Special Alerts:

Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, 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). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Pronunciation:

(nef AY zoe done)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Lactation:

Contraindications:

Warnings/Precautions:

Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The risk of postural hypotension is low relative to other antidepressants. Use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or history of bowel obstruction (due to anticholinergic effects). The degree of anticholinergic blockade produced by this agent is very low relative to other cyclic antidepressants.

The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. 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 occur.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Nefazodone is not FDA approved for use in children.

Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in patients with renal dysfunction and in elderly patients. Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). However, the risk of conduction abnormalities with this agent is very low relative to other antidepressants.

Adverse Reactions:

>10%:

Central nervous system: Headache, drowsiness, insomnia, agitation, dizziness

Gastrointestinal: Xerostomia, nausea, constipation

Neuromuscular & skeletal: Weakness

1% to 10%:

Cardiovascular: Bradycardia, hypotension, peripheral edema, postural hypotension, vasodilation

Central nervous system: Chills, fever, incoordination, lightheadedness, confusion, memory impairment, abnormal dreams, decreased concentration, ataxia, psychomotor retardation, tremor

Dermatologic: Pruritus, rash

Endocrine & metabolic: Breast pain, impotence, libido decreased

Gastrointestinal: Gastroenteritis, vomiting, dyspepsia, diarrhea, increased appetite, thirst, taste perversion

Genitourinary: Urinary frequency, urinary retention

Hematologic: Hematocrit decreased

Neuromuscular & skeletal: Arthralgia, hypertonia, paresthesia, neck rigidity, tremor

Ocular: Blurred vision (9%), abnormal vision (7%), eye pain, visual field defect

Otic: Tinnitus

Respiratory: Bronchitis, cough, dyspnea, pharyngitis

Miscellaneous: Flu syndrome, infection

<1%: Abdomen enlarged, abnormal gait, accommodation abnormality, acne, allergic reaction, alopecia, ALT increased, amenorrhea, anemia, angina pectoris, anorgasmia, apathy, arthritis, AST increased, asthma, attention decreased, AV block, breast enlargement, bruising, bursitis, cellulitis, cerebrovascular accident, colitis, CHF, conjunctivitis, cystitis, deafness, depersonalization, derealization, diplopia, dry eyes, dry skin, dehydration, dysarthria, ear pain, eczema, ejaculation abnormal, epistaxis, eructation, esophagitis, euphoria, face edema, gastritis, gingivitis, glaucoma, gout, halitosis, hallucinations, hangover effect, hematuria, hemorrhage, hernia, hiccup, hostility, hyperacusis, hypercholesteremia, hyperesthesia, hyperkinesia, hypertension, hyperventilation, hypoglycemia, hypotonia, keratoconjunctivitis, kidney calculus, lactic dehydrogenase increased, laryngitis, leukopenia, libido increased, liver function tests abnormal, lymphadenopathy, maculopapular rash, malaise, menorrhagia, metrorrhagia, mouth ulceration, muscle stiffness, myoclonus, mydriasis, neuralgia, neuroleptic malignant syndrome, night blindness, nocturia, oliguria, oral moniliasis, pallor, paranoid reaction, pelvic pain, periodontal abscess, peptic ulcer, photophobia, photosensitivity, pneumonia, polyuria, ptosis, rectal hemorrhage, salivation increased, stomatitis, suicide attempt, suicidal thoughts, suicide, syncope, tachycardia, taste loss, tendonitis, contracture, tenosynovitis, thinking abnormal, twitching, ulcerative colitis, urticaria, uterine fibroids enlarged, uterine hemorrhage, urinary incontinence, urinary urgency, ventricular extrasystoles, vaginal hemorrhage, varicose vein, vertigo, vesiculobullous rash, voice alteration, weight loss, yawn

Postmarketing and/or case reports: Angioedema, convulsions, galactorrhea, grand mal seizure, gynocomastia, hepatic failure, hepatic necrosis, hepatitis, hyponatremia, priapism, prolactin increased, rhabdomyolysis (with lovastatin/simvastatin), serotonin syndrome, Stevens-Johnson syndrome, thrombocytopenia

Overdosage/Toxicology:

Drug Interactions:

Antiarrhythmics: Serum concentrations may be increased due to enzyme inhibition; monitor; includes amiodarone, lidocaine, propafenone, quinidine

Antipsychotics: Serum concentrations of some antipsychotics may be increased by nefazodone due to enzyme inhibition; includes clozapine, haloperidol, mesoridazine, pimozide, quetiapine, and risperidone

Benzodiazepines: Nefazodone inhibits the metabolism of triazolam (decrease dose by 75%) and alprazolam (decrease dose by 50%); triazolam is contraindicated per manufacturer

Buspirone: Concurrent use may result in serotonin syndrome; serum concentrations may be increased due to enzyme inhibition; these combinations are best avoided or limit buspirone to 2.5 mg/day

Calcium channel blockers: Serum concentrations may be increased due to enzyme inhibition; monitor for increased effect (hypotension)

Carbamazepine: Significantly reduces serum concentrations of nefazodone; coadministration is contraindicated

Cisapride: Nefazodone likely increases cisapride serum concentrations via CYP3A4 inhibition; this combination may lead to cardiac arrhythmias; concurrent use is contraindicated

Cyclosporine and tacrolimus: Serum levels and toxicity may be increased by nefazodone; monitor

CYP2D6 inhibitors: May increase the levels/effects of nefazodone. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of nefazodone. Example inducers include aminoglutethimide, carbamazepine (contraindicated), nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of nefazodone. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

CYP3A4 substrates: Nefazodone may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Digoxin: Serum levels may be increased by nefazodone (modest increases); monitor for digoxin toxicity or increased serum levels

Donepezil: Serum concentrations may be increased due to enzyme inhibition; monitor

HMG-CoA reductase inhibitors (statins) have been associated with myositis and rhabdomyolysis when used in combination with nefazodone; this has been associated most strongly with lovastatin and simvastatin. Concomitant use of lovastatin with nefazodone should be avoided.

Linezolid: Due to MAO inhibition (see note on MAO inhibitors), this combination should be avoided

MAO inhibitors: Concurrent use may lead to serotonin syndrome; avoid concurrent use or use within 14 days

Meperidine: Combined use theoretically may increase the risk of serotonin syndrome

Methadone: Serum concentrations may be increased due to enzyme inhibition; monitor

Oral contraceptives: Serum concentrations may be increased due to enzyme inhibition; monitor

Pimozide: Serum concentrations may be increased due to enzyme inhibition; may result in life-threatening arrhythmias (also see note on antipsychotics); avoid use

Protease inhibitors: Indinavir, ritonavir saquinavir; serum concentrations may be increased due to enzyme inhibition; monitor

Quinidine: Metabolism is likely to be inhibited by nefazodone; avoid concurrent use

Selegiline: Concurrent use with nefazodone may be associated with a risk of serotonin syndrome, particularly at higher dosages (>10 mg/day)

Serotonin agonists: Theoretically may increase the risk of serotonin syndrome; includes sumatriptan, naratriptan, rizatriptan, and zolmitriptan

Sibutramine: Serum concentrations may be increased by nefazodone; monitor

Sildenafil, vardenafil: Serum concentrations may be increased by nefazodone via inhibition of CYP3A4; use caution. Specific dosage adjustment guidelines have not been established. Recommendations for other strong CYP3A4 inhibitors include single sildenafil dose not to exceed 25 mg in a 48-hour period, a single tadalafil dose not to exceed 10 mg in a 72-hour period, or a single vardenafil dose not to exceed 2.5 mg in a 24-hour period.

SSRIs: Combined use of nefazodone with an SSRI may produce serotonin syndrome; in addition, nefazodone may increase serum concentrations of some SSRIs due to enzyme inhibition (fluoxetine and citalopram)

Tricyclic antidepressants: Serum concentrations of some tricyclic antidepressants (amitriptyline, clomipramine) may be increased; monitor for increased effect or toxicity

Venlafaxine: Combined use with nefazodone may increase the risk of serotonin syndrome

Vinca alkaloids (vincristine, and vinblastine): Serum concentrations may be increased due to enzyme inhibition; may result in increased toxicity

Zolpidem: Serum concentrations may be increased due to enzyme inhibition; monitor

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Nefazodone absorption may be delayed and bioavailability may be decreased if taken with food.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).

Stability:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Onset of action: Therapeutic: Up to 6 weeks

Metabolism: Hepatic to three active metabolites: Triazoledione, hydroxynefazodone, and m-chlorophenylpiperazine (mCPP)

Bioavailability: 20% (variable)

Half-life elimination: Parent drug: 2-4 hours; active metabolites persist longer

Time to peak, serum: 1 hour, prolonged in presence of food

Excretion: Primarily urine (as metabolites); feces

Dosage:

Children and Adolescents (unlabeled use): Depression: Target dose: 300-400 mg/day (mean: 3.4 mg/kg)

Adults: Depression: 200 mg/day, administered in 2 divided doses initially, with a range of 300-600 mg/day in 2 divided doses thereafter

Administration:

Monitoring Parameters:

Reference Range:

Patient Education:

Nursing Implications:

Additional Information:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Child/Adolescent Considerations:

Wilens TE, Spencer TJ, Biederman J, et al, "Case Study: Nefazodone for Juvenile Mood Disorders,"J Am Acad Child Adolesc Psychiatry, 1997, 36(4):481-5.

Dosage Forms:

Tablet, as hydrochloride: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg

Serzone® [DSC]: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg

International Brand Names: