Paroxetine 40 mg Tablet, Film Coated, 15-count — NDC 43353-544-15 (Billing 43353-0544-15)

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 nine 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. 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 t… [Excerpted — this section continues on DailyMed.]

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: Major Depressive Disorder OCD Panic Disorder Social Anxiety Disorder Generalized Anxiety Disorder Paroxetine Hydrochloride Placebo Paroxetine Hydrochloride Placebo Paroxetine Hydrochloride Placebo Paroxetine Hydrochloride Placebo Paroxetine Hydrochloride Placebo CNS Somnolence 2.3% 0.7% - 1.9% 0.3% 3.4% 0.3% 2% 0.2% Insomnia - - 1.7% 0% 1.3% 0.3% 3.1% 0% Agitation 1.1% 0.5% - Tremor 1.1% 0.3% - 1.7% 0% Anxiety - - - 1.1% 0% Dizziness - - 1.5% 0% 1.9% 0% 1% 0.2% Gastrointestinal Constipation - 1.1% 0% Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 4% 0.3% 2% 0.2% Diarrhea 1% 0.3% - Dry mouth 1% 0.3% - Vomiting 1% 0.3% - 1% 0% Flatulence 1% 0.3% Other Asthenia 1.6% 0.4% 1.9% 0.4% 2.5% 0.6% 1.8% 0.2% Abnormal ejaculation Incidence corrected for gender.

1.6% 0% 2.1% 0% 4.9% 0.6% 2.5% 0.5% Sweating 1% 0.3% - 1.1% 0% 1.1% 0.2% Impotence * - 1.5% 0% Libido Decreased 1% 0% Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine hydrochloride was not >1% or was not greater than or equal to 2 times the incidence of placebo. 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 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 Disorder The 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 Disorder The 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 Disorder The 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 Disorder The 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 fr… [Excerpted — this section continues on DailyMed.]

Drug Interactions Tryptophan 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 hydrochloride. Consequently, concomitant use of paroxetine hydrochloride with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome ).

Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS . Pimozide In 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 C max of 62%, compared to pimozide administered alone. The increase in pimozide AUC and C max 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 hydrochloride is contraindicated (see CONTRAINDICATIONS ). Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol or St.

John's Wort (see WARNINGS: Serotonin Syndrome ). The concomitant use of paroxetine hydrochloride with MAOIs (including linezolid and intravenous methylene blue) is contradicated (see CONTRADICATIONS ). The concomitant use of paroxetine hydrochloride with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan ).

Thioridazine See CONTRAINDICATIONS and WARNINGS . Warfarin 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 hydrochloride and warfarin should be undertaken with caution (see PRECAUTIONS: Information for Patients: Drugs That Interfere with Hemostasis ).

Triptans There have been rare post-marketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine hydrochloride 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 Cimetidine inhibits many cytochrome P 450 (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 hydrochloride after the 20 mg starting dose should be guided by clinical effect.

The effect of paroxetine on cimetidine’s pharmacokinetics was not studied. Phenobarbital Phenobarbital induces many cytochrome P 450 (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 T 1/2 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 hydrochloride exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the two drugs are both being chronically dosed.… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Activation of Mania/Hypomania During premarketing testing, hypomania or mania occurred in approximately 1% 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.

Seizures During 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 Hydrochloride Recent 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 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 one 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 hydrochloride. 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 hydrochloride in pediatric patients.

Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions ). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen.

One study suggests that the risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. Akathisia The 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 us… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Controlled Substance Class Paroxetine hydrochloride is not a controlled substance. Physical and Psychologic Dependence Paroxetine hydrochloride has 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 hydrochloride (e.g., development of tolerance, incrementations of dose, drug seeking behavior).

Controlled Substance Class Paroxetine hydrochloride is not a controlled substance.