indication

For the treatment of depression.

pharmacology

Nefazodone, an antidepressant synthetically derived phenylpiperazine, is used to treat major depression. Although it is structurally similar to trazodone, nefazodone has a mechanism of action different from other antidepressants and, hence, lacks the risk for major cardiovascular toxicity seen with tricyclics and insomnia and inhibition of REM sleep seen with the selective serotonin reuptake inhibitors.

mechanism of action

Within the serotonergic system, nefazodone acts as an antagonist at type 2 serotonin (5-HT₂) post-synaptic receptors and, like fluoxetine-type antidepressants, inhibits pre-synaptic serotonin (5-HT) reuptake. These mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally. Nefazodone also antagonizes alpha(1)-adrenergic receptors, producing sedation, muscle relaxation, and a variety of cardiovascular effects. Nefazodone's affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, and beta or alpha(2)-adrenergic receptors is not significant.

toxicity

Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone.

biotransformation

Hepatic.

absorption

Nefazodone is rapidly and completely absorbed. Its absolute bioavailability is low (about 20%).

half life

2-4 hours

route of elimination

Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine.

drug interactions

Almotriptan: Increased risk of CNS adverse effects

Aprepitant: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Atorvastatin: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if nefazodone is initiated, discontinued or dose changed.

Bromazepam: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if nefazodone is initiated, discontinued or dose changed. Dosage adjustments may be required.

Buspirone: Nefazodone increases the effect of buspirone

Carbamazepine: Nefazodone increases the effect of carbamazepine

Cerivastatin: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of cerivastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if nefazodone is initiated, discontinued or dose changed.

Cilostazol: Nefazodone increases the effect of cilostazol

Cisapride: Nefazodone increases serum levels of cisapride

Cyclosporine: The antidepressant increases the effect and toxicity of cyclosporine

Dabigatran etexilate: P-Glycoprotein inducers such as nefazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Dantrolene: Nefazodone may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if nefazodone is initiated, discontinued or dose changed.

Darifenacin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dihydroergotamine: Possible ergotism and severe ischemia with this combination

Eletriptan: Increased risk of CNS adverse effects

Eplerenone: Nefazodone increases the effect and toxicity of eplerenone

Ergotamine: Possible ergotism and severe ischemia with this combination

Erlotinib: This CYP3A4 inhibitor increases levels/toxicity of erlotinib

Frovatriptan: Increased risk of CNS adverse effects

Isocarboxazid: Possible severe adverse reaction with this combination

Linezolid: Combination associated with possible serotoninergic syndrome

Loratadine: Increased risk of cardiotoxicity

Lovastatin: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of lovastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if nefazodone is initiated, discontinued or dose changed.

Naratriptan: Increased risk of CNS adverse effects

Phenelzine: Possible severe adverse reaction with this combination

Pimozide: Nefazodone may increase the effect and toxicity of pimozide.

Rasagiline: Possible severe adverse reaction with this combination

Rizatriptan: Increased risk of CNS adverse effects

Sibutramine: Risk of serotoninergic syndrome

Simvastatin: Nefazodone may increase the effect and toxicity of simvastatin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of simvastatin if nefazodone is initiated, discontinued or dose changed.

Solifenacin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

St. John's Wort: St. John's Wort increases the effect and toxicity of the SSRI, nefazodone.

Sumatriptan: Increased risk of CNS adverse effects

Sunitinib: Possible increase in sunitinib levels

Tacrolimus: Nefazodone may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nefazodone therapy is initiated, discontinued or altered.

Tadalafil: Nefazodone may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Nefazodone may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Tamsulosin: Nefazodone, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Nefazodone is initiated, discontinued, or dose changed.

Telithromycin: Co-administration may result in altered plasma concentrations of Nefazodone and/or Telithromycin. Consider alternate therapy or monitor the therapeutic/adverse effects of both agents.

Temsirolimus: Nefazodone may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Nefazodone, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Nefazodone is initiated, discontinued or dose changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Nefazodone. Consider alternate therapy or monitor for therapeutic/adverse effects of Nefazodone if Terbinafine is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Tiagabine: The strong CYP3A4 inhibitor, Nefazodone, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Nefazodone is initiated, discontinued or dose changed.

Tolterodine: Nefazodone may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Nefazodone may increase tramadol toxicity by decreasing tramadol metabolism and clearance. Increased risk of serotonin syndrome. Monitor for tramadol toxicity and symptoms of serotonin syndrome.

Tranylcypromine: Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.

Trazodone: Increased risk of serotonin syndrome. The CYP3A4 inhibitor, Nefazodone, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for symtpoms of sertonin syndrome and changes in Trazodone efficacy/toxicity if Nefazodone is initiated, discontinued or dose changed.

Triazolam: Nefazodone increases the effect of triazolam

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. Nefazodone, a strong CYP3A4 inhibitor, may also decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Nefazodone is initiated, discontinued or dose changed.

Triprolidine: The CNS depressants, Triprolidine and Nefazodone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Vardenafil: Nefazodone, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Verapamil: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Nefazodone is initiated, discontinued or dose changed.

Vinblastine: Nefazodone, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Nefazodone is initiated, discontinued or dose changed.

Vincristine: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Nefazodone is initiated, discontinued or dose changed.

Vinorelbine: Nafazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Nefazodone is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of nefazodone by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nefazodone if voriconazole is initiated, discontinued or dose changed.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and nafazodone, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zolpidem: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if nefazodone is initiated, discontinued or dose changed.

Zonisamide: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if nefazodone is initiated, discontinued or dose changed.

Zopiclone: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if nefazodone is initiated, discontinued or dose changed.