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Active ingredient: Nefazodone - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Antidepressants
  • Analgesics
  • Serotonin Agents

Dosage Forms

  • Tablets

Brands / Synonyms

Dutonin; Nefazodona [Spanish]; Nefazodone; Nefazodone Hcl; Nefazodone Hydrochloride; Nefazodonum [Latin]; Serzone; Serzone

Indications

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.

Absorption

rapidly and completely absorbed, its absolute bioavailability is low, about 20%

Toxicity

Cases of life-threatening hepatic failure have been reported in patients treated with SERZONE; LD50=mg/kg (orally in rat)

Biotrnasformation / Drug Metabolism

Hepatic

Contraindications

Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with SERZONE (nefazodone hydrochloride) is contraindicated .

SERZONE tablets are contraindicated in patients who were withdrawn from SERZONE because of evidence of liver injury. SERZONE tablets are also contraindicated in patients who have demonstrated hypersensitivity to nefazodone hydrochloride, its inactive ingredients, or other phenylpiperazine antidepressants.

The coadministration of triazolam and nefazodone causes a significant increase in the plasma level of triazolam,and a 75% reduction in the initial triazolam dosage is recommended if the two drugs are to be given together. Because not all commercially available dosage forms of triazolam permit a sufficient dosage reduction, the coadministration of triazolam and SERZONE should be avoided for most patients, including the elderly.

Drug Interactions

DRUG INTERACTIONS

Drugs Highly Bound to Plasma Protein

Because nefazodone is highly bound to plasma protein,administration of SERZONE to a patient
taking another drug that is highly protein bound may cause increased free concentrations of
the other drug, potentially resulting in adverse events. Conversely, adverse effects could
result from displacement of nefazodone by other highly bound drugs.

Warfarin: There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics
of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been
pretreated for 2 weeks with warfarin. Although the coadministration of nefazodone did decrease
the subjects’ exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding
times indicates this modest change is not clinically significant. Although these results suggest
no adjustments in warfarin dosage are required when nefazodone is administered to patients
stabilized on warfarin, such patients should be monitored as required by standard medical practices.

CNS-Active Drugs

Monoamine Oxidase Inhibitors

Haloperidol: When a single oral 5-mg dose of haloperidol was coadministered with nefazodone (200 mg BID)
at steady state, haloperidol apparent clearance decreased by 35% with no significant increase in peak
haloperidol plasma concentrations or time of peak. This change is of unknown clinical significance.
Pharmacodynamic effects of haloperidol were generally not altered significantly. There were no changes
in the pharmacokinetic parameters for nefazodone. Dosage adjustment of haloperidol may be necessary
when coadministered with nefazodone.

Lorazepam: When lorazepam (2 mg BID) and nefazodone (200 mg BID) were coadministered to steady state,
there was no change in any pharmacokinetic parameter for either drug compared to each drug administered
alone. Therefore, dosage adjustment is not necessary for either drug when coadministered.

Triazolam/Alprazolam

Alcohol: Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in
experiments with normal subjects, the concomitant use of SERZONE and alcohol in depressed patients is
not advised.

Buspirone: In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of
buspirone (2.5 or 5 mg BID) with nefazodone (250 mg BID) resulted in marked increases in plasma buspirone
concentrations (increases up to 20-fold in Cmax and up to 50-fold in AUC) and statistically significant
decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine. With
5-mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites
hydroxynefazodone (17%) and mCPP (9%). Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID
experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either
drug alone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg QD) is
recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.

Pimozide: Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction with Drugs that
Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes.

Fluoxetine: When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there
were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly,
there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels
of the nefazodone metabolites mCPP and triazoledione increased by 3- to 6-fold and 1.3-fold,respectively.
When a 200-mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week,
there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or
paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone
without an adequate washout period may experience similar transient adverse events. The possibility of this
happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing
the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites, this washout
period may range from one to several weeks depending on the dose of fluoxetine and other individual patient
variables.

Phenytoin: Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a
single 300-mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics of phenytoin, the failure
to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility
of a clinically significant interaction with nefazodone when phenytoin is dosed chronically. However, no change
in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage
should be guided by usual clinical practices. Desipramine: When nefazodone (150 mg BID) and desipramine (75 mg QD)
were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite,
2-hydroxy desipramine. There were also no changes in the pharmacokinetics of nefazodone or its triazoledione
metabolite, but the AUC and Cmax of mCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreased
by 19%. No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given
concomitantly. Subsequent dose adjustments should be made on the basis of clinical response.

Lithium: In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5
days (steady-state conditions) was found to be well tolerated. When the two drugs were coadministered, there were
no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however,
there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and
triazoledione, which are considered not to be of clinical significance. Therefore, no dosage adjustment of either
lithium or nefazodone is required when they are coadministered.

Carbamazepine: The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine
who had achieved steady state (200 mg BID) was found to be well tolerated. Steady-state conditions for carbamazepine,
nefazodone, and several of their metabolites were achieved by day 5 of coadministration. With coadministration of
the two drugs there were significant increases in the steady-state Cmax and AUC of carbamazepine (23% and 23%,
respectively), while the steady-state Cmax and the AUC of the carbamazepine metabolite, 10, 11 epoxycarbamazepine,
decreased by 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state
Cmax and AUC of nefazodone by 86% and 93%, respec-tively.Similar reductions in the Cmax and AUC of HO-NEF were also
observed (85% and 94%),while the reductions in Cmax and AUC of mCPP and triazole-dione were more modest (13% and 44%
for the former and 28% and 57% for the latter).Due to the potential for coadministration of carbamazepine to result
in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for
SERZONE, it is recommended that SERZONE not be used in combination with carbamazepine (see CONTRAINDICATIONS and
WARNINGS).

General Anesthetics: Little is known about the potential for interaction between nefazodone and general anesthetics;
therefore, prior to elective surgery, SERZONE should be discontinued for as long as clinically feasible.

Other CNS-Active Drugs: The use of nefazodone in combination with other CNS-active drugs has not been systematically
evaluated. Consequently, caution is advised if concomitant administration of SERZONE (nefazodone hydrochloride) and
such drugs is required.

Cimetidine

When nefazodone (200 mg BID) and cimetidine (300 mg QID) were coadministered for one week, no change in the steady-state
pharmacokinetics of either nefazodone or cimetidine was observed compared to each dosed alone. Therefore, dosage
adjustment is not necessary for either drug when coadministered.

Theophylline

When nefazodone (200 mg BID) was given to patients being treated with theophylline (600-1200 mg/day) for chronic
obstructive pulmonary disease,there was no change in the steady-state pharmacokinetics of either nefazodone or
theophylline. FEV1 measurements taken when theophylline and nefazodone were coadministered did not differ from
baseline dosage (ie, when theophylline was administered alone).Therefore, dosage adjustment is not necessary for
either drug when coadministered.

Cardiovascular-Active Drugs

Digoxin: When nefazodone (200 mg BID) and digoxin (0.2 mg QD) were coadministered for 9 days to healthy male volunteers
(n=18) who were phenotyped as CYP2D6 extensive metabolizers, Cmax, Cmin, and AUC of digoxin were increased by 29%, 27%,
and 15%, respectively. Digoxin had no effects on the pharmacokinetics of nefazodone and its active metabolites. Because
of the narrow therapeutic index of digoxin,caution should be exercised when nefazodone and digoxin are coadministered;
plasma level monitoring for digoxin is recommended.

Propranolol: The coadministration of nefazodone (200 mg BID) and propranolol (40 mg BID) for 5.5 days to healthy male
volunteers (n=18), including 3 poor and 15 extensive CYP2D6 metabolizers, resulted in 30% and 14% reductions in Cmax
and AUC of propranolol, respectively, and a 14% reduction in Cmax for the metabolite, 4-hydroxypropranolol. The kinetics
of nefazodone, hydroxynefazodone, and triazoledione were not affected by coadministration of propranolol. However, Cmax,
Cmin, and AUC of m-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively. No change in initial dose
of either drug is necessary and dose adjustments should be made on the basis of clinical response.

HMG-CoA Reductase Inhibitors: When single 40-mg doses of simvastatin or atorvastatin, both substrates of CYP3A4, were
given to healthy adult volunteers who had received SERZONE 200 mg BID for 6 days, approximately 20-fold increases in
plasma concentrations of simvastatin and simvastatin acid and 3- to 4-fold increases in plasma concentrations of
atorvastatin and atorvastatin lactone were seen. These effects appear to be due to the inhibition of CYP3A4 by SERZONE
because, in the same study, SERZONE had no significant effect on the plasma concentrations of pravastatin, which is not
metabolized by CYP3A4 to a clinically significant extent.

There have been rare reports of rhabdomyolysis involving patients receiving the combination of SERZONE and either
simvastatin or lovastatin, also a substrate of CYP3A4 (see ADVERSE REACTIONS: Postintroduction Clinical Experience).
Rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors administered alone (at recommended
dosages) and in particular, for certain drugs in this class, when given in combination with inhibitors of the CYP3A4
isozyme.

Caution should be used if SERZONEis administered in combination with HMG-CoA reductase inhibitors that are metabolized
by CYP3A4, such as simvastatin, atorvastatin, and lovastatin, and dosage adjustments of these HMG-CoA reductase inhibitors
are recommended. Since metabolic interactions are unlikely between SERZONE and HMG-CoA reductase inhibitors that undergo
little or no metabolism by the CYP3A4 isozyme, such as pravastatin or fluvastatin, dosage adjustments should not be
necessary.

Immunosuppressive Agents

There have been reports of increased blood concentrations of cyclosporine and tacrolimus into toxic ranges when patients
received these drugs concomitantly with SERZONE. Both cyclosporine and tacrolimus are substrates of CYP3A4, and nefazodone
is known to inhibit this enzyme. If either cyclosporine or tacrolimus is administered with SERZONE, blood concentrations
of the immunosuppressive agent should be monitored and dosage adjusted accordingly.

Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction with Drugs that Inhibit and/or Are
Metabolized by Cytochrome P450 Isozymes

CYP3A4 Isozyme: Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. This is consistent with the interactions
observed between nefazodone and triazolam, alprazolam, buspirone, atorvastatin, and simvastatin, drugs metabolized by this
isozyme. Consequently, caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by
CYP3A4. In particular, the combined use of nefazodone with triazolam should be avoided for most patients, including the
elderly. The combined use of nefazodone with terfenadine, astemizole, cisapride, or pimozide is contraindicated (see
CONTRAINDICATIONS and WARNINGS).

CYP2D6 Isozyme: A subset (3% to 10%) of the population has reduced activity of the drug-metabolizing enzyme CYP2D6. Such
individuals are referred to commonly as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the
tricyclic antidepressants. The pharmacokinetics of nefazodone and its major metabolites are not altered in these "poor
metabolizers." Plasma concentrations of one minor metabolite (mCPP) are increased in this population; the adjustment of
SERZONE dosage is not required when administered to "poor metabolizers." Nefazodone and its metabolites have been shown
in vitro to be extremely weak inhibitors of CYP2D6. Thus, it is not likely that nefazodone will decrease the metabolic
clearance of drugs metabolized by this isozyme.

CYP1A2 Isozyme: Nefazodone and its metabolites have been shown in vitro not to inhibit CYP1A2. Thus, metabolic interactions
between nefazodone and drugs metabolized by this isozyme are unlikely.

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