nefazodone (Serzone, Dutonin, Nefador, Nefirel, Rezeril)
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Introduction
Tradename: Serzone. Britol-Myers to discontinue# 06/14/04[8] Generics to remain on the market.[9]
Indications
- depression, major depression
- with & without sleep disorder
- premenstrual syndrome
- anxiety
- sleep disorders
- mania[11]
Dosage
- start 100 mg PO BID
- max 600 mg/day
- after meal dosing may decrease lightheadedness & orthostatic hypotension, but may also decrease absorption
Tabs: 100, 150, 200, 250 mg.
Pharmacokinetics
- absolute bioavailability is 20% due to 1st pass metabolism
- food delays absorption & may reduce bioavailability
- metabolized by cyt P450 3A4 to 3 active metabolites
- 1/2life depends upon dosage
- parent compound: 2-8 hours
- parent plus active metabolites: 11-24 hours
- < 1% of the drug is excreted unchanged in the urine
- hepatic impairment decreases clearance of parent compound
- renal insufficiency decreases clearance of active metabolites
elimination via liver
1/2life = 2-8 hours
1/2life = 11-24 hours
Monitor
- serum ALT or serum AST within 180 days
- discontinue if serum AST or serum ALT > 3X upper limit of normal or if signs or symptoms of liver dysfunction develop[10]
Adverse effects
- common (> 10%)
- headache, drowsiness, insomnia, agitation, dizziness (17%), lightheadedness (10%), confusion, dry mouth (8%), nausea (5-22%), tremor
- less common (1-10%)
- uncommon (< 1%)
- diarrhea, priapism, hepatic failure (< 0.001%)[5]
- other
- moderate sedation
- moderate orthostatic hypotension
- very low anticholinergic effects
- headache
- somnolence
- less likely to cause priapism than trazodone
- adverse effects are dose-related & occur mainly with doses > 300 mg/day
- liver failure 0.00025% (removed from market in Europe)[7] (at least 20 deaths)[8]
Drug interactions
- MAO inhibitors in combination may result in serious, even fatal reactions - allow a 2 week washout period
- astemizole, terfenadine, cisapride in combination may result in QT prolongation
- nefazodone increases serum levels of alprazolam, triazolam, midazolam & possibly phenytoin
- nefazodone increases serum levels of digoxin
- nefazodone decreases effect of:
- carbamazepine
- decreased effect of beta-blockers
- any drug that inhibits cyt P450 3A4 may increase levels of nefazodone
- any drug that induces cyt P450 3A4 may diminish levels of nefazodone
- nefazodone inhibits cyt P450 3A4, thus inhibits its own metabolism & metabolism of other cyt P450 3A4 substrates
- drug interaction(s) of benzodiazepines with antidepressants
- drug interaction(s) of antidepressants with benzodiazepines
- drug interaction(s) of NSAIDs with antidepressants
Mechanism of action
- postsynaptic 5-HT receptor 2A antagonist
- some presynaptic serotonin re-uptake inhibition
- does not suppress REM sleep
- 5-HT 2A inhibits 5-HT 1A, thus inhibition of 5-HT 2A enhances action of 5-HT 1A
- weak alpha-1 adrenergic receptor antagonist[5]
- inhibits cyt P450 3A4 & cyt P450 2D6
More general terms
Additional terms
- cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
- serotonin [5HT]-2A receptor; 5-hydroxytryptamine receptor 2A; 5-HT-2A; 5-HT-2; serotonin receptor 2A (HTR2A, HTR2)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 5.0 5.1 5.2 UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ Prescriber's Letter 9(1):3 2002
- ↑ 7.0 7.1 Prescriber's Letter 10(2):8 2003
- ↑ 8.0 8.1 8.2 Netscape, Associated Press 05/14/04
- ↑ 9.0 9.1 Serzone Off the Market Prescriber's Letter 11(6):35 2004 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=200616&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 11.0 11.1 Deprecated Reference