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paroxetine hydrochloride hemihydrate tablet
----------PAROXETINE TABLETS, USP PACKAGE LABELS
SUICIDALITY AND ANTIDEPRESSANT DRUGSAntidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of paroxetine tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Paroxetine tablets are not approved for use in pediatric patients (see Warnings: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use).
DESCRIPTIONParoxetine tablets, USP are an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the molecular formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride hemihydrate is:
Paroxetine hydrochloride hemihydrate is an odorless, white to off-white crystalline powder, having a melting point range of 120° to 138°C. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in dichloromethane and slightly soluble in water.
Each paroxetine tablet, USP intended for oral administration contains paroxetine hydrochloride hemihydrate equivalent to 10 mg or 20 mg or 30 mg or 40 mg of paroxetine. In addition, each tablet contains the following inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose 6 cP,
lactose anhydrous, magnesium stearate, polyethylene glycol 6000, povidone, sodium starch glycolate, talc, and titanium dioxide.
The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting
from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine tablets, 30 mg daily for 30 days. Paroxetine is extensively metabolized and the metabolites are
considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).
Absorption and Distribution:
Paroxetine is equally bioavailable from the oral suspension and tablet. Paroxetine hydrochloride hemihydrate is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T1/2 were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes
paroxetine is readily saturable.
The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased
from 6.4 hours post-dosing to 4.9 hours.
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.
Metabolism and Excretion:
The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine tablets, 30 mg tablets daily for 30 days. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and
methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism
of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS).
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent
compound over the 10-day post-dosing period.
Other Clinical Pharmacology Information:
Renal and Liver Disease:
Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. was approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, Cmax). The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION).
In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION).
In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine
(see PRECAUTIONS-Drug Interactions).
Major Depressive Disorder:
The efficacy of paroxetine tablets as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine tablets were shown to be significantly more effective than placebo in treating
major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine tablets were significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor.
A study of outpatients with major depressive disorder who had responded to paroxetine tablets (HDRS total score less than 8) during an initial 8-week opentreatment phase and were then randomized to continuation on paroxetine tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.
Obsessive Compulsive Disorder:
The effectiveness of paroxetine tablets in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline
ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the
treatment of OCD. Patients receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term maintenance effects of paroxetine tablets in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.
The effectiveness of paroxetine tablets in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine
tablets were shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score.
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients.
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. Long-term maintenance effects of paroxetine tablets in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
Social Anxiety Disorder:
The effectiveness of paroxetine tablets in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlledstudies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine tablets compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS).
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively.
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over
placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day.
Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.
Generalized Anxiety Disorder:
The effectiveness of paroxetine tablets in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebocontrolled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine tablets were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient
evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose.
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine tablets demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine tablets over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine tablets, were randomized to continuation of paroxetine tablets at their same dose, or to placebo,
for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of greater than or equal to 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of less than or equal to 3. Relapse during the double-blind phase was defined as an increase of greater than or equal to 2 points compared to baseline on the CGI-Severity of Illness scale to a score of greater than or equal to 4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine tablets experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.
INDICATIONS AND USAGE
Major Depressive Disorder:
Paroxetine tablets, USP are indicated for the treatment of major depressive disorder.
The efficacy of paroxetine tablets, USP in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The effects of paroxetine tablets, USP in hospitalized depressed patients have not been adequately studied. The efficacy of paroxetine tablets, USP in maintaining a response in major depressive disorder for up to 1 year was demonstrated in a placebocontrolled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Obsessive Compulsive Disorder:
Paroxetine tablets, USP are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of paroxetine tablets, USP were established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials). Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION
CONTRAINDICATIONSConcomitant use in patients taking either monoamine oxidase inhibitors (MAOIs), including linezolid, an antibiotic which is a reversible non-selective MAOI, or thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS). Paroxetine tablets are contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in paroxetine tablets.
WARNINGSClinical Worsening and Suicide Risk:
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, 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.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION - Discontinuation of Treatment with Paroxetine Tablets, for a description of the risks of discontinuation of paroxetine tablets). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for paroxetine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder:
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that paroxetine tablets are not approved for use in treating bipolar depression.
Potential for Interaction with Monoamine Oxidase Inhibitors:
In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with paroxetine tablets, limited animal data on the effects of combined use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that paroxetine tablets not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI (see CONTRAINDICATIONS). At least 2 weeks should be allowed after stopping paroxetine tablets before starting an MAOI. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including treatment with paroxetine, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of paroxetine with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of paroxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of paroxetine with serotonin precursors (such as tryptophan) is not recommended. Treatment with paroxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Potential Interaction with Thioridazine:
Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose related. An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).
Usage in Pregnancy:
Epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS—Discontinuation of Treatment with Paroxetine Tablets). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options. A study based on Swedish national registry data evaluated infants of 6,896 women exposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population. Among the same paroxetine exposed infants, an examination of the data showed no increase in the overall risk for congenital malformations. A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine compared to other antidepressants (OR 1.5; 95% confidence interval 0.8-2.9). The prevalence of cardiovascular malformations following first trimester dispensing was 1.5% for paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with cardiovascular malformations whose mothers were
dispensed paroxetine in the first trimester had VSDs. This study also suggested an increased risk of overall major congenital malformations (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR 1.8; 95% confidence interval 1.2-2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants.
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the MRHD on an mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
Neonates exposed to paroxetine tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS—Potential for Interaction with Monoamine Oxidase Inhibitors). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs. When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class:
Paroxetine tablets are not controlled substance.
Physical and Psychologic Dependence:
Paroxetine tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of paroxetine tablets (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
Since the introduction of paroxetine tablets in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetinetreatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.
Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for paroxetine are known.
A specific caution involves patients who are taking or have recently taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS —Drugs Metabolized by Cytochrome CYP2D6). In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk
DOSAGE AND ADMINISTRATION
Major Depressive Disorder:
Usual Initial Dosage:
Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.
There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.
Obsessive Compulsive Disorder:
Usual Initial Dosage:
Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day.
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY— Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Usual Initial Dosage:
Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine tablets in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets. The maximum dosage should not exceed 60 mg/day.
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Social Anxiety Disorder:
Usual Initial Dosage:
Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY—Clinical Trials).
There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Generalized Anxiety Disorder:
Usual Initial Dosage:
Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week.
Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
Treatment of Pregnant Women During the Third Trimester:
Neonates exposed to paroxetine tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering paroxetine in the third trimester.
Dosage for Elderly or Debilitated Patients, and Patients with Severe Renal or Hepatic Impairment:
The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day.
Switching Patients to or from a Monoamine Oxidase Inhibitor:
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with paroxetine tablets. Similarly, at least 14 days should be allowed after stopping paroxetine tablets before starting an MAOI.
Discontinuation of Treatment with Paroxetine Tablets:
Symptoms associated with discontinuation of paroxetine tablets have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine tablets are being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of ‘ZC, 15 and bisect’ on one side and plain on other side, and are supplied as follows:
NDC 54458-990-10 in Shellpaks® of 30 tablets Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of ‘ZC, 16 and bisect’ on one side and plain on other side, and are supplied as follows:
NDC 54458-989-10 in Shellpaks® of 30 tablets Paroxetine Tablets USP, 30 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of ‘ZC17’ on one side and plain on other side, and are supplied as follows:
NDC 54458-988-10 in Shellpaks® of 30 tablets
Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature].
MEDICATION GUIDEMedication Guide
Paroxetine Tablets, USP
Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions
Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of
suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:
• All risks and benefits of treatment with antidepressant medicines
• All treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, andsuicidal thoughts or action?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also
called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when anantidepressant medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if youhave concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Trouble sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking (mania)
• Other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenlycan cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treatingdepression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with thehealthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects.Call your doctor for medical advice about side effects. You may report sideeffects to FDA at 1-800-FDA-1088.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep alist of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare providerfor more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
Activation of Mania/Hypomania:
SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs,warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstratedan association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events relatedto SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should becautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
Use in Patients with Concomitant Illness:
Clinical experience with paroxetine tablets in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine tablets. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine tablets are prescribed for patients with narrow angle glaucoma.
Paroxetine tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine tablets in double-blind, placebo-controlled trials, however, did not indicate that paroxetine tablets are associated with the development of significant ECG abnormalities. Similarly, paroxetine tablets do not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance less than 30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients:
Paroxetine should not be chewed or crushed, and should be swallowed whole. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine and triptans, tramadol, or other serotonergic agents.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for paroxetine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine.
Clinical Worsening and Suicide Risk:
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior,
worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin):
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Interference with Cognitive and Motor Performance:
Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine tablets have not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine tablets does not affect their ability to engage in such activities.
Completing Course of Therapy:
While patients may notice improvement with treatment with paroxetine tablets in 1 to 4 weeks, they should be advised to continue therapy as directed.
Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Although paroxetine tablets have not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS—Usage in Pregnancy: Teratogenic and Nonteratogenic Effects).
Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS—Nursing Mothers).
There are no specific laboratory tests recommended.
As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine tablets. Consequently, concomitant use of paroxetine tablets with tryptophan is not recommended (see WARNINGS-Serotonin Syndrome).
Monoamine Oxidase Inhibitors:
See CONTRAINDICATIONS and WARNINGS.
In a controlled study of healthy volunteers, after paroxetine tablets were titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine tablets is contraindicated (see CONTRAINDICATIONS).
Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS — SerotoninSyndrome). The concomitant use of paroxetine with MAOIs (including linezolid) is contraindicated (see CONTRAINDICATIONS). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS - Drug Interactions - Tryptophan).
See CONTRAINDICATIONS and WARNINGS.
Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine tablets and warfarin should be undertaken with caution (see Drugs That Interfere with Hemostasis).
There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS —Serotonin Syndrome).
Drugs Affecting Hepatic Metabolism:
The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where paroxetine tablets (30 mg once daily) were dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine tablets after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied.
Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30-mg dose of paroxetine tablets was administered at
phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine tablets exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine tablets is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
When a single oral 30-mg dose of paroxetine tablets was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 50% and 35%, respectively) compared to paroxetine tablets administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS— Postmarketing Reports).
Drugs Metabolized by CYP2D6:
Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (greater than 90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine tablets. In 1 study, daily dosing of paroxetine tablets (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T1/2 by an average of approximately 2-, 5-, and 3- fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine.
Concomitant use of paroxetine tablets with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine tablets or the other drug. Therefore, coadministration of paroxetine tablets with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, tamoxifen, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine,
paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS).
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite and hence reduced efficacy of tamoxifen. At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS—Tricyclic Antidepressants).
Drugs Metabolized by Cytochrome CYP3A4:
An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
Tricyclic Antidepressants (TCAs):
Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine tablets, because paroxetine may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine tablets (see PRECAUTIONS—Drugs Metabolized by Cytochrome CYP2D6).
Drugs Highly Bound to Plasma Protein:
Because paroxetine is highly bound to plasma protein, administration of paroxetine tablets to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.
Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have
demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
Although paroxetine tablets do not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets.
A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine tablets and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine tablets are coadministered with lithium.
The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.
Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.
Daily oral dosing of paroxetine tablets (30 mg once daily) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.
In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine tablets (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS— Postmarketing Reports).
Reports of elevated theophylline levels associated with treatment with paroxetine tablets have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.
Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
Electroconvulsive Therapy (ECT):
There are no clinical studies of the combined use of ECT and paroxetine tablets.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, and GAD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.
Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
Impairment of Fertility:
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for
major depressive disorder, social anxiety disorder, and GAD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2 basis).
Pregnancy Category D. (see WARNINGS-Usage in Pregnancy: Teratogenic and Nonteratogenic Effects).
Labor and Delivery:
The effect of paroxetine on labor and delivery in humans is unknown.
Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine tablets are administered to a
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with paroxetine tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine tablets in a child or adolescent must balance the potential risks with the clinical need.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine tablets and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.
Events reported upon discontinuation of treatment with paroxetine tablets in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine tablets and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see Discontinuation of Treatment with Paroxetine Tablets).
SSRIs and SNRIs, including paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). In worldwide premarketing clinical trials with paroxetine tablets, 17% of patients treated with paroxetine tablets (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Associated with Discontinuation of Treatment:
1. Incidence corrected for gender.
Commonly Observed Adverse Events:
Major Depressive Disorder:
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 2) were: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders.
Obsessive Compulsive Disorder:
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.
Social Anxiety Disorder:
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence.
Generalized Anxiety Disorder:
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.
Incidence in Controlled Clinical Trials:
The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied.
Major Depressive Disorder:
Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
2. Includes mostly “lump in throat” and “tightness in throat.”
3. Percentage corrected for gender.
4. Mostly “ejaculatory delay.”
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.”
6. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine tablets who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day.
Revised: 02/2011 International Labs, Inc.
Reproduced with permission of U.S. National Library of Medicine
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