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:

(VEN la faks een)

U.S. Brand Names:

Generic Available:

Canadian Brand Names:

Use:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

May worsen psychosis in some patients or 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. May increase the risks associated with electroconvulsive therapy. Use cautiously in patients with a history of seizures. 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 risks of cognitive or motor impairment, as well as the potential for anticholinergic effects are very low. May cause or exacerbate sexual dysfunction. May impair platelet aggregation, resulting in bleeding.

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. Venlafaxine is not FDA approved for use in children.

Abrupt discontinuation or dosage reduction after extended (6 weeks) therapy may lead to agitation, dysphoria, nervousness, anxiety, and other symptoms. When discontinuing therapy, dosage should be tapered gradually over at least a 2-week period. 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. Use caution in patients with increased intraocular pressure or at risk of acute narrow-angle glaucoma.

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.

Adverse Reactions:

10%:

Central nervous system: Headache (25%), somnolence (23%), dizziness (19%), insomnia (18%), nervousness (13%)

Gastrointestinal: Nausea (37%), xerostomia (22%), constipation (15%), anorexia (11%)

Genitourinary: Abnormal ejaculation/orgasm (12%)

Neuromuscular & skeletal: Weakness (12%)

Miscellaneous: Diaphoresis (12%)

1% to 10%:

Cardiovascular: Vasodilation (4%), hypertension (dose related; 3% in patients receiving <100 mg/day, up to 13% in patients receiving >300 mg/day), tachycardia (2%), chest pain (2%), postural hypotension (1%)

Central nervous system: Anxiety (6%), abnormal dreams (4%), yawning (3%), agitation (2%), confusion (2%), abnormal thinking (2%), depersonalization (1%), depression (1%)

Dermatologic: Rash (3%), pruritus (1%)

Endocrine & metabolic: Decreased libido

Gastrointestinal: Diarrhea (8%), vomiting (6%), dyspepsia (5%), flatulence (3%), taste perversion (2%), weight loss (1%)

Genitourinary: Impotence (6%), urinary frequency (3%), impaired urination (2%), orgasm disturbance (2%), urinary retention (1%)

Neuromuscular & skeletal: Tremor (5%), hypertonia (3%), paresthesia (3%), twitching (1%)

Ocular: Blurred vision (6%), mydriasis (2%)

Otic: Tinnitus (2%)

Miscellaneous: Infection (6%), chills (3%), trauma (2%)

<1%, postmarketing, and/or case reports (limited to important or life-threatening): Abnormal bleeding, abnormal vision, agranulocytosis, akathisia, anaphylaxis, aplastic anemia, arrhythmia, asthma, bronchitis, catatonia, delirium, dyskinesia, dyspnea, ecchymosis, ECG abnormalities, emotional lability, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, extrapyramidal symptoms, hallucinations, hemorrhage (including ophthalmic and gastrointestinal), hepatic failure, hepatic necrosis, hirsutism, hostility (up to 1% in children/adolescents), hyponatremia, increased transaminases/GGT, manic reaction (0.5%), metrorrhagia, pancreatitis, prostatitis, psychosis, rhabdomyolysis; rash (maculopapular, pustular, or vesiculobullous); seizure, serotonin syndrome, shock-like electrical sensations, SIADH, Stevens-Johnson syndrome, suicidal ideation (reported at a frequency up to 2% in children/adolescents with major depressive disorder), tardive dyskinesia, tinnitus, torticollis, vaginitis, ventricular tachycardia, vertigo. Height and weight may be adversely affected when used in children.

Overdosage/Toxicology:

Drug Interactions:

Buspirone: Concurrent use may result in serotonin syndrome; these combinations are best avoided

Clozapine: Addition of venlafaxine has been associated with case reports of increased clozapine serum concentrations and seizures.

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

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

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

Haloperidol: Serum levels may be increased during concurrent administration; AUC may be increased by as much as 70%

Indinavir: Serum levels may be reduced by venlafaxine (AUC reduced by 28%); clinical significance unknown

Lithium: Concurrent use may increase risk of serotonin syndrome.

MAO inhibitors: Serotonin syndrome may result when venlafaxine is used in combination or within 2 weeks of an MAO inhibitor; these combinations should be avoided

Meperidine: Concurrent use may increase risk of serotonin syndrome

Mirtazapine: Concurrent use may increase risk of serotonin syndrome

Nefazodone: Concurrent use may increase risk of serotonin syndrome; in addition, nefazodone may inhibit the metabolism of venlafaxine

Selegiline: Concurrent use may predispose to serotonin syndrome

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

Sibutramine: Concurrent use may increase risk of serotonin syndrome

SSRIs: Concurrent use may increase risk of serotonin syndrome

Trazodone: Concurrent use may increase risk of serotonin syndrome

Tricyclic antidepressants: Concurrent use may increase risk of serotonin syndrome

Warfarin: Case reports of increased INR when venlafaxine was added to therapy.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS effects).

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

Mechanism of Action:

Pharmacodynamics/Kinetics:

Absorption: Oral: 92% to 100%; food has no significant effect on the absorption of venlafaxine or formation of the active metabolite O-desmethylvenlafaxine (ODV)

Distribution: At steady state: Venlafaxine 7.5 ± 3.7 L/kg, ODV 5.7 ± 1.8 L/Kg

Protein binding: Bound to human plasma protein: Venlafaxine 27%, ODV 30%

Metabolism: Hepatic via CYP2D6 to active metabolite, O-desmethylvenlafaxine (ODV); other metabolites include N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine

Bioavailability: Absolute: ~45%

Half-life elimination: Venlafaxine: 3-7 hours; ODV: 9-13 hours; Steady-state, plasma: Venlafaxine/ODV: Within 3 days of multiple-dose therapy; prolonged with cirrhosis (Adults: Venlafaxine: ~30%, ODV: ~60%) and with dialysis (Adults: Venlafaxine: ~180%, ODV: ~142%)

Time to peak:

Immediate release: Venlafaxine: 2 hours, ODV: 3 hours

Extended release: Venlafaxine: 5.5 hours, ODV: 9 hours

Excretion: Urine (~87%, 5% as unchanged drug, 29% as unconjugated ODV, 26% as conjugated ODV, 27% as minor metabolites) within 48 hours

Clearance at steady state: Venlafaxine: 1.3 ± 0.6 L/hour/kg, ODV: 0.4 ± 0.2 L/hour/kg

Clearance decreased with:

Cirrhosis: Adults: Venlafaxine: ~50%, ODV: ~30%

Severe cirrhosis: Adults: Venlafaxine: ~90%

Renal impairment (Clcr 10-70 mL/minute): Adults: Venlafaxine: ~24%

Dialysis: Adults: Venlafaxine: ~57%, ODV: ~56%; due to large volume of distribution, a significant amount of drug is not likely to be removed.

Dosage:

Children and Adolescents:

ADHD (unlabeled use): Initial: 12.5 mg/day

Children <40 kg: Increase by 12.5 mg/week to maximum of 50 mg/day in 2 divided doses

Children 40 kg: Increase by 25 mg/week to maximum of 75 mg/day in 3 divided doses.

Mean dose: 60 mg or 1.4 mg/kg administered in 2-3 divided doses

Autism (unlabeled use): Initial: 12.5 mg/day; adjust to 6.25-50 mg/day

Adults:

Depression:

Immediate-release tablets: 75 mg/day, administered in 2 or 3 divided doses, taken with food; dose may be increased in 75 mg/day increments at intervals of at least 4 days, up to 225-375 mg/day

Extended-release capsules: 75 mg once daily taken with food; for some new patients, it may be desirable to start at 37.5 mg/day for 4-7 days before increasing to 75 mg once daily; dose may be increased by up to 75 mg/day increments every 4 days as tolerated, up to a maximum of 225 mg/day

GAD, social anxiety disorder: Extended-release capsules: 75 mg once daily taken with food; for some new patients, it may be desirable to start at 37.5 mg/day for 4-7 days before increasing to 75 mg once daily; dose may be increased by up to 75 mg/day increments every 4 days as tolerated, up to a maximum of 225 mg/day

Note: When discontinuing this medication after more than 1 week of treatment, it is generally recommended that the dose be tapered. If venlafaxine is used for 6 weeks or longer, the dose should be tapered over 2 weeks when discontinuing its use.

Dosing adjustment in renal impairment: Clcr 10-70 mL/minute: Decrease dose by 25%; decrease total daily dose by 50% if dialysis patients; dialysis patients should receive dosing after completion of dialysis

Dosing adjustment in moderate hepatic impairment: Reduce total daily dosage by 50%

Administration:

Extended release capsule: Swallow capsule whole; do not crush or chew. Alternatively, contents may be sprinkled on a spoonful of applesauce and swallowed immediately without chewing; followed with a glass of water to ensure complete swallowing of the pellets.

Monitoring Parameters:

Reference Range:

Dietary Considerations:

Patient Education:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Child/Adolescent Considerations:

Hollander E, Kaplan A, Cartwright C, et al, "Venlafaxine in Children, Adolescents, and Young Adults With Autism Spectrum Disorders: An Open Retrospective Clinical Report,"J Child Neurol, 2000, 15(2):132-5.

Mandoki MW, Tapia MR, Tapia MA, et al, "Venlafaxine in the Treatment of Children and Adolescents With Major Depression,"Psychopharmacol Bull, 1997, 33(1):149-54.

Olvera RL, Pliszka SR, Luh J, et al, "An Open Trial of Venlafaxine in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents,"J Child Adolesc Psychopharmacol, 1996, 6(4):241-50.

Weller EB, Weller RA, and Davis HP, "Use of Venlafaxine in Children and Adolescents: A Review of Current Literature,"Depression and Anxiety, 2000, 12(Suppl 1): 85-9.

Dosage Forms:

Capsule, extended release, as hydrochloride (Effexor® XR): 37.5 mg, 75 mg, 150 mg

Tablet, as hydrochloride (Effexor®): 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg

International Brand Names: