RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Warnings and Precautions (5.2, 5.5) 8/2023

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of paroxetine tablets in the treatment of MDD, SAD, OCD, PD, GAD, and PTSD is unknown, but 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).

12.2 Pharmacodynamics

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 (SSRI) and has only very weak effects on norepinephrine and dopamine neuronal reuptake.

12.3 Pharmacokinetics

Nonlinearity in pharmacokinetics is observed with increasing doses of paroxetine tablets.

In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females.

Absorption

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.

Paroxetine is equally bioavailable from the oral suspension and tablet.

Effect of Food

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.

Distribution

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.

Elimination

Metabolism

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine tablets.

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 Drug Interactions (7)]. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

Excretion

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.

Drug Interaction Studies

There are clinically significant, known drug interactions between paroxetine and other drugs [see Drug Interactions (7)].

Figure 1. Impact of Paroxetine on the Pharmacokinetics of Co-Administered Drugs (log scale)

Figure 2. Impact of Co-Administered Drugs on the Pharmacokinetics of Paroxetine

Theophylline

Reports of elevated theophylline levels associated with paroxetine tablets treatment 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.

Drugs Metabolized by Cytochrome CYP3A4

An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for 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. Paroxetine’s extent of inhibition of CYP3A4 activity is not expected to be of clinical significance.

Specific Populations

The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3.

The recommended starting dosage and maximum dosage of paroxetine tablets are reduced in elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment [see Dosage and Administration (2.4)].

Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale)

INDICATIONS & USAGE SECTION

Highlight: Paroxetine tablets are a selective serotonin reuptake inhibitor (SSRI) indicated in adults for the treatment of (1):

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Major Depressive Disorder (MDD)

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Obsessive Compulsive Disorder (OCD)

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Panic Disorder (PD)

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Social Anxiety Disorder (SAD)

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Generalized Anxiety Disorder (GAD)

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Posttraumatic Stress Disorder (PTSD)

1 INDICATIONS AND USAGE

Paroxetine tablets are indicated in adults for the treatment of:

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Major depressive disorder (MDD)

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Obsessive compulsive disorder (OCD)

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Panic disorder (PD)

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Social anxiety disorder (SAD)

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Generalized anxiety disorder (GAD)

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Posttraumatic stress disorder (PTSD)

DOSAGE & ADMINISTRATION SECTION

Highlight: •

Recommended starting and maximum daily dosage for MDD, OCD, PD, and PTSD: (2.2)  

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Recommended starting dosage for SAD and GAD is 20 mg daily. (2.3)

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Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dosage is 10 mg daily. Maximum dosage is 40 mg daily. (2.4)

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When discontinuing paroxetine tablets, reduce dosage gradually. (2.6, 5.7)

2 DOSAGE AND ADMINISTRATION

2.1 Administration Information

Administer paroxetine tablets as a single daily dose in the morning, with or without food.

2.2 Recommended Dosage for MDD, OCD, PD, and PTSD

The recommended starting dosages and maximum dosages of paroxetine tablets in patients with MDD, OCD, PD, and PTSD are presented in Table 1.

In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability.

2.3 Recommended Dosage for SAD and GAD

SAD

The starting and recommended dosage in patients with SAD is 20 mg daily. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 mg to 60 mg daily. While the safety of paroxetine tablets has been evaluated in patients with SAD at doses up to 60 mg daily, available information does not suggest any additional benefit for doses above 20 mg daily [see Clinical Studies (14.4)].

GAD

The starting and recommended dosage in patients with GAD is 20 mg daily. In clinical trials the effectiveness of paroxetine tablets in GAD was demonstrated in patients dosed in a range of 20 mg to 50 mg daily. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg daily [see Clinical Studies (14.5)].

In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability.

2.4 Screen for Bipolar Disorder Prior to Starting Paroxetine Tablets

Prior to initiating treatment with paroxetine tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)].

2.5 Recommended Dosage for Elderly Patients, Patients with Severe Renal

Impairment, and Patients with Severe Hepatic Impairment

The recommended initial dosage is 10 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Dosage should not exceed 40 mg/day.

2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI)

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI and initiation of paroxetine tablets. In addition, at least 14 days must elapse after stopping paroxetine tablets before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)].

2.7 Discontinuation of Treatment With Paroxetine Tablets

Adverse reactions may occur upon discontinuation of paroxetine tablets [see Warnings and Precautions (5.7)]. Gradually reduce the dosage rather than stopping paroxetine tablets abruptly whenever possible.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: •

Tablets: 10 mg, scored; 20 mg, scored; 30 mg; and 40 mg tablets. (3)

3 DOSAGE FORMS AND STRENGTHS

Paroxetine Tablets, USP are available containing paroxetine hydrochloride, USP (hemihydrate) equivalent to 10 mg, 20 mg, 30 mg or 40 mg of paroxetine.

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The 10 mg tablets are blue, film-coated, modified capsule-shaped, scored tablets debossed with**M**on one side of the tablet and** N**to the left of the score and** 1**to the right of the score on the other side. 

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The 20 mg tablets are blue, film-coated, modified capsule-shaped, scored tablets debossed with**M**on one side of the tablet and** N**to the left of the score and** 2**to the right of the score on the other side. 

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The 30 mg tablets are blue, film-coated, round, unscored tablets debossed with**M** over**N3** on one side of the tablet and blank on the other side. 

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The 40 mg tablets are blue, film-coated, round, unscored tablets debossed with**M** over**N4** on one side of the tablet and blank on the other side.

CONTRAINDICATIONS SECTION

Highlight: •

Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOI. (4, 5.3, 7)

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Concomitant use of pimozide or thioridazine. (4, 5.3, 7)

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Known hypersensitivity to paroxetine or to any of the inactive ingredients in paroxetine tablets. (4)

4 CONTRAINDICATIONS

Paroxetine tablets are contraindicated in patients:

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Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)].

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Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3) and Drug Interactions (7)].

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Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interactions (7)].

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With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients in paroxetine tablets [see Adverse Reactions (6.1), (6.2)].

Boxed Warning section

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant- treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Paroxetine tablets are not approved for use in pediatric patients. (5.1,8.4)

DRUG INTERACTIONS SECTION

Highlight: •

 Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of paroxetine tablets or other protein-bound drugs (e.g., warfarin) as warranted. (7)

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 Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7)

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 Concomitant Use with Tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. (5.11, 7)

7 DRUG INTERACTIONS

Table 9 presents clinically significant drug interactions with paroxetine tablets.

USE IN SPECIFIC POPULATIONS SECTION

Highlight: •

 Pregnancy: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. (8.1)

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 Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.5) and Clinical Considerations].

Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. If paroxetine is used during pregnancy, or if the patient becomes pregnant while taking paroxetine, advise the patient of the potential hazard to the fetus.

Clinical Considerations

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 Warnings and Precautions (5.7)]. For

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A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery.

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A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).

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Two large case-control studies using separate databases, each with > 9,000 birth defect cases and > 4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, 7 exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).

Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta- analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations.

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 Warnings and Precautions (5.7)]. 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 [see Warnings and Precautions (5.4)].

Treatment of Pregnant Women During Their Third Trimester

Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including paroxetine tablets, 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 and Precautions (5.2)].

Exposure 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 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. A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy. The women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Maternal Adverse Reactions

Use of paroxetine tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)].

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 6 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 75 mg) on an mg/m2 basis. These studies have revealed no evidence of developmental 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 which is than 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.

8.3 Nursing Mothers

Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from paroxetine tablets, a decision should be made whether to discontinue nursing infants or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of paroxetine tablets in pediatric patients have not been established [see Box Warning]. Effectiveness was not demonstrated in three placebo-controlled trials in 752 paroxetine tablets-treated pediatric patients with MDD.

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)]. Decreased appetite and weight loss have been observed in association with the use of SSRIs.

In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions 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.

Adverse reactions 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 and 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.

8.5 Geriatric Use

In 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;, however, no overall differences in safety or effectiveness were observed between elderly and younger patients [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

SSRIs including paroxetine tablets, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.7)].

8.6 Renal and Hepatic Impairment

Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage of paroxetine tablets should be reduced in patients with severe renal impairment and in patients with severe hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

The efficacy of paroxetine tablets as a treatment for major depressive disorder (MDD) has been established in 6 placebo-controlled studies of patients with MDD (aged 18 to 73). In these studies, paroxetine tablets were shown to be statistically significantly more effective than placebo in treating MDD 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 statistically significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor.

Long-term efficacy of paroxetine tablets for treatment of MDD in outpatients was demonstrated in a randomized withdrawal study. Patients who responded to paroxetine tablets (HDRS total score < 8) during an initial 8-week open-label treatment phase were then randomized to continue paroxetine tablets or placebo, for up to 1 year. Patients treated with paroxetine tablets demonstrated a statistically significant lower relapse rate during the withdrawal phase (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.

14.2 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 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. In study 1, a dose-range finding study, patients received fixed daily doses of paroxetine tablets 20 mg, 40 mg, or 60 mg. Study 1 demonstrated that daily doses of paroxetine tablets 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving doses of paroxetine tablets 40 mg and 60 mg experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was statistically 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 tablets 20 mg to 60 mg daily with clomipramine 25 mg to 250 mg daily or placebo). In this study, patients receiving paroxetine tablets experienced a mean reduction of approximately 7 points on the YBOCS total score, which was statistically 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 efficacy of paroxetine tablets for the treatment of OCD was established in a long-term extension to Study 1. Patients who responded to paroxetine tablets during the 3-month double-blind phase and a 6-month extension on open-label paroxetine tablets 20 mg to 60 mg daily were randomized to either paroxetine tablets or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine tablets were statistically significantly less likely to relapse than placebo-treated patients.

14.3 Panic Disorder

The effectiveness of paroxetine tablets in the treatment of panic disorder (PD) was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1, 2, and 3). Patients had PD (DSM- IIIR), with or without agoraphobia. In these studies, paroxetine tablets were shown to be statistically significantly more effective than placebo in treating PD 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 received fixed doses of paroxetine tablets 10 mg, 20 mg, or 40 mg daily or placebo. A statistically significant difference from placebo was observed only for the paroxetine tablets 40 mg daily group. At endpoint, 76% of patients receiving paroxetine tablets 40 mg daily were free of panic attacks, compared to 44% of placebo- treated patients.

Study 2 was a 12-week flexible-dose study comparing paroxetine tablets 10 mg to 60 mg daily and placebo. At endpoint, 51% of paroxetine tablets-treated patients were free of panic attacks compared to 32% of placebo-treated patients.

Study 3 was a 12-week flexible-dose study comparing paroxetine tablets 10 mg to 60 mg daily to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine tablets- treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo-treated patients.

In Studies 2 and 3, the mean paroxetine tablets dose for completers at endpoint was approximately 40 mg daily.

Long-term efficacy of paroxetine tablets in PD was demonstrated in an extension to Study 1. Patients who responded to paroxetine tablets during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine tablets 10 mg, 20 mg, or 40 mg daily or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine tablets were statistically significantly less likely to relapse than placebo-treated patients.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

14.4 Social Anxiety Disorder

The effectiveness of paroxetine tablets in the treatment of social anxiety disorder (SAD) was demonstrated in three 12-week, multicenter, placebo- controlled studies (Studies 1, 2, and 3) of adult outpatients with SAD (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 tablets 20 mg to 50 mg daily and placebo. Paroxetine tablets 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 tablets-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 tablets- and placebo-treated patients, respectively.

Study 3 was a 12-week study comparing fixed doses of paroxetine tablets 20 mg, 40 mg, or 60 mg daily with placebo. Paroxetine tablets 20 mg was statistically 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 paroxetine tablets 40 mg and 60 mg daily dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg daily.

Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.

14.5 Generalized Anxiety Disorder

The effectiveness of paroxetine tablets 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 GAD (DSM-IV).

Study 1 was an 8-week study comparing fixed doses of paroxetine tablets 20 mg or 40 mg daily with placebo. Doses of paroxetine tablets 20 mg or 40 mg were both demonstrated to be statistically 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 paroxetine tablets 40 mg daily dose compared to the 20 mg daily dose.

Study 2 was a flexible-dose study comparing paroxetine tablets 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, a flexible-dose study comparing paroxetine tablets 20 mg to 50 mg daily to placebo, 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 long-term trial, 566 patients meeting DSM-IV criteria for GAD, who had responded during a single-blind, 8-week acute treatment phase with paroxetine tablets 20 mg to 50 mg daily, 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 ≥ 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 continuing to receive paroxetine tablets experienced a statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.

14.6 Posttraumatic Stress Disorder

The effectiveness of paroxetine tablets in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo- controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from 0.1 year to 57 years). The percentage of patients with secondary MDD or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (1) the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (2) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The 2 primary outcomes for each trial were (1) change from baseline to endpoint on the CAPS-2 total score (17 items), and (2) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved).

Study 1 was a 12-week study comparing fixed doses of paroxetine tablets 20 mg or 40 mg daily to placebo. Doses of paroxetine tablets 20 mg and 40 mg were demonstrated to be statistically significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg daily dose compared to the 20 mg daily dose.

Study 2 was a 12-week flexible-dose study comparing paroxetine tablets 20 mg to 50 mg daily to placebo. Paroxetine tablets were demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.

A third study, a flexible-dose study comparing paroxetine tablets 20 mg to 50 mg daily to placebo, demonstrated paroxetine tablets to be statistically significantly superior to placebo on change from baseline for CAPS-2 total score, but not on proportion of responders on the CGI-I.

The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively.

OVERDOSAGE SECTION

10 OVERDOSAGE

The following have been reported with paroxetine tablet overdosage:

•

Seizures, which may be delayed, and altered mental status including coma. 

•

Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. 

•

Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). 

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose.

Consider contacting a Poison Center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Sexual Dysfunction: Advise patients that use of paroxetine tablets may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.13)].

**Suicidal Thoughts and Behaviors:**Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

**Serotonin Syndrome:**Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of paroxetine tablets with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)].

**Concomitant Medications:**Advise patients 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 drug-drug interactions [see Warning and Precautions (5.3), Drug Interactions (7)].

**Increased Risk of Bleeding:**Inform patients about the concomitant use of paroxetine tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)].

**Activation of Mania/Hypomania:**Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.6)].

**Discontinuation Syndrome:**Advise patients not to abruptly discontinue paroxetine tablets and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when paroxetine tablets are discontinued [see Warnings and Precautions (5.7)].

**Allergic Reactions:**Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.1, 6.2)].

Embryo-Fetal Toxicity: Advise women of the potential risk to the fetus [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy because of the risk to the fetus.

**Nursing:**Advise women to notify their healthcare provider if they are breastfeeding an infant [see Use in Specific Populations (8.3)].

SPL MEDGUIDE SECTION

Medication Guide

**Increased risk of suicidal thoughts or actions.**Paroxetine tablets and other antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the**first few months of treatment or when the dose is changed.Paroxetine tablets are not for use in children.**

**Depression or other mental illnesses are the most important causes of suicidal thoughts and actions.**
**How can I watch for and try to prevent suicidal thoughts and actions?**

Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.

Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions.

Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.

attempts to commit suicide

acting aggressive or violent

new or worse depression

feeling agitated, restless, angry, or irritable

an increase in activity and talking more than what is normal for you

acting on dangerous impulses

thoughts about suicide or dying

new or worse anxiety or panic attacks

trouble sleeping

other unusual changes in behavior or mood

A certain type of depression called Major Depressive Disorder (MDD)

Obsessive Compulsive Disorder (OCD)

Panic Disorder (PD)

Social Anxiety Disorder (SAD)

Generalized Anxiety Disorder (GAD)

Posttraumatic Stress Disorder (PTSD)

take a monoamine oxidase inhibitor (MAOI)

have stopped taking an MAOI in the last 14 days

are being treated with the antibiotic linezolid or the intravenous methylene blue

are taking pimozide

are taking thioridazine

are allergic to paroxetine or any of the ingredients in paroxetine tablets. See the end of this Medication Guide for a complete list of ingredients in paroxetine tablets.

have heart problems

have or had bleeding problems

have, or have a family history of, bipolar disorder, mania or hypomania

have or had seizures or convulsions

have glaucoma (high pressure in the eye)

have low sodium levels in your blood

have bone problems

have kidney or liver problems

are pregnant or plan to become pregnant. Paroxetine tablets may harm your unborn baby. Talk to your healthcare provider about the risks to your unborn baby if you take paroxetine tablets during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with paroxetine tablets.

are breastfeeding or plan to breastfeed. Paroxetine passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with paroxetine tablets.

medicines used to treat migraine headaches called triptans

tricyclic antidepressants

lithium

tramadol, fentanyl, meperidine, methadone, or other opioids

tryptophan

buspirone

amphetamines

St. John’s Wort

medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin

diuretics

tamoxifen

medicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin reuptake (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

Take paroxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose of paroxetine tablets until it is the right dose for you.

Take paroxetine tablets 1 time each day in the morning.

Paroxetine tablets may be taken with or without food.

If you take too many paroxetine tablets, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.

See,**“What is the most important information I should know about paroxetine tablets?”**

**Serotonin syndrome.**A potentially life-threatening problem called serotonin syndrome can happen when you take paroxetine tablets with certain other medicines. See, “Who should not take paroxetine tablets?”**Call your healthcare provider or go to the nearest hospital emergency room right away**if you have any of the following signs and symptoms of serotonin syndrome:

agitation

seeing or hearing things that are not real (hallucinations)

confusion

coma

fast heart beat

changes in blood pressure

dizziness

sweating

flushing

high body temperature (hyperthermia)

shaking (tremors), stiff muscles, or muscle twitching

loss of coordination

seizures

nausea, vomiting, diarrhea

**Eye problems (angle-closure glaucoma).**Paroxetine tablets may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye.

**Medicine interactions.**Taking paroxetine tablets with certain other medicines including thioridazine and pimozide may increase the risk of developing a serious heart problem called QT prolongation.

**Seizures (convulsions).**

**Manic episodes.**Manic episodes may happen in people with bipolar disorder who take paroxetine tablets. Symptoms may include:

greatly increased energy

racing thoughts

unusually grand ideas

talking more or faster than usual

severe problems sleeping

reckless behavior

excessive happiness or irritability

**Discontinuation syndrome.**Suddenly stopping paroxetine tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:

nausea

sweating

changes in your mood

irritability and agitation

dizziness

electric shock feeling (paresthesia)

tremor

anxiety

confusion

headache

tiredness

problems sleeping

hypomania

ringing in your ears (tinnitus)

seizures

**Low sodium levels in your blood (hyponatremia).**Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with paroxetine tablets. Elderly people and people who take certain medicines may be at a greater risk for developing low sodium levels in your blood. Signs and symptoms may include:

headache

difficulty concentrating

memory changes

confusion

weakness and unsteadiness on your feet which can lead to falls  

seeing or hearing things that are not real (hallucinations)

fainting

seizures

coma

stopping breathing (respiratory arrest)

**Abnormal bleeding.**Taking paroxetine tablets with aspirin, NSAIDs, or blood thinners may increase this risk. Tell your healthcare provider about any unusual bleeding or bruising.

**Bone fractures.**

**Sexual problems (dysfunction).**Taking selective serotonin reuptake inhibitors (SSRIs), including paroxetine tablets, may cause sexual problems.
Symptoms in males may include:

Delayed ejaculation or inability to have an ejaculation

Decreased sex drive

Problems getting or keeping an erection
Symptoms in females may include:

Decreased sex drive

Delayed orgasm or inability to have an orgasm
Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with paroxetine tablets. There may be treatments your healthcare provider can suggest.

male and female sexual function problems

constipation

diarrhea

dry mouth

problems sleeping

nervousness

sweating

yawning

weakness (asthenia)

decreased appetite

dizziness

infection

nausea

sleepiness

shaking (tremor)

Store paroxetine tablets between 20° to 25°C (68° to 77°F).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Manufactured by:
ALPHAPHARM PTY LTD
15 Garnet Street
Carole Park QLD 4300
Australia

Revised: 2/2024

ALP:PXTT:R15mh/ALP:MG:PXTT:R7mh

(2848/8)

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Paroxetine Tablets, USP are available containing paroxetine hydrochloride, USP (hemihydrate) equivalent to 10 mg, 20 mg, 30 mg or 40 mg of paroxetine.

The 10 mg tablets are blue, film-coated, modified capsule-shaped, scored tablets debossed withMon one side of the tablet and** Nto the left of the score and 1**to the right of the score on the other side. They are available as follows:

NDC 0378-7001-93
bottles of 30 tablets

NDC 0378-7001-10
bottles of 1000 tablets

The 20 mg tablets are blue, film-coated, modified capsule-shaped, scored tablets debossed withMon one side of the tablet and** Nto the left of the score and 2**to the right of the score on the other side. They are available as follows:

NDC 0378-7002-93
bottles of 30 tablets

NDC 0378-7002-10
bottles of 1000 tablets

The 30 mg tablets are blue, film-coated, round, unscored tablets debossed with M overN3 on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-7003-93
bottles of 30 tablets

NDC 0378-7003-10
bottles of 1000 tablets

The 40 mg tablets are blue, film-coated, round, unscored tablets debossed with M overN4 on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-7004-93
bottles of 30 tablets

NDC 0378-7004-10
bottles of 1000 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.