Nefazodone dosage

A 40-year-old man had taken clozapine 450 mg/day and risperidone 6 mg/day for several years. Nefazodone 200 mg/day was added in an attempt to improve persistent negative symptoms, and after a week the dosage was increased to 300 mg/day. One week later, he reported anxiety and dizziness and was hypotensive. The combined concentrations of clozapine and its active metabolite norclozapine had increased from 309 ng/ml before nefazodone to 566 ng/ml. The nefazodone dosage was reduced to 200 mg/day and the anxiety, dizziness, and hypotension resolved over the next 7 days. At the same time plasma concentrations of clozapine and norclozapine fell to 370 ng/ml. 

Information is limited, but it would seem prudent to monitor for signs of carbamazepine toxicity if nefazodone is added to established treatment, especially with doses of carbamazepine above 800 mg. The nefazodone dosage may need to be increased in the presence of carbamazepine, so be alert for a reduced effect. Nefazodone has largely been withdrawn, but the US manufacturer of nefazodone did contraindicate its concurrent use with carbamazepine. ... 

Amitriptyline. A woman who had been taking amitriptyline 10 mg at night and thioridazine developed the serotonin syndrome after taking half a tablet of nefazodone (dosage unspecified). ... 

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. 

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... 

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. 

Three men (aged 28-63 years) had troublesome burning sensations, not clearly localized to any one area of the body, 3 days to 3 weeks after starting to take nefazodone (4). The episodes lasted for about 30 minutes and recurred several times each day. The symptoms responded to nefazodone withdrawal or dosage reduction. These unpleasant sensations appeared to be linked to nefazodone, but the mechanism was obscure. 

CYP450 3A4 inhibitors (e.g., nefazodone, fluvoxamine, fluoxetine) can raise clozapine levels, but dosage adjustment usually not necessary... 

Khouzam FIR. The antidepressant nefazodone. A review of its pharmacology, clinical efficacy, adverse effects, dosage, and administration. Journal of Psychosocial Nursing and Mental Flealth Services 2000 38 20-25. 

A 16-year-old boy had a five-fold increase in tacrohmus blood concentrations and a two-fold increase in creatinine concentrations within 4 weeks of nefazodone treatment. Complete normalization occurred after replacement with paroxetine and a transient reduction in tacrohmus dosage. 

Fluvoxamine inhibits liver drug-metabolizing enzymes. Dosages of alprazolam, theophylline, and warfarin must be reduced if any of these drugs are given concomitantly with fluvoxamine. Nefazodone may also decrease the metabolism of benzodiazepines, and venlafaxine may inhibit haloperidol metabolism. The answer is (B). 

The incidence of this interaction is unknown. All the evidence suggests that some patients require a moderate inerease in warfarin dose when starting trazodone. Be aware of this interaetion in all patients taking warfarin if trazodone is started or stopped, and adjust the dosage if necessary. The interaction can occur within a few days. The elinieal relevance of the 12% decrease in 5-warfarin levels see with nefazodone is likely to be minor. The authors of the study eoneluded that no ehange in warfarin dose is likely to be required on eoneurrent use. ... 

A placebo-controlled study in 12 healthy subjects found that nefazodone 200 mg twice daily caused an almost twofold increase in the plasma levels of alprazolam 1 mg twice daily taken for 7 days. Another study found that impairment of psychomotor performance and increased sedation occurred when nefazodone was given with alprazolam. A case report describes benzodiazepine withdrawal symptoms in a woman taking alprazolam after nefazodone was withdrawn following several years of concurrent use. She needed an alprazolam dosage increase from 500 micrograms to 4 mg daily to control her symptoms. ... 

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. 

In a study in 12 healthy subjects, nefazodone 200 mg twice daily was given alone for 5 days. After a washout period, lithium was given for 11 days, in escalating doses from 250 mg twice daily to 500 mg twice daily. When therapeutic steady-state lithium levels were achieved nefazodone 200 mg twice daily was added for 5 days. The pharmacokinetics of both nefazodone and lithium were unaltered by concurrent use, although there were some small changes in the pharmacokinetics of the nefazodone metabolites. However, since the combination was well tolerated, no dosage adjustments were considered necessary on concurrent use. ... 

Desipramine. The manufacturer of nefazodone reported that desipramine 75 mg daily did not change the pharmacokinetics of nefazodone 150 mg twice daily, but levels of the nefazodone metabolite, meta-chlorophenyl-piperazine, were increased by up to 50%. There was no change in the pharmacokinetics of desipramine or its metabolite. No specific dosage adjustments were said to be required on concurrent use. ... 

A study in 11 healthy subjects found that ketoconazole 200 mg daily for 5 days increased the plasma coneentrations of a single 4-mg dose of reboxetine, taken on the second day, by about 50%. Although the adverse effeet profile of reboxetine was not altered, beeause reboxetine has a narrow therapeutic index it was coneluded that eaution should be used and a reduetion in reboxetine dosage eonsidered if it is given with ketoconazole. The manufacturer recommends that potent inhibitors of CYP3A4, ineluding azoles, macrolides (erythromycin) and nefazodone should not... 

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