Nefazodone dosing

A woman who had been hospitalised for serious depression was given nefazodone 300 mg daily. A few days later she began to take isoniazid 300 mg daily, and was later discharged on an inereased nefazodone dose of400 mg daily. She was reported to have had no problems while taking both drugs over a 5 month period. ... 

A large open-label flexible dose study (Sanchez-Lacay etal, 2001) utilizing nefa-zodone in the treatment of major depression in a predominantly monolingual, Hispanic Caribbean population (Dominican Republic, Puerto Rico, and Cuba) revealed similar response rates and an endpoint mean dosage when compared to previous nefazodone trials with non-Hispanic patients. No serious adverse events were reported, but 42% of the subjects did not complete the study for various reasons including side effects, family, or work responsibilities. 

Alprazolam dose should be reduced by 50% if nefazodone (Serzone) or fluvoxamine is added. 

Trazodone and nefazodone cause minimal anticholinergic effects. Sedation, dizziness, and orthostatic hypotension are the most frequent dose-limiting side effects. 

Serotonin-Boosting Antidepressants. The SSRIs have also been studied in the treatment of generalized social anxiety disorder, and paroxetine, sertraline, and venlafaxine are effective. Preliminary data suggests that the serotonin-boosting atypical antidepressants (mirtazapine and nefazodone) may also be helpful. Like the MAOIs, they appear to be effective at doses comparable to those used to treat depression. They may help avoidant patients to gradually increase their social interaction and become more assertive. 

Coadministration with CYP450 inhibitors- Nhen coadministered with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, nefazodone), do not exceed a daily dose of darifenacin 7.5 mg. 

Maintenance/Continuation/Extended treatment There is no evidence to indicate how long the depressed patient should be treated with nefazodone. However, it is generally agreed that pharmacologic treatment for acute episodes of depression should continue for at least 6 months. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain euthymia is unknown. In clinical trials, more than 250 patients were treated for at least 1 year. Switching to or from a monoamine oxidase inhibitor (MAOi) At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with nefazodone. In addition, wait at least 7 days after stopping nefazodone before starting an MAOI. 

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,... 

Bromocriptine (Parl el) [Antiparkinsonian Agent/Dopamine Receptor Agonist] Uses Parkin on Dz, hyperprolactinemia, acromegaly, pituitary tumors Action Direct-acting on the striatal dopamine receptors X prolactin secretion Dose Initial, 1.25 mg PO bid titrate to effect, w/ food Caution [B, ] Contra Severe ischemic heart Dz or PVD Disp Tabs, caps SE X BP, Raynaud phenomenon (vasospastic disorder resulting in discoloration of the fmgers/toes), dizziness, N, hallucinations Interactions T Effects W/ erythromycin, fluvoxamine, nefazodone, sympathomimetics, antihypertensives X effects W/ phenothiazines, antipsychotics EMS Monitor BP may cause intolerance to EtOH OD May cause NA, severe hypotension give IV fluids symptomatic and supportive... 

Nefazodone is not approved by the FDA for use in children, and the literature on its efficacy in the pediatric population is limited. A small case study of children and adolescents who suffered from treatment-refractory depressive disorders (n = 7 mean age of 12.4) were treated with a mean daily dose of 357 151 mg (3.4 mg/kg) for 13 8 weeks. Over half of the subjects (4/7) were judged to be much to very much improved as rated by the Clinical Global Impression (CGI) (Wilens et al., 1997). More recently, an open-label study of nefazodone in children and adolescents (n = 28) with depression yielded significant improvement in depressive symptoms as measured by the Children s Depression Rating Scale, Revised (Findling et al., 2000). 

Similar starting strategies are required for nefazodone and trazodone. However, the dose adjustment of tra-... 

Currently, the antidepressants of choice are the SSRIs because they have been shown to be efficacious and safe for the treatment of children and adolescents with MDD, but further research on the other new antidepressants (e.g., bupropion, venlafaxine, nefazodone, mirtazapine) is needed. Patients should be treated with adequate doses for at least 6 weeks before declaring lack of response to treatment (treatment of nonresponders is described below) (AACAP, 1998 Hughes et ah, 1999 Fig. 36.1). 

Dose-dependent sustained diastolic hypertension Nausea, dry mouth, dizziness, constipation orthostatic hypotension sedation priapism (trazodone only) mCPP, an anxiogenic metabolite of nefazodone, can accumulate during CYP2D6 inhibition Drowsiness (greater at low doses ) Appetite/weight gain... 

The initial reports from open studies (Artigas et al. 1994 Blier and Bergeron 1995) suggest that the combination is associated with improved efficacy with probable faster onset of action. This rapid response was reported with augmentation of fluoxetine and paroxetine, and more recently with nefazodone (Bakish et al. 1997), but interestingly not with sertraline or low doses of fluvoxamine. These results needed to be confirmed in placebo-controlled studies, and the reports from large studies do indeed find an acceleration of response measured as time to response and possible superiority of action with some antidepressants at the end of treatment (Perez et al. 1997 Tome de la Granja et al. 1997). 

Clinical pharmacology. Following absorption, peak plasma concentrations occur 1-3 hours after oral administration (Franc et al. 1991). Following extensive hepatic metabolism, the bioavailability of nefazodone is between 15% and 23%, after which it is 99% protein bound. Nefazodone reaches steady-state plasma levels in 3 days and is eliminated from the body within 24 hours, reflecting its half-life of 2-4 hours (Franc et al. 1991). Therapeutic doses in young adults have been found to range from 100 to 300 mg twice daily (E. Fontaine 1994). Lower doses are recommended in patients with concomitant liver disease and the elderly, as plasma concentrations can be double those seen in younger patients. 

Adverse effects. Side effects that occurred with nefazodone to a greater degree than with placebo and that were dose related included somnolence, dry mouth, nausea, and dizziness. Furthermore, there is no need to taper the dose if discontinuation is being considered (L. Friedman et al. 1992 L. H. Gold and Balster 1991]. More than 2,256 patients have been studied in clinical trials, and, to date, only two cases of overdose (>3,600 mg ingested] have been reported both patients recovered with no sequelae. 

Coadministration with most medications that are metabolized by CYP 3A3/4 should be undertaken with caution, and the doses of the other medications that are CYP 3A3/4 substrates (see Table 1-1) should be reduced. The interaction between nefazodone and MAOIs has not yet been evaluated, but it may be as dangerous as... 

Buspirone is metabolized by CYP 3A3/4. Therefore, the initial dose should be lower in patients who are also taking medications known to inhibit these enzymes, such as nefazodone. 

Eszopiclone is metabolized in the liver by CYP 3A4. Eszopiclone should not be used in patients with severe hepatic impairment. Dose adjustment and caution are recommended in patients taking enzyme inhibitors such as ketoconazole, ciprofloxacin, erythromycin, iso-niazid, and nefazodone. Other sedative-hypnotics are not recommended with administration of this medication. 

---