Nefazodone liver

A black box warning for life-threatening liver failure was added to the prescribing information for nefazodone. Treatment with nefazodone should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. 

A controlled trial of duloxetine (Cymbalta)—like venlafaxine a dual serotonin-norepinephrine reuptake inhibitor—in the treatment of GAD is currently underway. Anecdotal data suggests that nefazodone (Serzone) and mirtazapine (Remeron) may be effective in the treatment of GAD, though no controlled data is available. In addition, recent concerns regarding nefazodone and liver toxicity have limited this medication s utility. Please refer to Chapter 3 for more information regarding these antidepressants. 

Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone treatment. 

Discontinue nefazodone if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels at least 3 times the upper limit of normal while on nefazodone should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone is reintroduced. Accordingly, do not consider such patients for retreatment. 

Coadministration with cisapride, pimozide, or carbamazepine (see Warnings and Drug Interactions) patients who were withdrawn from nefazodone because of evidence of liver injury (see Warning box. Warnings) hypersensitivity to nefazodone or other phenylpiperazine antidepressants. 

Hepatic cirrhosis In patients with cirrhosis of the liver, the AUC values of nefazodone and its metabolite HO-NEF were increased by about 25%. 

Nefazodone is rapidly absorbed after oral administration. It undergoes extensive first-pass metabolism in the liver, causing bioavailability to be limited to approximately 20%. Peak plasma levels are achieved between... 

It may be prudent to consider liver function testing of patients being treated with nefazodone. Periodic serum transaminase testing has not been proven to prevent serious injury, but it is generally believed that early detection of drug-induced hepatic injury, along with immediate discontinuation of the medication enhances the likelihood for recovery. 

A large study demonstrated efficacy of nefazodone for social phobia in adults (Van Amerigen et ah, 1999), but no controlled pediatric study of nefazodone treatment for anxiety disorders or any psychiatric disorder has been published. The package insert for nefazopone (2002) now includes a black-box warning about potential hepatotoxicity, so liver function tests need to be closely monitored. 

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. 

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. 

Nefazodone Headache, dry mouth, somnolence, nausea, dizziness, constipation, elevation in liver enzymes... 

Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is l-(2-pyrimidyl)-piperazine (1-PP), which has K2-adrenoceptor-blocking actions and which enters the central nervous system to reach higher levels than the parent drug. It is not known what role (if any) 1-PP plays in the central actions of buspirone. The elimination half-life of buspirone is 2-4 hours, and liver dysfunction may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. 

Kalgutkar, A. S., et al. (2005). Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab. Dispos. 33 243-253. 

Peterman, S. M., Duczak, N., Jr., Kalgutkar, A. S., Lame, M. E., and Soglia, J. R. (2006). Application of a linear ion trap/orbitrap mass spectrometer in metabohte characterization studies Examination of the human liver microsomal metabolism of the non-tricyclic antidepressant nefazodone using data-dependent accurate mass measurements. J. Am. Soc. Mass Spectrom. 17 363-375. 

Von Moltke LL, Greenblatt DJ, Duan SX, et al. Phenacetin O-deethylation hy human liver micro-somes in vitro inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine. Psychopharmacology 1996 128 398-407. 

These selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and, most recently, escitalopram (Lexapro see the appendix). These drugs block the removal of the neurotransmitter serotonin from the synaptic cleft. A number of other antidepressants are potent nonselective serotonin reuptake inhibitors (NSRIs). These include the atypical venlafaxine (Effexor) and the tricyclic clomipramine (Anafra-nil). Nefazodone (Serzone) has been withdrawn from the market due to liver damage. 

There have been several reports of serious hepatotoxicity associated with nefazodone, in some cases leading to liver failure. 

A 27-year-old man developed hepatitis (with raised bilirubin and liver enzymes) without overt jaundice after taking nefazodone 200 mg/day for 12 weeks (7). No other cause for the hepatitis could be established and the abnormal liver function tests settled 4 weeks after nefazodone withdrawal. They became abnormal again 1 week after nefazodone rechallenge and settled once again on withdrawal. 

Four women, aged 16-73 years, developed catastrophic liver failure while taking nefazodone (8,9). Nefazodone was given for 14—28 weeks before the onset of symptoms. The cases had similar histological appearances, with prominent centrilobular necrosis. Three died, one survived after liver transplantation, and one improved sufficiently to obviate the need for transplantation. The duration of nefazodone treatment before the onset of symptoms was 7-28 weeks. The patients had no history of liver disease and other causes were excluded as far as possible. 

An 80-year-old man developed acute fatal liver failure while taking nefazodone 50 mg/day (8). 

A 52-year-old man with a 10-day history of fatigue and jaundice had been taking nefazodone (300 mg/day) for depression for about 6 weeks. Biochemical investigations showed acute liver failure. Infective hepatitis and immune disorders were excluded. He failed to respond to medical treatment, and hepatic transplantation was performed. Histological examination of the liver showed parenchymal necrosis, particularly in centrilobular areas, together with lymphocytic infiltration (10). 

A 46-year-old woman developed fatigue and jaundice about 20 weeks after she started to take nefazodone (300 mg/day). She had raised liver enzymes and bilirubin concentrations. There was no evidence of infectious hepatitis or immune disorders. Liver biopsy showed ballooning degeneration and necrosis of... 

Lucena MI, Andrade RJ, Gomez-Outes A, Rubio M, Cabello MR. Acute liver failure after treatment with nefazodone. Dig Dis Sci 1999 44(12) 2577-9. 

Jr. Nefazodone-induced liver failure report of three cases. Ann Intern Med 1999 130(4 Part l) 285-8. 

Eloubeidi MA, Gaede JT, Swaim MW. Reversible nefazodone-induced liver failure. Dig Dis Sci 2000 45(5) 1036-8. 

A therapeutic role for nefazodone 100 mg bd has been suggested in the treatment of neuroleptic drug-induced extrapyramidal signs, based on the results of a placebo-controlled, randomized study in 49 patients (197). There were no differences in akathisia or tardive dyskinesia between the two groups. However it should be noted that nefazodone has been withdrawn in most countries owing to the risk of severe liver damage. 

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