Nefazodone

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

: All antidepressants whose actions include increasing brain concentrations of serotonin, including nefazodone, should not be taken with any of the MAO (monoamine oxidase) inhibitor class of antidepressants, for example, isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), procarbazine (Matulane), and selegiline (Eldepryl). Such combinations may lead to confusion, high blood pressure, tremor, and increased activity. If a patient is switched from nefazodone to an MAO inhibitor, at least one week should be allowed after stopping nefazodone before starting the MAO inhibitor. Two weeks should be allowed between stopping an MAO inhibitor and initiating treatment with nefazodone.

Nefazodone may increase the blood concentration of several drugs by reducing their removal by the liver. Through this mechanism nefazodone may markedly increase the blood concentrations of triazolam (Halcion) and alprazolam (Xanax), resulting in excessive sedation and impaired ability to perform tasks. It is recommended that people taking triazolam who need to be started on nefazodone should have their triazolam dose reduced by 75%. Similarly, those people taking alprazolam who need to take nefazodone should have their alprazolam dose reduced by 50%. Nefazodone also may increase the blood concentration and possibly the side effects of eletriptan (Relpax), eplerenone (Inspra), pimozide (Orap), ranolazine (Ranexa), and silodosin (Rapaflo).

Carbamazepine (Tegretol, Tegretol XR, Equetro, Carbatrol) may decrease nefazodone blood levels and possibly its effectiveness by increasing nefadone's removal by the liver. Conversely, nefazodone may increase the levels of carbamazepine, possibly leading to toxicity, by decreasing the removal of carbamazepine by the liver.

Hepatotoxicity (See BOXED WARNING.)

SERZONE (nefazodone) should be discontinued if clinical signs or symptoms suggest liver failure (see PRECAUTIONS: Information for Patients). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥3 times the upper limit of NORMAL, while on SERZONE (nefazodone) should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if SERZONE (nefazodone) is reintroduced. Accordingly, such patients should not be considered for re-treatment.

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in shortterm studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term, placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, ie, beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for SERZONE (nefazodone) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that SERZONE (nefazodone) is not approved for use in treating bipolar depression.

Interaction studies of nefazodone with two triazolobenzodiazepines, ie, triazolam and alprazolam, metabolized by cytochrome P450 3A4, have revealed substantial and clinically important increases in plasma concentrations of these compounds when administered concomitantly with nefazodone.

When a single oral 0.25-mg dose of triazolam was coadministered with nefazodone (200 mg BID) at steady state, triazolam half-life and AUC increased 4-fold and peak concentrations increased 1.7-fold. Nefazodone plasma concentrations were unaffected by triazolam. Coadministration of nefazodone potentiated the effects of triazolam on psychomotor performance tests. If triazolam is coadministered with SERZONE (nefazodone) , a 75% reduction in the initial triazolam dosage is recommended. Because not all commercially available dosage forms of triazolam permit sufficient dosage reduction, coadministration of triazolam with SERZONE (nefazodone) should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with SERZONE (nefazodone) may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS).

When alprazolam (1 mg BID) and nefazodone (200 mg BID) were coadministered, steady-state peak concentrations, AUC and half-life values for alprazolam increased by approximately 2-fold.Nefazodone plasma concentrations were unaffected by alprazolam. If alprazolam is coadministered with SERZONE (nefazodone) , a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment is required for SERZONE (nefazodone) .

Terfenadine, astemizole, cisapride, and pimozide are all metabolized by the cytochrome P450 3A4 (CYP3A4) isozyme, and it has been demonstrated that ketoconazole, erythromycin, and other inhibitors of CYP3A4 can block the metabolism of these drugs, which can result in increased plasma concentrations of parent drug. Increased plasma concentrations of terfenadine, astemizole, cisapride, and pimozide are associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, due principally to ventricular tachycardia of the torsades de pointes type. Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. Consequently, it is recommended that nefazodone not be used in combination with either terfenadine, astemizole, cisapride, or pimozide (see CONTRAINDICATIONS and PRECAUTIONS).

The coadministration of carbamazepine 200 mg BID with nefazodone 200 mg BID, at steady state for both drugs, resulted in almost 95% reductions in AUCs for nefazodone and hydroxynefazodone, likely resulting in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for SERZONE (nefazodone) . Consequently, it is recommended that SERZONE (nefazodone) not be used in combination with carbamazepine (see CONTRAINDICATIONS and PRECAUTIONS).

Human Experience

In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One nonstudy participant took 2000-3000 mg of nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented). None of these patients died.

In postmarketing experience, overdose with SERZONE (nefazodone) alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established.

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians Desk Reference (PDR).

If you take too much nefazodone, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

• Store nefazodone at room temperature.
• Keep this and all medicines out of the reach of children.

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of nefazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nefazodone hydrochloride tablets are not approved for use in pediatric patients.

Warning- Liver Failure

Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone hydrochloride tablets. 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 hydrochloride treatment. The total patient-years is a summation of each patient’s duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc.

Ordinarily, treatment with nefazodone hydrochloride tablets should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure, however, baseline abnormalities can complicate patient monitoring.

Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur.

Nefazodone hydrochloride tablets should be discontinued if clinical signs or symptoms suggest liver failure (see PRECAUTIONS, Information for Patients). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥ 3 times the upper limit of NORMAL, while on nefazodone hydrochloride tablets should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone hydrochloride is reintroduced. Accordingly, such patients should not be considered for re-treatment.

Nefazodone is an antidepressant. It is used to treat depression, including major depressive disorder.

Nefazodone is not chemically similar to other groups of antidepressants, such as selective serotonin reuptake inhibitors or "SSRIs", tricyclic antidepressants, or monoamine oxidase inhibitors or "MAOIs."

Nefazodone may also be used for other purposes not listed in this medication guide.

Usual Adult Dose for Depression:

Initial dose: 200 mg orally per day in two divided doses
Maintenance dose: 300 to 600 mg orally per day

Comments:
-Dose increases should occur in increments of 100 mg per day to 200 mg per day, on a BID schedule, at intervals of no less than 1 week.

Use: Treatment of depression

Usual Geriatric Dose for Depression:

Elderly or debilitated patients:
Initial dose: 100 mg orally per day administered in two divided doses

Comments:
-Since these patients often have reduced drug clearance and/or increased sensitivity to the side effects, it may be appropriate to modify the rate of subsequent dose titration.

Use: Treatment of depression

• If you have an allergy to nefazodone or any other part of nefazodone.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have had liver problems in the past while taking this medicine.
• If you are taking any of these drugs: Astemizole, carbamazepine, cisapride, pimozide, terfenadine, or triazolam.
• If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for Parkinson's disease like selegiline or rasagiline in the last 14 days. Taking nefazodone within 14 days of those drugs can cause very bad high blood pressure.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take nefazodone with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table1.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.Such monitoring should include daily observation by families and caregivers. Prescriptions for Nefazodone hydrochloride tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Nefazodone hydrochloride tablets are not approved for use in treating bipolar depression.

Hepatotoxicity

(See BOXED WARNING.)

Cases of life-threatening hepatic failure have been reported in patients treated with Nefazodone hydrochloride tablets.

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. This represents a rate of about 3 to 4 times the estimated background rate of liver failure. This rate is an underestimate because of under reporting, and the true risk could be considerably greater than this. A large cohort study of antidepressant users found no cases of liver failure leading to death or transplant among Nefazodone users in about 30,000 patient-years of exposure. The spontaneous report data and the cohort study results provide estimates of the upper and lower limits of the risk of liver failure in Nefazodone-treated patients, but are not capable of providing a precise risk estimate.

The time to liver injury for the reported liver failure cases resulting in death or transplant generally ranged from 2 weeks to 6 months on Nefazodone therapy. Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symptoms), other reports did not describe the onset of clear prodromal symptoms prior to the onset of jaundice.

The physician may consider the value of liver function testing. 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 withdrawal of the suspect drug enhances the likelihood for recovery.

Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.

Nefazodone should be discontinued if clinical signs or symptoms suggest liver failure (see PRECAUTIONS, Information for Patients). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥ 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, such patients should not be considered for re-treatment.

Potential for Interaction With Monoamine Oxidase Inhibitors

In patients receiving antidepressants with pharmacological properties similar to Nefazodone in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor (SSRI), these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI.

Although the effects of combined use of Nefazodone and MAOI have not been evaluated in humans or animals, because Nefazodone is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that Nefazodone not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. At least 1 week should be allowed after stopping Nefazodone before starting an MAOI.

Interaction With Triazolobenzodiazepines

Interaction studies of Nefazodone with two triazolobenzodiazepines, i.e., triazolam and alprazolam, metabolized by cytochrome P450 3A4, have revealed substantial and clinically important increases in plasma concentrations of these compounds when administered concomitantly with Nefazodone.

When a single oral 0.25 mg dose of triazolam was coadministered with Nefazodone (200 mg BID) at steady state, triazolam half-life and AUC increased 4 fold and peak concentrations increased 1.7 fold. Nefazodone plasma concentrations were unaffected by triazolam. Coadministration of Nefazodone potentiated the effects of triazolam on psychomotor performance tests. If triazolam is coadministered with Nefazodone, a 75% reduction in the initial triazolam dosage is recommended. Because not all commercially available dosage forms of triazolam permit sufficient dosage reduction, coadministration of triazolam with Nefazodone should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with Nefazodone may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS).

When alprazolam (1 mg BID) and Nefazodone (200 mg BID) were coadministered, steady-state peak concentrations, AUC and half-life values for alprazolam increased by approximately 2 fold. Nefazodone plasma concentrations were unaffected by alprazolam. If alprazolam is coadministered with Nefazodone, a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment is required for Nefazodone.

Potential Terfenadine, Astemizole, Cisapride, and Pimozide Interactions

Terfenadine, astemizole, cisapride, and pimozide are all metabolized by the cytochrome P450 3A4 (CYP3A4) isozyme, and it has been demonstrated that ketoconazole, erythromycin, and other inhibitors of CYP3A4 can block the metabolism of these drugs, which can result in increased plasma concentrations of parent drug. Increased plasma concentrations of terfenadine, astemizole, cisapride, and pimozide are associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, due principally to ventricular tachycardia of the torsade de pointes type. Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. Consequently, it is recommended that Nefazodone not be used in combination with either terfenadine, astemizole, cisapride, or pimozide (see CONTRAINDICATIONS and PRECAUTIONS).

Interaction With Carbamazepine

The coadministration of carbamazepine 200 mg BID with Nefazodone 200 mg BID, at steady state for both drugs, resulted in almost 95% reductions in AUCs for Nefazodone and hydroxyNefazodone, likely resulting in insufficient plasma Nefazodone and hydroxyNefazodone concentrations for achieving an antidepressant effect for Nefazodone. Consequently, it is recommended that Nefazodone not be used in combination with carbamazepine (see CONTRAINDICATIONS and PRECAUTIONS).

Human Experience

In premarketing clinical studies, there were seven reports of Nefazodone overdose alone or in combination with other pharmacological agents. The amount of Nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of Nefazodone included nausea, vomiting, and somnolence. One nonstudy participant took 2000 to 3000 mg of Nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented). None of these patients died.

In postmarketing experience, overdose with Nefazodone alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of Nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to Nefazodone has been established.

Overdosage Management

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered. Due to the wide distribution of Nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for Nefazodone are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

(nef AY zoe done)

Cmax and AUC for nefazodone and hydroxynefazodone were twice as high in patients older than 65 years after single doses and 10% to 20% higher after multiple doses.

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Nefazodone is not FDA approved for use in children.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occurs.

Concerns related to adverse effects:

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is very low relative to other antidepressants (APA, 2010).

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). The degree of sedation is moderate relative to other antidepressants (Bauer, 2013).

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012).

• Hepatic failure: [US Boxed Warning]: Cases of hepatic failure resulting in death or transplant have been reported at a rate of approximately 1 case per 250,000 to 300,000 patient-years of nefazodone treatment, which is 3 to 4 times the estimated background rate of liver failure. There is no evidence that preexisting liver disease increases this risk. The time to liver injury in reported, severe cases ranged from 2 weeks to 6 months; not all cases had a clear prodromal onset of symptoms. Treatment should not ordinarily be initiated in patients with active liver disease or elevated baseline serum transaminases. There is no evidence that periodic monitoring of serum transaminases will prevent serious hepatic injury, but it can be used for early detection in symptomatic patients. Discontinue if clinical signs or symptoms (such as jaundice, anorexia, gastrointestinal complaints, malaise, or increased serum AST or ALT levels ≥3 times the upper limit of normal) suggest liver failure. Patients who develop symptoms while on nefazodone should not be considered for re-treatment. Doses as low as 100 mg/day have been associated with hepatotoxicity (Stewart 2002).

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Orthostatic hypotension: May cause orthostatic hypotension (risk is low relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, dehydration, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

• Sexual dysfunction: Rare reports of priapism have occurred. The incidence of sexual dysfunction with nefazodone is generally lower than with SSRIs (APA, 2010; Bauer, 2013).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk conduction abnormalities with this agent is very low relative to other antidepressants (APA 2010; Bauer, 2013).

• Hepatic impairment: [US Boxed Warning]: Treatment should not ordinarily be initiated in patients with active liver disease or elevated baseline serum transaminases. Use with caution in patients with hepatic impairment.

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder, including details regarding family history of suicide, bipolar disorder, and depression. Nefazodone is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation.. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

Initial dose: 200 mg orally per day in two divided doses
Maintenance dose: 300 to 600 mg orally per day

Comments:
-Dose increases should occur in increments of 100 mg per day to 200 mg per day, on a BID schedule, at intervals of no less than 1 week.

Use: Treatment of depression

Elderly or debilitated patients:
Initial dose: 100 mg orally per day administered in two divided doses

Comments:
-Since these patients often have reduced drug clearance and/or increased sensitivity to the side effects, it may be appropriate to modify the rate of subsequent dose titration.

Use: Treatment of depression

Data not available

Monitoring:
-Hepatic: Patients should be monitired for elevated baseline serum transaminases.
-Psychiatric: Patients should be monitored for worsening and emergence of suicidal thoughts.

Patient advice:
-Patients should be cautioned accordingly since this drug may impair the mental and/or physical abilities required for the performance of operating an automobile or machinery.