Paroxetine
Generic Name: Paroxetine hydrochloride
Dosage Form: tablets
Suicidality and Antidepressant Drugs
Antidepressants 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.)
Paroxetine Description
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Paroxetine hydrochloride is 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. The structural formula is:
C19H20FNO3•HCl•½H2O M.W. 374.8 (329.4 as free base)
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 141° to 145°C and a solubility range of 1 to 10 mg/mL in water.
Each film-coated tablet contains Paroxetine hydrochloride equivalent to Paroxetine as follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue; 40 mg–green. Inactive ingredients consist of calcium phosphate dibasic anhydrous, hypromellose (2910, 3 cP +6 cP), magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium starch glycolate, and titanium dioxide. In addition, the 10 mg and 40 mg strengths contain FD&C yellow #5 lake, the 10 mg strength contains FD&C yellow #6 lake, the 20 mg strength contains FD&C red #40 lake and carmine, the 30 mg and 40 mg strengths contain FD&C blue #2 lake, and the 40 mg strength contains FD&C blue #1 lake.
Paroxetine - Clinical Pharmacology
Pharmacodynamics
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.
Pharmacokinetics
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 30 mg tablets of Paroxetine 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 DistributionParoxetine is equally bioavailable from the oral suspension and tablet.
Paroxetine hydrochloride 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 T½ 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 ExcretionThe mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of Paroxetine hydrochloride. 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
Specific PopulationsRenal 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. were 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 DOSAGEAND ADMINISTRATION).
Elderly patients
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).
Drug-drug interactions
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).
Clinical Trials
Major Depressive DisorderThe efficacy of Paroxetine hydrochloride 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 hydrochloride was 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 hydrochloride was 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 hydrochloride (HDRS total score < 8) during an initial 8 week open-treatment phase and were then randomized to continuation on Paroxetine hydrochloride or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking Paroxetine hydrochloride (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.
Obsessive Compulsive DisorderThe effectiveness of Paroxetine hydrochloride 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.
| OutcomeClassification | Placebo(n = 74) | Paroxetine Hydrochloride20 mg(n = 75) | Paroxetine Hydrochloride 40 mg(n = 66) | Paroxetine Hydrochloride 60 mg(n = 66) |
| Worse | 14% | 7% | 7% | 3% |
| No Change | 44% | 35% | 22% | 19% |
| Minimally Improved | 24% | 33% | 29% | 34% |
| Much Improved | 11% | 18% | 22% | 24% |
| Very Much Improved | 7% | 7% | 20% | 20% |
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 hydrochloride 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.
Panic DisorderThe effectiveness of Paroxetine hydrochloride in the treatment of panic disorder was demonstrated in three 10 to 12 week multicenter, placebo-controlled studies of adult outpatients (Studies 1 through 3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, Paroxetine hydrochloride was 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 hydrochloride 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 DisorderThe effectiveness of Paroxetine hydrochloride in the treatment of social anxiety disorder was demonstrated in three 12 week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of Paroxetine hydrochloride 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 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 DisorderThe effectiveness of Paroxetine hydrochloride in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8 week, multicenter, placebo-controlled 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 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 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 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, were randomized to continuation of Paroxetine hydrochloride 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 ≥ 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤ 3. Relapse during the double-blind phase was defined as an increase of ≥ 2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥ 4, or withdrawal due to lack of efficacy. Patients receiving continued Paroxetine hydrochloride experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.
Indications and Usage for Paroxetine
Major Depressive Disorder
Paroxetine tablets are indicated for the treatment of major depressive disorder.
The efficacy of Paroxetine hydrochloride 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 hydrochloride in hospitalized depressed patients have not been adequately studied.
The efficacy of Paroxetine hydrochloride in maintaining a response in major depressive disorder for up to 1 year was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY, Clinical Trials). Nevertheless, the physician who elects to use Paroxetine hydrochloride for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Obsessive Compulsive Disorder
Paroxetine tablets 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 hydrochloride was 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 for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder
Paroxetine tablets are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
The efficacy of Paroxetine hydrochloride was established in three 10 to 12 week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY, Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
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). Nevertheless, the physician who prescribes Paroxetine tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Social Anxiety Disorder
Paroxetine tablets are indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of Paroxetine hydrochloride was established in three 12 week trials in adult patients with social anxiety disorder (DSM-IV). Paroxetine hydrochloride has not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY, Clinical Trials).
The effectiveness of Paroxetine hydrochloride in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to prescribe Paroxetine hydrochloride for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Generalized Anxiety Disorder
Paroxetine tablets are indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
The efficacy of Paroxetine hydrochloride in the treatment of GAD was established in two 8 week placebo-controlled trials in adults with GAD. Paroxetine hydrochloride has not been studied in children or adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY, Clinical Trials).
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance.
The efficacy of Paroxetine hydrochloride in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8 week acute treatment phase while taking Paroxetine tablets and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY, Clinical Trials). Nevertheless, the physician who elects to use Paroxetine tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Contraindications
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) 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.
Warnings
Clinical 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 long-standing 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 to 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.
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated |
| Increases Compared to Placebo | |
| < 18 | 14 additional cases |
| 18 to 24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25 to 64 | 1 fewer case |
| ≥ 65 | 6 fewer cases |
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 withParoxetine 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 DisorderA 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 InhibitorsIn 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 hydrochloride, 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, or within 14 days of discontinuing treatment with an MAOI. At least 2 weeks should be allowed after stopping Paroxetine tablets before starting an MAOI.
Serotonin SyndromeThe development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including Paroxetine, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). 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).
The concomitant use of Paroxetine with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction With Monoamine Oxidase Inhibitors).
If concomitant treatment with 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 (see PRECAUTIONS, Drug Interactions).
The concomitant use of Paroxetine with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions).
Potential Interaction With ThioridazineThioridazine 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 PregnancyTeratogenic effects
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 to 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 U.S. 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 to 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 to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for Paroxetine vs. 2% for other antidepressants.
Animal findings
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.
Nonteratogenic effects
Neonates exposed to Paroxetine hydrochloride 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 to 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 ANDADMINISTRATION). 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.
Precautions
General
Activation of Mania/HypomaniaDuring premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with Paroxetine hydrochloride compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for Paroxetine hydrochloride and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, Paroxetine hydrochloride should be used cautiously in patients with a history of mania.
SeizuresDuring premarketing testing, seizures occurred in 0.1% of patients treated with Paroxetine hydrochloride, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine hydrochloride should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
Discontinuation of Treatment With Paroxetine TabletsRecent clinical trials supporting the various approved indications for Paroxetine hydrochloride employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and other clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped.
With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for Paroxetine hydrochloride and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention.
During marketing of Paroxetine hydrochloride and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring, upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Paroxetine tablets. 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 (see DOSAGE AND ADMINISTRATION).
See also PRECAUTIONS, Pediatric Use, for adverse events reported upon discontinuation of treatment with Paroxetine tablets in pediatric patients.
AkathisiaThe use of Paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.
HyponatremiaSeveral cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when Paroxetine hydrochloride was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Abnormal BleedingPublished case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In 2 studies, concurrent use of a non-steroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of Paroxetine with NSAIDs, aspirin, or other drugs that affect coagulation.
Use in Patients With Concomitant IllnessClinical experience with Paroxetine hydrochloride 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 hydrochloride. 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 hydrochloride has 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 hydrochloride in double-blind, placebo-controlled trials, however, did not indicate that Paroxetine hydrochloride is associated with the development of significant ECG abnormalities. Similarly, Paroxetine hydrochloride does 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 < 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 tablets 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 tablets.
Clinical Worsening and Suicide RiskPatients, 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 (NSAIDs, Aspirin, Warfarin, etc.)Patients should be cautioned about the concomitant use of Paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding.
Interference With Cognitive and Motor PerformanceAny psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Paroxetine hydrochloride has 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 hydrochloride does not affect their ability to engage in such activities.
Completing Course of TherapyWhile patients may notice improvement with treatment with Paroxetine hydrochloride in 1 to 4 weeks, they should be advised to continue therapy as directed.
Concomitant MedicationPatients 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.
AlcoholAlthough Paroxetine hydrochloride has 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.
PregnancyPatients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS, Usage in Pregnancy, Teratogenic effects and Nonteratogeniceffects).
NursingPatients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS, Nursing Mothers).
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
TryptophanAs 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 hydrochloride with tryptophan is not recommended (see WARNINGS, Serotonin Syndrome).
Monoamine Oxidase InhibitorsSee CONTRAINDICATIONS and WARNINGS.
PimozideIn a controlled study of healthy volunteers, after Paroxetine hydrochloride was titrated to 60 mg daily, coadministration 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. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and Paroxetine hydrochloride is contraindicated (see CONTRAINDICATIONS).
Serotonergic DrugsBased 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, Serotonin Syndrome). The concomitant use of Paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS, Drug Interactions, Tryptophan).
ThioridazineSee CONTRAINDICATIONS and WARNINGS.
WarfarinPreliminary 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 (NSAIDs, Aspirin, Warfarin, etc.)).
TriptansThere 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 MetabolismThe metabolism and pharmacokinetics of Paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
CimetidineCimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where Paroxetine hydrochloride (30 mg once daily) was 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.
PhenobarbitalPhenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30 mg dose of Paroxetine hydrochloride was administered at phenobarbital steady state (100 mg once daily for 14 days), Paroxetine AUC and T½ 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 hydrochloride 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.
PhenytoinWhen a single oral 30 mg dose of Paroxetine hydrochloride was administered at phenytoin steady state (300 mg once daily for 14 days), Paroxetine AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to Paroxetine hydrochloride 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 CYP2D6Many 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 (> 90%), this CYP2D6 isozyme is saturated early during dosing with Paroxetine hydrochloride. In 1 study, daily dosing of Paroxetine hydrochloride (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ 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 hydrochloride with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either Paroxetine hydrochloride 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, 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).
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 (TCAs)).
Drugs Metabolized by Cytochrome CYP3A4An 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 hydrochloride, 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 CYP2D6).
Drugs Highly Bound to Plasma ProteinBecause 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 (NSAIDs, Aspirin, Warfarin, etc.)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 potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with Paroxetine.
AlcoholAlthough Paroxetine hydrochloride does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Paroxetine tablets.
LithiumA multiple-dose study has shown that there is no pharmacokinetic interaction between Paroxetine hydrochloride and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when Paroxetine tablets are coadministered with lithium.
DigoxinThe 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.
DiazepamUnder steady-state conditions, diazepam does not appear to affect Paroxetine kinetics. The effects of Paroxetine on diazepam were not evaluated.
ProcyclidineDaily oral dosing of Paroxetine hydrochloride (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.
Beta-BlockersIn 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 hydrochloride (30 mg once daily) for the final 10 days. The effects of propranolol on Paroxetine have not been evaluated (see ADVERSE REACTIONS, Postmarketing Reports).
TheophyllineReports of elevated theophylline levels associated with treatment with Paroxetine hydrochloride 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.
Fosamprenavir/RitonavirCoadministration 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 hydrochloride.
Carcinogenesis, Mutagenesis, Impairment of Fertility
CarcinogenesisTwo-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.
MutagenesisParoxetine 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 cytogenic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
Impairment of FertilityA 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
Teratogenic EffectsPregnancy category D
See WARNINGS, Usage in Pregnancy, Teratogeniceffects and Nonteratogenic effects.
Labor and Delivery
The effect of Paroxetine on labor and delivery in humans is unknown.
Nursing Mothers
Like many other drugs, Paroxetine is secreted in human milk, and caution should be exercised when Paroxetine tablets are administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOXWARNING and WARNINGS, Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with Paroxetine hydrochloride, 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 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, hyperkinesias, and agitation.
Events reported upon discontinuation of treatment with Paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received Paroxetine hydrochloride 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).
Geriatric Use
In worldwide premarketing clinical trials with Paroxetine hydrochloride, 17% of patients treated with Paroxetine hydrochloride (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).
Adverse Reactions
Associated With Discontinuation of Treatment
Twenty percent (1,199/6,145) of patients treated with Paroxetine hydrochloride in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with Paroxetine hydrochloride in worldwide trials in social anxiety disorder, OCD, panic disorder, and GAD, respectively, discontinued treatment due to an adverse event. The most common events (≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for Paroxetine hydrochloride compared to placebo) included the following:
Commonly Observed Adverse Events
Major Depressive DisorderThe most commonly observed adverse events associated with the use of Paroxetine (incidence of 5% or greater and incidence for Paroxetine hydrochloride 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 DisorderThe most commonly observed adverse events associated with the use of Paroxetine (incidence of 5% or greater and incidence for Paroxetine hydrochloride 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.
Panic DisorderThe most commonly observed adverse events associated with the use of Paroxetine (incidence of 5% or greater and incidence for Paroxetine hydrochloride 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 DisorderThe most commonly observed adverse events associated with the use of Paroxetine (incidence of 5% or greater and incidence for Paroxetine hydrochloride 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 DisorderThe most commonly observed adverse events associated with the use of Paroxetine (incidence of 5% or greater and incidence for Paroxetine hydrochloride 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 DisorderTable 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.
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety DisorderTable 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on Paroxetine hydrochloride 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 hydrochloride 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 hydrochloride 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.
Generalized Anxiety DisorderTable 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on Paroxetine hydrochloride who participated in placebo-controlled trials of 8 weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day.
Dose Dependency of Adverse EventsA comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of Paroxetine hydrochloride with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of Paroxetine hydrochloride, as shown in the following table: