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:

(pa ROKS e teen)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Paxil CR™: Treatment of depression; panic disorder; premenstrual dysphoric disorder (PMDD); social anxiety disorder (social phobia)

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

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. Paroxetine 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 hepatic or dysfunction and in elderly patients. May cause hyponatremia/SIADH. Use with caution in patients at risk of bleeding or receiving anticoagulant therapy - may cause impairment in platelet aggregation. Use with caution in patients with renal insufficiency or other concurrent illness (due to limited experience). May cause or exacerbate sexual dysfunction.

Upon discontinuation of paroxetine therapy, gradually taper dose and monitor for discontinuation symptoms (eg, dizziness, dysphoric mood, irritability, agitation, confusion, paresthesias). 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. 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.

Adverse Reactions:

>10%:

Central nervous system: Headache, somnolence, dizziness, insomnia

Gastrointestinal: Nausea, xerostomia, constipation, diarrhea

Genitourinary: Ejaculatory disturbances

Neuromuscular & skeletal: Weakness

Miscellaneous: Diaphoresis

1% to 10%:

Cardiovascular: Palpitations, vasodilation, postural hypotension

Central nervous system: Nervousness, anxiety, yawning, abnormal dreams, agitation

Dermatologic: Rash

Endocrine & metabolic: Libido decreased, delayed ejaculation

Gastrointestinal: Anorexia, flatulence, vomiting, dyspepsia, taste perversion, weight gain

Genitourinary: Urinary frequency, impotence

Neuromuscular & skeletal: Tremor, paresthesia, myopathy, myalgia

Ocular: Blurred vision

Respiratory: Rhinitis

<1%: Acne, akinesia, alopecia, amenorrhea, anaphylactoid reaction, anemia, angioedema, arthritis, asthma, atrial fibrillation, bradycardia, bruxism, bundle branch block, colitis, dysphasia, EPS, ear pain, erythema multiforme, exfoliative dermatitis, eye pain, hypotension, leukopenia, mania, migraine, myasthenia, thirst

Postmarketing and/or case reports: Acute renal failure, allergic alveolitis, anaphylaxis, aplastic anemia, agranulocytosis, bone marrow aplasia, eclampsia, gastrointestinal bleeding, Guillain-Barré syndrome, hemolytic anemia, hepatic necrosis, laryngismus, neuroleptic malignant syndrome, optic neuritis, pancreatitis, pancytopenia, porphyria, priapism, pulmonary hypertension, seizure (including status epilepticus), serotonin syndrome, SIADH, thrombocytopenia, torsade de pointes, toxic epidermal necrolysis, ventricular fibrillation, ventricular tachycardia, withdrawal reactions (dizziness; sensory disturbances - eg, paresthesia such as electric shock sensations; agitation; anxiety; nausea; diaphoresis - particularly following abrupt withdrawal)

Overdosage/Toxicology:

Drug Interactions:

Amphetamines: SSRIs may increase the sensitivity to amphetamines, and amphetamines may increase the risk of serotonin syndrome

Aspirin (and other antiplatelet drugs): Concomitant use of paroxetine and NSAIDs, aspirin, or other drugs affecting coagulation has been associated with an increased risk of bleeding; monitor.

Buspirone: Combined use with SSRIs may cause serotonin syndrome

Carvedilol: Serum concentrations may be increased; monitor carefully for increased carvedilol effect (hypotension and bradycardia)

Cimetidine: Cimetidine may reduce the first-pass metabolism of paroxetine resulting in elevated paroxetine serum concentrations; consider an alternative H2 antagonist

Clozapine: May increase serum levels of clozapine; monitor for increased effect/toxicity

CYP2B6 substrates: Paroxetine may increase the levels/effects of CYP2B6 substrates. Example substrates include bupropion, promethazine, propofol, selegiline, and sertraline.

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

CYP2D6 substrates: Paroxetine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Paroxetine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

Cyproheptadine: May inhibit the effects of serotonin reuptake inhibitors; monitor for altered antidepressant response; cyproheptadine acts as a serotonin agonist

Dextromethorphan: Metabolism of dextromethorphan may be inhibited; visual hallucinations occurred; monitor

Haloperidol: Metabolism may be inhibited and cause extrapyramidal symptoms (EPS); monitor patients for EPS if combination is utilized

HMG-CoA reductase inhibitors: Metabolism may be inhibited by SSRIs; particularly lovastatin and simvastatin resulting in myositis and rhabdomyolysis; paroxetine appears to have weak interaction with CYP3A4, and therefore, appears to have a low risk of this interaction

Lithium: Patients receiving SSRIs and lithium have developed neurotoxicity; if combination is used; monitor for neurotoxicity

Loop diuretics: SSRIs may cause hyponatremia; additive hyponatremic effects may be seen with combined use of a loop diuretic (bumetanide, furosemide, torsemide); monitor for hyponatremia

MAO inhibitors: SSRIs should not be used with nonselective MAO inhibitors (isocarboxazid, phenelzine); fatal reactions have been reported; this combination should be avoided

Meperidine: Combined use may cause serotonin syndrome; monitor

Mesoridazine: Paroxetine may inhibit the metabolism of mesoridazine, resulting in increased plasma levels and increasing the risk of QTc interval prolongation. Concurrent use is contraindicated.

Nefazodone and trazodone: May increase the risk of serotonin syndrome with SSRIs; monitor

NSAIDs: Concomitant use of paroxetine and NSAIDs, aspirin, or other drugs affecting coagulation has been associated with an increased risk of bleeding; monitor.

Phenytoin: Metabolism of phenytoin may be inhibited, resulting in phenytoin toxicity; monitor for toxicity (ataxia, confusion, dizziness, nystagmus, involuntary muscle movement).

Procyclidine: Paroxetine increases AUC of procyclidine by 35%; this may result in increased anticholinergic effects; procyclidine dose reduction may be necessary.

Risperidone: Paroxetine, a potent CYP2D6 inhibitor, inhibits the metabolism of risperidone (CYP2D6 substrate) resulting in elevated plasma risperidone levels. The clinical implications are unclear, but clinicians should monitor for potential extrapyramidal symptoms (EPS).

Ritonavir: Combined use of paroxetine with ritonavir may cause serotonin syndrome; monitor

Selegiline: SSRIs have been reported to cause mania or hypertension when combined with selegiline; this combination is best avoided; concurrent use with SSRIs has also 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

Serotonergic uptake inhibitors: Combined use with other drugs which inhibit the reuptake may cause serotonin syndrome

Sibutramine: May increase the risk of serotonin syndrome with SSRIs; avoid coadministration

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

Sympathomimetics: May increase the risk of serotonin syndrome with SSRIs

Theophylline: Paroxetine may elevate serum levels of theophylline; monitor

Thioridazine: Paroxetine may inhibit the metabolism of thioridazine, resulting in increased plasma levels and increasing the risk of QTc interval prolongation. Concurrent use is contraindicated.

Tramadol: Combined use may cause serotonin syndrome; monitor

Tricyclic antidepressants: The metabolism of tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline) may be inhibited by SSRIs resulting is elevated serum levels; if combination is warranted, a low dose of TCA (10-25 mg/day) should be utilized

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

Warfarin: May alter the hypoprothrombinemic response to warfarin; monitor INR

Zolpidem: At least one case of acute delirium in association with combined therapy has been reported

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol.

Food: Peak concentration is increased, but bioavailability is not significantly altered by food.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava.

Stability:

Suspension: Store at 25°C (77°F)

Tablet: Store at 15°C to 30°C (59°F to 86°F)

Mechanism of Action:

Pharmacodynamics/Kinetics:

Absorption: Completely absorbed following oral administration

Distribution: Vd: 8.7 L/kg (3-28 L/kg)

Protein binding: 93% to 95%

Metabolism: Extensively hepatic via CYP enzymes via oxidation and methylation; nonlinear pharmacokinetics may be seen with higher doses and longer duration of therapy. Saturation of CYP2D6 appears to account for the nonlinearity. Cmin concentrations 70% to 80% greater in the elderly compared to nonelderly patients; clearance is also decreased.

Half-life elimination: 21 hours (3-65 hours)

Time to peak, serum: Immediate release: 5.2 hours; controlled release: 6-10 hours

Excretion: As metabolites in urine and bile; 2% as unchanged drug in urine

Dosage:

Children:

Depression (unlabeled use; not recommended by FDA): Initial: 10 mg/day and adjusted upward on an individual basis to 20 mg/day

OCD (unlabeled use): Initial: 10 mg/day and titrate up as necessary to 60 mg/day

Self-injurious behavior (unlabeled use): 20 mg/day

Social phobia (unlabeled use): 2.5-15 mg/day

Adults:

Depression:

Paxil®, Pexeva™: Initial: 20 mg once daily, preferably in the morning; increase if needed by 10 mg/day increments at intervals of at least 1 week; maximum dose: 50 mg/day

Paxil CR™: Initial: 25 mg once daily; increase if needed by 12.5 mg/day increments at intervals of at least 1 week; maximum dose: 62.5 mg/day

GAD (Paxil®): Initial: 20 mg once daily, preferably in the morning; doses of 20-50 mg/day were used in clinical trials, however, no greater benefit was seen with doses >20 mg. If dose is increased, adjust in increments of 10 mg/day at 1-week intervals.

OCD (Paxil®, Pexeva™): Initial: 20 mg once daily, preferably in the morning; increase if needed by 10 mg/day increments at intervals of at least 1 week; recommended dose: 40 mg/day; range: 20-60 mg/day; maximum dose: 60 mg/day

Panic disorder:

Paxil®, Pexeva™: Initial: 10 mg once daily, preferably in the morning; increase if needed by 10 mg/day increments at intervals of at least 1 week; recommended dose: 40 mg/day; range: 10-60 mg/day; maximum dose: 60 mg/day

Paxil CR™: Initial: 12.5 mg once daily; increase if needed by 12.5 mg/day at intervals of at least 1 week; maximum dose: 75 mg/day

PMDD (Paxil CR™): Initial: 12.5 mg once daily in the morning; may be increased to 25 mg/day; dosing changes should occur at intervals of at least 1 week. May be given daily throughout the menstrual cycle or limited to the luteal phase.

PTSD (Paxil®): Initial: 20 mg once daily, preferably in the morning; increase if needed by 10 mg/day increments at intervals of at least 1 week; range: 20-50 mg

Social anxiety disorder:

Paxil®: Initial: 20 mg once daily, preferably in the morning; recommended dose: 20 mg/day; range: 20-60 mg/day; doses >20 mg may not have additional benefit

Paxil CR™: Initial: 12.5 mg once daily, preferably in the morning; may be increased by 12.5 mg/day at intervals of at least 1 week; maximum dose: 37.5 mg/day

Vasomotor symptoms of menopause (unlabeled use, Paxil CR™): 12.5-25 mg/day

Elderly:

Paxil®, Pexeva™: Initial: 10 mg/day; increase if needed by 10 mg/day increments at intervals of at least 1 week; maximum dose: 40 mg/day

Paxil CR™; Initial: 12.5 mg/day; increase if needed by 12.5 mg/day increments at intervals of at least 1 week; maximum dose: 50 mg/day

Note: Upon discontinuation of paroxetine therapy, gradually taper dose:

Paxil®: 10 mg/day at weekly intervals; when 20 mg/day dose is reached, continue for 1 week before treatment is discontinued. Some patients may need to be titrated to 10 mg/day for 1 week before discontinuation.

Paxil CR™: Patients receiving 37.5 mg/day in clinical trials had their dose decreased by 12.5 mg/day to a dose of 25 mg/day and remained at a dose of 25 mg/day for 1 week before treatment was discontinued.

Dosage adjustment in severe renal/hepatic impairment: Adults:

Clcr<30 mL/minute: Mean plasma concentration is ~4 times that seen in normal function.

Clcr 30-60 mL/minute and hepatic dysfunction: Plasma concentration is 2 times that seen in normal function.

Paxil®, Pexeva™: Initial: 10 mg/day; increase if needed by 10 mg/day increments at intervals of at least 1 week; maximum dose: 40 mg/day

Paxil CR™: Initial: 12.5 mg/day; increase if needed by 12.5 mg/day increments at intervals of at least 1 week; maximum dose: 50 mg/day

Administration:

Monitoring Parameters:

Dietary Considerations:

Patient Education:

Additional Information:

Anesthesia and Critical Care Concerns/Other Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Child/Adolescent Considerations:

Depression: Paroxetine was shown to be effective and generally well tolerated in a recent randomized, double-blind, placebo-controlled parallel-design study; 275 adolescents (12-18 years of age) with major depression were randomized to receive paroxetine, imipramine, or placebo; 93 patients (mean age: 14.8 ± 1.6 years) received paroxetine at initial doses of 20 mg/day given in the morning; doses were increased if needed at week 5 to 30 mg/day (given in divided doses) and at weeks 6-8 to 40 mg/day (given in divided doses); 48% of patients remained at the initial starting dose of 20 mg/day; mean optimal daily dose: 28 ± 8.54 mg (Keller, 2001). Paroxetine was shown to be effective and well tolerated in an open label clinical trial in 45 children <14 years of age (mean: 10.7 ± 2 years) with major depression (Rey-Sanchoz, 1997). Doses were initiated at 10 mg/day and adjusted upward on an individual basis with a mean dose of 16.2 mg/day used for an average of 8.4 months. Further studies are needed.

Obsessive-compulsive disorder (OCD): Twenty OCD outpatients 8-17 years of age were treated with daily doses ranging from 10-60 mg/day for 12 weeks (Rosenberg, 1999).

Self-injurious behavior: A 15-year old autistic male with self-injurious behavior was successfully treated with 20 mg/day (Snead, 1994). Further studies are needed.

Social phobia: A small case series reported the effective use of paroxetine in 5 pediatric patients with social phobia [2 children (7 and 11 years of age) and 3 adolescents (16, 17, and 18 years of age)]; comorbid diagnoses (obsessive compulsive disorder and/or dysthymia) existed in 3 patients; doses were adjusted on an individual basis; the 7-year old was started on 2.5 mg/day and increased to 5 mg/day after 4 weeks; the 11-year old was started on 5 mg/day and the dose was titrated upwards by 5 mg/day increments every 3-4 weeks to 15 mg/day; adolescents were started on 20 mg/day (Mancini, 1999); further studies are needed.

A recent report described the SSRI discontinuation syndrome in 6 children; the syndrome was similar to that reported in adults (Diler, 2002).

Diler RS and Avci A, "Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome in Children: Six Case Reports,"Current Therapeutic Research, 2002, 63(3):188-97.

Keller MB, Ryan ND, Strober M, et al, "Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial,"J Am Acad Child Adolesc Psychiatry, 2001, 40(7):762-72.

Mancini C, Van Ameringen M, Oakman JM, et al, "Serotonergic Agents in the Treatment of Social Phobia in Children and Adolescents: A Case Series,"Depress Anxiety, 1999, 10(1):33-9.

Rey-Sanchez F and Guitierrez-Cassares JR, "Paroxetine in Children With Major Depressive Disorder: An Open Trial,"J Am Acad Child Adolesc Psychiatry, 1997, 36(10):1443-7.

Rosenberg DR, Stewart CM, Fitzgerald KD, et al, "Paroxetine Open-Label Treatment of Pediatric Outpatients With Obsessive-Compulsive Disorder,"J Am Acad Child Adolesc Psychiatry, 1999, 38(9):1180-5.

Snead RW, Boon F, and Presberg J, "Paroxetine for Self-Injurious Behavior,"J Am Acad Child Adolesc Psychiatry, 1994, 33(6):909-10.

Dosage Forms:

Suspension, oral, as hydrochloride (Paxil®): 10 mg/5 mL (250 mL) [orange flavor]

Tablet, as hydrochloride (Paxil®): 10 mg, 20 mg, 30 mg, 40 mg

Tablet, as mesylate (Pexeva™): 10 mg, 20 mg, 30 mg, 40 mg

Tablet, controlled release, as hydrochloride (Paxil CR™): 12.5 mg, 25 mg, 37.5 mg

International Brand Names: