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.

Key adverse effects:

Suicidal risk: 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.

Suicidal risk and children: 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. Duloxetine is not FDA approved for use in children.

Urinary hesitancy: May cause increased urinary resistance; advise patient to report symptoms of urinary hesitation/difficulty.

CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.

Concurrent disease:

Hepatic impairment and/or ethanol use: Avoid use in patients with hepatic impairment. May cause hepatotoxicity; avoid use in patients with substantial alcohol intake.

Narrow angle glaucoma: Use with caution in patients with controlled narrow angle glaucoma.

Sexual dysfunction: May cause or exacerbate sexual dysfunction. Use caution with renal impairment or with concomitant CNS depressants. Safety and efficacy in pediatric patients have not been established.

Bipolar disorder: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients should be screened for bipolar disorder, since using antidepressants alone may induce manic episodes with this condition.

Seizure disorders: Use caution with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism.

Concurrent drug therapy:

MAO inhibitors: Potential for severe reaction when used with MAO inhibitors; serotonin syndrome (hyperthermia, muscular rigidity, mental status changes/agitation, autonomic instability) may occur.

Agents which lower seizure threshold: Concurrent therapy with other drugs which lower the seizure threshold.

Special notes:

Withdrawal syndrome: Upon discontinuation of duloxetine therapy, gradually taper dose. If intolerable symptoms occur following a decrease in dosage or upon discontinuation of therapy, then resuming the previous dose with a more gradual taper should be considered.

Counseling: 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 not to abruptly discontinue this medication, but notify their healthcare provider if any of these symptoms or worsening depression occur.

>10%:

Central nervous system: Insomnia (8% to 11%%), somnolence (7% to 12%), dizziness (9% to 17%), headache (up to 15%)

Gastrointestinal: Nausea (20% to 22%), xerostomia (5% to 7%), constipation (5% to 11%), appetite decreased (8% to 11%)

1% to 10%:

Central nervous system: Fatigue (8% to 10%), anxiety (3%), fever (up to 1%), irritability, lethargy, nervousness, restlessness, sleep disorder, nightmares

Dermatologic: Pruritus, rash

Endocrine & metabolic: Libido decreased (3% to 6%), orgasm abnormality (3% to 4%), hot flushes (2%), hypoglycemia (1%), hypoesthesia (1%)

Gastrointestinal: Diarrhea (7% to 11%), appetite decreased (5% to 8%), vomiting (5%), dyspepsia (4%), loose stools (3%), anorexia (3%), weight loss (2%), gastritis (1%), weight gain (1%)

Genitourinary: Erectile dysfunction (1%), ejaculation delayed (3%), ejaculatory dysfunction (3%), urinary symptoms (hesitancy, obstructive symptoms; 1%), dysuria

Hepatic: Transaminases increased: Occasionally associated with hyperbilirubinemia and/or increased alkaline phosphatase (1%)

Neuromuscular & skeletal: Myalgia (4%), muscle cramp (4%), tremor (3% to 5%), rigors (1%)

Ocular: Blurred vision (4%)

Respiratory: Cough (up to 3%), pharyngolaryngeal pain (1%)

Miscellaneous: Diaphoresis increased (6%), night sweats

<1%: Abdominal pain, acne, alopecia, anemia, aphthous stomatitis, ataxia, atrial fibrillation, bundle branch block, CHF, colitis, diplopia, dysarthria, dysphagia, ecchymosis, edema (peripheral), erythema, esophageal stenosis, facial edema, flu-like syndrome, gastric emptying impaired, gastric ulcer, gingivitis, glaucoma, hepatic steatosis, hypercholesterolemia, hyperlipidemia, hypertensive crisis, hypertriglyceridemia, irritable bowel syndrome, leukopenia, lymphadenopathy, macular degeneration, mania, melena, MI, muscle weakness, oropharyngeal edema, phlebitis, photosensitivity, seizure, suicide, thrombocytopenia, urinary retention, withdrawal syndrome (including headache, dizziness, nightmares, irritability, paresthesia and/or vomiting)

Buspirone: Concurrent use of duloxetine with buspirone may cause serotonin syndrome; avoid concurrent use.

CYP1A2 inducers: May decrease the levels/effects of duloxetine. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of duloxetine. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

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

Desipramine: Duloxetine may increase desipramine levels.

Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with agents which inhibit MAO (serotonin syndrome); this combination should be avoided.

MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with MAO inhibitors (serotonin syndrome); this combination is contraindicated. Wait 5 days after discontinuation of duloxetine before initiating therapy with a MAO inhibitor.

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

Moclobemide: Concurrent use of duloxetine with moclobemide may cause serotonin syndrome; avoid concurrent use.

Nefazodone: Concurrent use of duloxetine with nefazodone may cause serotonin syndrome.

Selegiline: Concurrent use with SSRIs has been reported to cause serotonin syndrome; as an MAO type B inhibitor, the risk of serotonin syndrome may be less than with nonselective MAO inhibitors, and reports indicate that this combination has been well tolerated in Parkinson's patients.

SSRIs: Concurrent use with serotonin reuptake inhibitors may increase the risk of serotonin syndrome.

Sibutramine: May increase the risk of serotonin syndrome with SNRIs.

Sumatriptan (and other serotonin agonists): Concurrent use may result in toxicity; weakness, hyper-reflexia, and incoordination have been observed with sumatriptan and SSRIs (and/or SNRIs). In addition, concurrent use may theoretically increase the risk of serotonin syndrome; includes almotriptan, sumatriptan, naratriptan, rizatriptan, and zolmitriptan.

Thioridazine: Duloxetine may increase serum concentrations of thioridazine, which has been associated with the development of malignant ventricular arrhythmias; use caution

Tramadol: Concurrent use of duloxetine with tramadol may cause serotonin syndrome; avoid concurrent use.

Trazodone: Concurrent use of duloxetine with trazodone may cause serotonin syndrome.

Tricyclic antidepressants: Serum levels/effects may be increased by duloxetine; use caution

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

Ethanol: Avoid ethanol (may increase CNS depression and/or hepatotoxic potential of duloxetine).

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava, and gotu kola (may increase CNS depression).

Absorption: Well absorbed, 2-hour delay in absorption after ingestion

Distribution: 1640 L

Protein binding: >90%

Metabolism: Hepatic, via CYP1A2 and CYP2D6; forms multiple metabolites (inactive)

Half-life elimination: 12 hours (range 8-17 hours)

Time to peak: 6 hours

Excretion: As metabolites; urine (70%), feces (20%)

Adults:

Treatment of major depressive disorder: Initial: 40-60 mg/day; dose may be divided (ie, 20 or 30 mg twice daily) or given as a single daily dose of 60 mg; maximum dose: 60 mg/day

Management of diabetic neuropathy: 60 mg once daily; lower initial doses may be considered in patients where tolerability is a concern and/or renal impairment is present

Management of chronic pain syndromes (unlabeled use): 60 mg once daily

Management of fibromyalgia (unlabeled use): 60 mg twice daily

Management of stress incontinence (unlabeled use): 40 mg twice daily

Elderly:

Treatment of major depressive disorder: Initial dose: 20 mg 1-2 times/day; increase to 40-60 mg/day as a single daily dose or in divided doses

Other indications: Refer to Adults dosing

Dosage adjustment in renal impairment: Not recommended for use in Clcr<30 mL/minute or ESRD; in mild-moderate impairment, lower initial doses may be considered with titration guided by response and tolerability

Dosage adjustment in hepatic impairment: Not recommended for use in hepatic impairment

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