[Posted 05/02/2007] FDA notified healthcare professionals that the Agency proposed that makers of all antidepressant medications update the existing black box warning on the prescribing information for their products to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment. The proposed labeling changes also state that scientific data did not show this increased risk in adults older than 24 years of age and that adults 65 years of age and older taking antidepressants have a decreased risk of suicidality. The proposed updates apply to the entire category of antidepressants. Individuals currently taking prescribed antidepressant medications should not stop taking them and should notify their healthcare professional if they have concerns. Manufacturers of antidepressant medications will have 30 days to submit their revised product labeling and revised Medication Guides to FDA for review. See the FDA press release for the list of products affected by the proposed antidepressant product labeling changes. For more information visit the FDA website at: [Web], [Web] and [Web].
[Posted 07/19/2006] FDA notified healthcare professionals and consumers of important information from two recent studies that should be considered when making treatment decisions in pregnant women who take antidepressants. The studies included pregnant women who were treated with selective serotonin reuptake inhibitors (SSRIs), or in a few cases, other antidepressant medications.
One study illustrated the potential risk of relapsed depression after stopping antidepressant medication during pregnancy. In this study, women who stopped their medicine were five times more likely to have a relapse of depression during their pregnancy than were women who continued to take their antidepressant medicine while pregnant.
The second study suggests there may be additional, though rare, risks of taking SSRI medications during pregnancy. This study focused on newborn babies with persistent pulmonary hypertension (PPHN), which is a serious and life-threatening lung condition that occurs soon after birth. Babies born with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. In this study, PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of pregnancy compared to babies whose mothers did not take an antidepressant. The study was too small to compare the risk of one drug compared to another. The finding of PPHN in babies of mothers who used a SSRI antidepressant in the second half of pregnancy adds to concerns from previous reports that infants of mothers taking SSRIs late in pregnancy may experience difficulties such as irritability, difficulty feeding and in very rare cases, difficulty breathing.
Additionally, the labeling for paroxetine (Paxil) was recently changed to add information about findings in an epidemiologic study that suggests that exposure to the drug in the first trimester of pregnancy may be associated with an increased risk of cardiac birth defects.
Women who are pregnant or thinking about becoming pregnant should not stop any antidepressant medication without first consulting their physician. The FDA is seeking additional information about the possible risk of PPHN in newborn babies of mothers who took SSRI antidepressants in pregnancy. FDA has asked the sponsors of all SSRIs to change prescribing information to describe the potential risk for PPHN. For more information visit the FDA website at: [Web] and [Web].
[Posted 07/19/2006] FDA notified healthcare professionals and consumers of new safety information regarding taking medications used to treat migraine headaches (triptans) together with certain types of antidepressant and mood disorder medications (selective serotonin reuptake inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs). A life-threatening condition called serotonin syndrome may occur when triptans are used together with a SSRI or a SNRI.
Serotonin syndrome occurs when the body has too much of a chemical found in the nervous system (serotonin). Each of the above medications (triptans, SSRIs, and SNRIs), cause an increase in serotonin levels. Symptoms of serotonin syndrome may include restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea.
Healthcare professionals prescribing a triptan, SSRI or SNRI should keep in mind that triptans are often used intermittently and either the triptan, SSRI or SNRI may be prescribed by a different physician; weigh the potential risk of serotonin syndrome with the expected benefit of using the above combination; discuss the possibility of serotonin syndrome with patients if a triptan and an SSRI or SNRI will be used together; and follow patients closely during treatment if a triptan and an SSRI or SNRI are used together.
Patients taking a triptan along with an SSRI or SNRI should talk to their doctor before stopping their medication and should immediately seek medical attention if they experience any of the above symptoms. FDA requested that all manufacturers of triptans, SSRIs and SNRIs update their prescribing information to warn of the possibility of serotonin syndrome when these medications are taken together. For more information visit the FDA website at: [Web] and [Web].
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Major Depressive Disorder
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Management of PTSD (alone or in combination with psychotherapy).
Premenstrual Dysphoric Disorder (PMDD)
Management of PMDD.
Premature Ejaculation
Has been used for the management of premature ejaculation†.
Diabetic Neuropathy
Has been used for the management of diabetic neuropathy†.
Chronic Headache
Has been used for the management of chronic headache†.
Dosage and Administration
General
Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of paroxetine, and vice versa.
Monitor for possible worsening of depression or suicidality, especially at the beginning of therapy or during periods of dosage adjustments. (See Worsening of Depression and Suicidality Risk under Cautions.)
Sustained therapy may be required; monitor periodically for need for continued therapy.
Avoid abrupt discontinuance of therapy; to avoid withdrawal reactions, taper dosage gradually over a period of several weeks. (See Withdrawal of Therapy under Cautions.)
Consider cautiously tapering dosage during third trimester of pregnancy prior to delivery. (See Pregnancy under Cautions.)
Administration
Oral Administration
Administer orally once daily (in the morning) without regard to meals; however, administration with food may minimize adverse GI effects.
Shake oral suspension well just prior to administration.
Swallow extended-release tablets whole; do not chew or crush.
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Oral
Conventional tablets or suspension: Initially, 20 mg once daily. If no improvement, dosage may be increased in 10-mg increments at weekly intervals.
Extended-release tablets: Initially, 25 mg once daily. If no improvement, dosage may be increased in 12.5-mg increments at weekly intervals.
Optimum duration not established; may require several months of therapy or longer. Antidepressant efficacy demonstrated for up to 1 year at mean dosage of 30 mg daily as conventional tablets or suspension, which corresponds to a 37.5 mg daily dosage as extended-release tablets.
Obsessive-Compulsive Disorder
Oral
Conventional tablets or suspension: Initially, 20 mg once daily. If no improvement, dosage may be increased in 10-mg increments at weekly intervals, to 40 mg daily.
Optimum duration not established; efficacy has been demonstrated in a 6-month relapse prevention trial. Obsessive-compulsive disorder is chronic and requires several months or longer of sustained therapy. May continue therapy in responding patients, but use lowest effective dosage and periodically reassess need for continued therapy.
Panic Disorder
Oral
Conventional tablets or suspension: Initially, 10 mg once daily. If no improvement, dosage may be increased in 10-mg increments at weekly intervals, to 40 mg daily.
Extended-release tablets: Initially, 12.5 mg once daily. If no improvement, dosage may be increased in 12.5-mg increments at weekly intervals.
Optimum duration not established; efficacy demonstrated in a 3-month relapse prevention trial. May continue therapy in responding patients, but use lowest effective dosage and periodically reassess need for continued therapy.
Social Phobia
Oral
Conventional tablets or suspension: 20 mg once daily; no additional clinical benefit was observed with higher dosages.
Extended-release tablets: Initially, 12.5 mg once daily. If dosage is increased, use increments of 12.5-mg increments at weekly intervals.
Long-term efficacy (>12 weeks) not demonstrated; may consider continuation in patient who responds, but use lowest effective dosage and periodically reassess need for continued therapy.
Anxiety Disorders
Oral
Conventional tablets or suspension: Initially, 20 mg daily; no additional clinical benefit was observed with higher dosages. If needed, dosage may be increased in 10-mg increments at weekly intervals.
Optimum duration not established; efficacy has been demonstrated in a 24-week relapse prevention trial. Generalized anxiety disorder is chronic. May continue therapy in responding patients. If used for extended periods, adjust dosage so that patients are maintained on lowest effective dosage and periodically reassess need for continued therapy.
Posttraumatic Stress Disorder
Oral
Conventional tablets or suspension: 20 mg daily; insufficient evidence to suggest greater clinical benefit with higher dosages. If needed, dosage may be increased in 10-mg increments at weekly intervals.
Consider alternative therapy if patient fails to achieve ≥25% reduction in PTSD symptoms at week 8. If >75% reduction in PTSD symptoms and response maintained for ≥3 months, may consider up to 24 months of drug therapy. If used for extended periods, adjust dosage so that patients are maintained on lowest effective dosage and periodically reassess need for continued therapy.
Premenstrual Dysphoric Disorder
Oral
Conventional tablets or suspension†: 5–30 mg daily.
Extended-release tablets: Initially, 12.5 mg once daily; may be administered daily throughout menstrual cycle or only during luteal phase. Dosage may be increased in intervals of ≥1 week. Dosages of 12.5–25 mg were effective in clinical studies.
Premature Ejaculation
Oral
Conventional tablets or suspension: 10–40 mg once daily. Alternatively, 20 mg taken 3–4 hours before planned intercourse on an “as needed” basis.†
Diabetic Neuropathy
Oral
Conventional tablets or suspension: 40 mg daily.†
Chronic Headache
Oral
Conventional tablets or suspension: 10–50 mg daily for 3–9 months.†
Prescribing Limits
Adults
Major Depressive Disorder
Oral
Conventional tablets or suspension: Maximum 50 mg daily.
Extended-release tablets: 62.5 mg daily.
Obsessive-Compulsive Disorder
Oral
Conventional tablets or suspension: Maximum 60 mg daily.
Panic Disorder
Oral
Conventional tablets or suspension: Maximum 60 mg daily.
Extended-release tablets: 75 mg daily.
Social Phobia
Oral
Extended-release tablets: 37.5 mg daily.
Special Populations
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Hepatic Impairment
Oral
In patients with severe hepatic impairment, an initial dosage of 10 mg daily (as conventional tablets or suspension) or 12.5 mg daily (as extended-release tablets). If no clinical improvement is apparent, dosage may be titrated with caution up to a maximum of 40 mg daily (for conventional tablets or suspension) or 50 mg (for extended-release tablets).
Renal Impairment
Oral
In patients with severe renal impairment, an initial dosage of 10 mg daily (as conventional tablets or suspension) or 12.5 mg daily (as extended-release tablets). If no clinical improvement is apparent, dosage may be titrated with caution up to a maximum of 40 mg daily (for conventional tablets or suspension) or 50 mg (for extended-release tablets).
Geriatric or Debilitated Patients
Initially, 10 mg daily (as conventional tablets or suspension) or 12.5 mg daily (as extended-release tablets); if no clinical improvement is apparent, dosage may be titrated up to a maximum of 40 mg daily (as conventional tablets or suspension) or 50 mg daily (as extended-release tablets).
Cautions
Contraindications
Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.
Concurrent therapy with thioridazine. (See Drug Interactions under Warnings.)
Concomitant use of some SSRIs with MAO inhibitor associated with serious, sometimes fatal reactions, including manifestations resembling serotonin syndrome (e.g., hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes) or neuroleptic malignant syndrome (NMS). (See Contraindications.)
May inhibit CYP2D6, resulting in increased risk of QT prolongation and/or ventricular tachycardia of the torsades de pointes type associated with elevated plasma concentrations of thioridazine. (See Contraindications.)
Worsening of Depression and Suicidality Risk
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) in both adult and pediatric patients with major depressive disorder; may persist until clinically important remission occurs with therapy.
Possible increased risk of suicidal behavior in young adult patients (18–30 years of age), particularly those with major depressive disorder. Increased risk of suicidal behavior and thoughts in patients with a history of suicidal behavior or thoughts and in patients exhibiting a substantial degree of suicidal ideation prior to initiating therapy. Increased risk of suicidal behavior was observed despite evidence of paroxetine efficacy in patients being treated for major depressive disorder.
Closely supervise pediatric patients receiving paroxetine for any reason and adult patients with major depressive disorder or other psychiatric illness with comorbid depression during initiation of therapy and during periods of dosage adjustments. (See Boxed Warning.) Carefully monitor all patients, particularly young adults and those that are improving, during paroxetine therapy regardless of the condition being treated.
If anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and/or mania occur, consider changing or discontinuing therapy, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms. If decision is made to discontinue therapy, taper paroxetine dosage as rapidly as is feasible but consider risks of abrupt discontinuance. (See General under Dosage and Administration.)
Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.
Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder) or nonpsychiatric disorders.
Bipolar Disorder
May unmask bipolar disorder. (See Activation of Mania or Hypomania under Cautions.) Paroxetine is not approved for use in treating bipolar depression.
Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.
Fetal/Neonatal Morbidity and Mortality
May increase risk of fetal defects (e.g., cardiovascular malformations, principally ventricular and atrial septal defects; other major congenital malformations) when administered to pregnant women.
If a patient becomes pregnant during treatment, advise patient of the potential hazard to the fetus. Unless the potential benefits to the mother justify continuing treatment, consider discontinuing paroxetine therapy or switching to another antidepressant. For women who intend to become pregnant or are in their first trimester of pregnancy, initiate paroxetine only after consideration of other available treatment options.
Possible complications, sometimes severe and requiring prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in neonates exposed to paroxetine, other SSRIs, or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) late in the third trimester; may arise immediately upon delivery.
Increased risk of persistent pulmonary hypertension of the newborn (PPHN) in infants exposed to SSRIs during late pregnancy; associated with substantial neonatal morbidity and mortality.
Carefully consider both the potential risks and benefits of treatment when used during the third trimester of pregnancy. Be aware that in a longitudinal study involving women with a history of major depressive disorder who were euthymic while receiving antidepressant therapy at the beginning of pregnancy, women who discontinued antidepressant therapy during pregnancy were more likely to experience a relapse of depression than those who remained on antidepressant therapy. Consider cautiously tapering dose during third trimester prior to delivery.
General Precautions
Activation of Mania or Hypomania
Possible activation of mania or hypomania. Use with caution in patients with a history of mania. (See Bipolar Disorder under Cautions.)
Seizures
Seizures have been reported. Limited experience with use of paroxetine in patients with a history of seizures; use with caution in such patients. Discontinue if seizures occur.
Akathisia
Akathisia has been reported. Most likely to occur within the first few weeks of therapy.
Hyponatremia
May occur secondary to SIADH; apparently reversible following discontinuance of the drug and/or fluid restriction. Occurs mainly in older patients and those receiving diuretics or otherwise volume depleted. (See Geriatric Use under Cautions.)
Abnormal Bleeding
Possible increased risk of bleeding, including upper GI bleeding; use with caution.
Concomitant use of an NSAIA (e.g., aspirin) or warfarin may potentiate such risk.
Concomitant Disease
May be less cardiotoxic than most older antidepressant agents but experience is limited in patients with recent MI or unstable heart disease. Use with caution.
Does not appear to produce substantial cognitive or motor impairment, but patients should be cautioned to avoid activities requiring alertness or physical coordination until effects on individual are known.
Withdrawal of Therapy
Possible withdrawal reactions following abrupt discontinuance or intermittent noncompliance with therapy. Avoid abrupt discontinuance of therapy; taper dosage gradually over a period of several weeks.
If intolerable symptoms occur, reinstitute at the previously prescribed dosage until such symptoms abate. Clinicians may resume dosage reductions at that time but at a more gradual rate.
Electroconvulsive Therapy (ECT)
Effects of concomitant use with ECT have not been systematically evaluated.
Specific Populations
Pregnancy
Category D. See Fetal/Neonatal Morbidity and Mortality under Cautions.
Lactation
Distributed into human milk; use with caution.
Pediatric Use
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Safety and efficacy not established in children <18 years of age.
Greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, obsessive-compulsive disorder, or other psychiatric disorders based on pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others). No suicides occurred in these trials. If considering use of paroxetine in a child or adolescent, balance potential risks with clinical need. (See Worsening of Depression and Suicidality Risk under Cautions.)
Geriatric Use
Possible decreased clearance; however, efficacy and adverse effects similar to those in younger adults. Initiate therapy at a lower dosage. (See Geriatric or Debilitated Patients under Dosage and Administration.)
May be more likely than younger patients to develop hyponatremia and transient SIADH. Periodically monitor serum sodium concentrations, especially during the first several months of therapy.
Hepatic Impairment
Increased plasma concentrations and decreased clearance reported. Use with caution; use at a reduced initial dosage if impairment is severe. (See Hepatic Impairment under Dosage and Administration.)
Renal Impairment
Increased plasma concentrations and decreased clearance reported. Use with caution; use at a reduced initial dosage if impairment is severe. (See Renal Impairment under Dosage and Administration.)
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Metabolized partially by CYP2D6. Inhibits the activity of CYP2D6 and to a lesser extent CYP3A4.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2D6 or CYP3A4: possible increased plasma concentrations of the substrates.
Use with caution and consider reducing dosage of concomitantly administered CYP2D6 substrate, particularly those with a narrow therapeutic index, such as TCAs, class IC antiarrhythmics and some phenothiazines.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors or inducers of CYP isoenzymes (e.g., CYP2D6): potential pharmacokinetic interaction (altered paroxetine metabolism and plasma concentrations).
Drugs Associated with Serotonin Syndrome
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Potential pharmacodynamic interaction (serotonin syndrome). Although usually mild, serious complications and death occasionally have been reported. Serotonin syndrome most commonly occurs when serotonergic agents with different mechanisms of action are given concurrently or in close succession. Avoid such use, or use with caution.
Drugs Affecting Hemostasis
Potential pharmacologic interaction (increased risk of bleeding) with concomitant use of drugs that affect hemostasis. Use with caution.
Specific Drugs
Drug
Interaction
Comments
Alcohol
Does not potentiate cognitive and motor effects of alcohol; possible serotonergically mediated pharmacodynamic interaction in CNS
Paroxetine did not affect plasma propranolol concentrations; effects of propranolol on plasma paroxetine concentrations not evaluated
Protein-bound drugs
Potential for displacement of paroxetine or other protein-bound drugs from binding sites
Monitor patients for potential adverse effects
Risperidone
Increased plasma risperidone concentrations, decreased plasma 9-hydroxyrisperidone (active metabolite) concentrations, and increased plasma concentrations of active moiety (risperidone plus 9-hydroxyrisperidone)
Generally well tolerated; possible risk of parkinsonian symptoms
Completely absorbed following oral administration.
Oral bioavailability in humans not fully elucidated to date.
Equally bioavailable from commercially available conventional tablets and suspension.
Food
Food does not substantially affect the absorption of paroxetine.
Special Populations
In geriatric patients, trough paroxetine concentrations are 70–80% greater than in younger patients.
In patients with renal impairment (Clcr <30 mL/minute), mean plasma paroxetine concentrations are approximately 4 times greater than those seen in healthy individuals.
Hepatic impairment may increase plasma concentrations twofold.
Distribution
Extent
Widely distributed in the body, including the CNS and breast milk.
Plasma Protein Binding
≥93%
Elimination
Metabolism
Extensively metabolized, partially by CYP2D6. Metabolites are essentially inactive. Inhibits activity of CYP2D6.
Elimination Route
Eliminated principally in urine and feces (probably via bile).
Half-life
Averages approximately 21–24 hours.
Special Populations
In geriatric individuals, elimination half-life may be increased (e.g., to about 36 hours).
Stability
Storage
Oral
Conventional Tablets
15–30°C.
Extended-release Tablets
≤25°C.
Suspension
≤25°C.
Actions
Mechanism of action as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the CNS resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).
Has little or no effect on other neurotransmitters or any clinically important anticholinergic, antihistaminic, or adrenergic (α1, α2, β) blocking activity at usual therapeutic dosages.
Generally less sedating than most older antidepressants.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Importance of continuing therapy even if improvement is not evident for 4 weeks, unless directed otherwise by clinician.
Importance of avoiding some activities (e.g., operating machinery, driving a motor vehicle) until effects on the individual are known.
Risk of suicidalility; importance of patients, caregivers, and families immediately reporting emergence of suicidality, worsening depression, or other manifestations associated with increased risk of worsening depression or suicidality. FDA recommends providing written patient information (medication guide) explaining risks in pediatric patients each time the drug is dispensed.
Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, or of use of alcohol-containing beverages or products.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Paxil® (with parabens, propylene glycol, saccharin sodium, and sorbitol)
GlaxoSmithKline
Tablets, extended-release, film-coated
12.5 mg (of paroxetine)
Paxil CR®
GlaxoSmithKline
25 mg (of paroxetine)
Paxil CR®
GlaxoSmithKline
37.5 mg (of paroxetine)
Paxil CR®
GlaxoSmithKline
Tablets, film-coated
10 mg (of paroxetine)*
Paxil® (scored)
GlaxoSmithKline
20 mg (of paroxetine)*
Paxil® (scored)
GlaxoSmithKline
30 mg (of paroxetine)*
Paxil®
GlaxoSmithKline
40 mg (of paroxetine)*
Paxil®
GlaxoSmithKline
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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