome P450 isoenzyme CYP3A4 so that they accumulate in the body. Lorazepam is unaffected because it is primarily excreted as a conjugate. 

The interactions of nefazodone with alprazolam, midazolam, triazolam and zopiclone are established and clinically important. The practical consequences are that the effects of alprazolam, midazolam and triazolam are expected to be increased but the extent is uncertain. Be alert for any evidence of any psychomotor impairment, drowsiness etc. and reduce the benzodiazepine dosage if necessary. More study is needed. Lorazepam does not interact with nefazodone. There seems to be no direct information about other benzodiazepines and related drugs. 

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