PAROXETINE

1 INDICATIONS AND USAGE Paroxetine Extended-Release Tablets, USP are indicated in adults for the treatment of: Major depressive disorder (MDD) Panic disorder (PD) Social anxiety disorder (SAD) Premenstrual dysphoric disorder (PMDD) Paroxetine Extended-Release Tablets are a selective serotonin reuptake inhibitor (SSRI) indicated in adults for the treatment of ( 1 ): Major Depressive Disorder (MDD) Panic Disorder (PD) Social Anxiety Disorder (SAD) Premenstrual Dysphoric Disorder (PMDD)

2 DOSAGE AND ADMINISTRATION Swallow tablet whole; do not chew or crush. ( 2.1 ) Recommended starting and maximum daily dosage: ( 2.2 , 2.3 ) Indication Starting Dose Maximum Dose MDD 25 mg/day 62.5 mg/day PD 12.5 mg/day 75 mg/day SAD 12.5 mg/day 37.5 mg/day PMDD 12.5 mg/day 25 mg/day For PMDD, dose continuously or intermittently (luteal phase only). ( 2.3 ) If inadequate response to starting dosage, titrate in 12.5 mg per day increments once weekly. ( 2.2 , 2.3 ) Elderly patients, patients with severe renal impairment, or severe hepatic impairment: Starting dose is 12.5 mg per day. Do not exceed 50 mg per day for treatment of MDD and PD and 37.5 mg per day for treatment of SAD. ( 2.5 ) When discontinuing Paroxetine Extended-Release Tablets, reduce dose gradually. ( 2.7 ) 2.1 Important Administration Instructions Administer Paroxetine Extended-Release Tablets as a single daily dose in the morning, with or without food. Swallow tablets whole and do not chew or crush. 2.2 Dosage in Patients with Major Depressive Disorder, Panic Disorder, and Social Anxiety Disorder The recommended initial dosage and maximum dosage of Paroxetine Extended-Release Tablets in patients with MDD, PD, and SAD are presented in Table 1. In patients with an inadequate response, dosage may be increased in increments of 12.5 mg per day at intervals of at least 1 week, depending on tolerability. Table 1: Recommended Daily Dosage of Paroxetine Extended-Release Tablets in Patients with MDD, PD, and SAD Indication Starting Dose Maximum Dose MDD 25 mg 62.5 mg PD 12.5 mg 75 mg SAD 12.5 mg 37.5 mg 2.3 Dosage in Patients with Premenstrual Dysphoric Disorder The recommended starting dosage in women with PMDD is 12.5 mg per day. Paroxetine Extended-Release Tablets may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing is repeated with each new cycle. In patients with an inadequate response, the dosage may be increased to the maximum recommended dosage of 25 mg per day, depending on tolerability. Institute dosage adjustments at intervals of at least 1 week. 2.4 Screen for Bipolar Disorder Prior to Starting Paroxetine Extended-Release Tablets Prior to initiating treatment with Paroxetine Extended-Release 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 Dosage Modifications for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment The recommended initial dose of Paroxetine Extended-Release Tablets is 12.5 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Reduce initial dose and increase up-titration intervals if necessary. Dosage should not exceed 50 mg per day for MDD or PD and should not exceed 37.5 mg per day for SAD [see Use in Specific Populations (8.5 , 8.6) ]. 2.6 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of Paroxetine Extended-Release Tablets. In addition, at least 14 days must elapse after stopping Paroxetine Extended-Release Tablets before starting an MAOI antidepressant [see Contraindications (4) , Warnings and Precautions (5.2) ] . 2.7 Discontinuation of Treatment with Paroxetine Extended-Release Tablets Adverse reactions may occur upon discontinuation of Paroxetine Extended-Release Tablets [see Warnings and Precautions (5.7) ]. Gradually reduce the dosage rather than stopping Paroxetine Extended-Release Tablets abruptly whenever possible.

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If serotonin syndrome occurs, discontinue Paroxetine Extended-Release Tablets and serotonergic agents and initiate supportive measures. ( 5.2 ) Embryofetal Toxicity: May cause fetal harm. Meta-analysis of epidemiological studies has shown increased risk (less than 2-fold) of cardiovascular malformations with exposure during the first trimester. ( 5.4 , 8.1 ) Increased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. ( 5.5 ) Activation of Mania/Hypomania : Screen patients for bipolar disorder. ( 5.6 ) Seizures : Use with caution in patients with seizure disorders. ( 5.8 ) Angle-Closure Glaucoma : Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9 ) Sexual Dysfunction : Paroxetine Extended-Release Tablets may cause symptoms of sexual dysfunction. ( 5.13 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2. Table 2: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Paroxetine Extended-Release Tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including Paroxetine Extended-Release Tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) ,…

4 CONTRAINDICATIONS Paroxetine Extended-Release Tablets are contraindicated in patients: 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) ]. Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3) , Drug Interactions (7) ] . Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3) , Drug Interactions (7) ] . With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in Paroxetine Extended-Release Tablets [see Adverse Reactions (6.1 , 6.2) ] . Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOIs. ( 4 , 5.2 , 7 ) Concomitant use of pimozide or thioridazine. ( 4 , 5.3 , 7 ) Known hypersensitivity to paroxetine or to any of the inactive ingredients in Paroxetine Extended-Release Tablets. ( 4 )

7 DRUG INTERACTIONS Drugs Highly Bound to Plasma Protein : Monitor for adverse reactions and reduce dosage of Paroxetine Extended-Release Tablets or other protein-bound drugs (e.g., warfarin) as warranted. ( 7 ) Drugs Metabolized by CYP2D6 : Reduce dosage of drugs metabolized by CYP2D6 as warranted. ( 7 ) Concomitant use with Tamoxifen : Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. ( 5.11 , 7 ) 7.1 Clinically Significant Drug Interactions with Paroxetine Extended-Release Tablets Table 6 includes clinically significant drug interactions with Paroxetine Extended-Release Tablets Table 6: Clinically Significant Drug Interactions with Paroxetine Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including Paroxetine Extended-Release Tablets, and MAOIs increases the risk of serotonin syndrome. Intervention Paroxetine Extended-Release Tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.6) , Contraindications (4) , Warnings and Precautions (5.2) ] . Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Pimozide and Thioridazine Clinical Impact Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias. Intervention Paroxetine Extended-Release Tablets are contraindicated in patients taking pimozide or thioridazine [see Contraindications (4) ]. Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with Paroxetine Extended-Release Tablets increases the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Paroxetine Extended-Release Tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2) ] . Examples Other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, St. John's Wort Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact The concurrent use of an antiplatelet agent or anticoagulant with Paroxetine Extended-Release Tablets may potentiate the risk of bleeding. Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of Paroxetine Extended-Release Tablets and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions (5.5) ] . Examples aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact Paroxetine Extended-Release Tablets are highly bound to plasma protein. The concomitant use of Paroxetine Extended-Release Tablets with another drug that is highly bound to plasma protein may increase free concentrations of Paroxetine Extended-Release Tablets or other tightly-bound drugs in plasma. Intervention Monitor for adverse reactions and reduce dosage of Paroxetine Extended-Release Tablets or other protein-bound drugs as warranted. Examples warfarin Drugs Metabolized by CYP2D6 Clinical Impact Paroxetine Extended-Release Tablets are a CYP2D6 inhibitor [see Clinical Pharmacology (12.3) ] . The concomitant use of Paroxetine Extended-Release Tablets with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention Decrease the dosage of a CYP2D6 substrate if needed with concomitant Paroxetine Extended-Release Tablets use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if Paroxetine Extended-Release Tablets are discontinued. Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone. Tamoxifen Clinical Im…

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 ]. Paroxetine Extended-Release Tablets are associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. While individual epidemiological studies on the association between paroxetine use and cardiovascular malformations have reported inconsistent findings, some meta-analyses of epidemiological studies have identified an increased risk of cardiovascular malformations (see Data ). There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data ) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including Paroxetine Extended-Release Tablets, during pregnancy. There also are risks associated with untreated depression in pregnancy (see Clinical Considerations ). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options. No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses are approximately 6 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 75 mg) on an mg/m 2 basis. When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m 2 basis (see Data ). The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of Paroxetine Extended-Release Tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5) ]. Fetal/Neonatal adverse reactions Neonates exposed to Paroxetine Extended-Release Tablets and other SSRIs 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, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs 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 (5.4) ] . Data Human Data Published epidemiological studies on the …

6 ADVERSE REACTIONS The following adverse reactions are included in more detail in other sections of the prescribing information: Hypersensitivity reactions to paroxetine [see Contraindications (4) ] Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1) ] Serotonin Syndrome [see Warnings and Precautions (5.2) ] Embryofetal Toxicity [see Warnings and Precautions (5.4) ] Increased Risk of Bleeding [see Warnings and Precautions (5.5) ] Activation of Mania/Hypomania [see Warnings and Precautions (5.6) ] Discontinuation Syndrome [see Warnings and Precautions (5.7) ] Seizures [see Warnings and Precautions (5.8) ] Angle-closure Glaucoma [see Warnings and Precautions (5.9) ] Hyponatremia [see Warnings and Precautions (5.10) ] Bone Fracture [see Warnings and Precautions (5.12) ] Sexual Dysfunction [see Warnings and Precautions (5.13) ] Most common adverse reactions (≥5% and at least twice placebo) in placebo-controlled MDD, PD, SAD, and PMDD clinical trials: abnormal ejaculation, abnormal vision, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, insomnia, libido decreased, nausea, somnolence, sweating, tremor. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals at 1-888-827-0616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data for Paroxetine Extended-Release Tablets is from 11 short-term, placebo-controlled clinical trials including 3 studies in patients with major depressive disorder (MDD) (Studies 1, 2, and 3), 3 studies in patients with panic disorder (PD) (Studies 4, 5, and 6), 1 study in patients with social anxiety disorder (SAD) (Study 7), and 4 studies in female patients with premenstrual dysphoric disorder (PMDD) (Studies 8, 9, 10, and 11) [see Clinical Studies (14) ] . These 11 trials included 1627 patients treated with Paroxetine Extended-Release Tablets. Studies 1 and 2 were 12-week studies that enrolled patients 18 to 65 years old who received Paroxetine Extended-Release Tablets at doses ranging from 25 mg to 62.5 mg once daily. Study 3 was a 12-week study in patients 60 to 88 years old who received Paroxetine Extended-Release Tablets at doses ranging from 12.5 mg to 50 mg once daily. Studies 4, 5, and 6 were 10-week studies in patients 19 to 72 years old who received Paroxetine Extended-Release Tablets at doses ranging from 12.5 mg to 75 mg once daily. Study 7 was a 12-week study that enrolled adult patients who received Paroxetine Extended-Release Tablets at doses ranging from 12.5 mg to 37.5 mg once daily. Studies 8, 9, and 10 were 12-week, placebo-controlled trials in female patients 18 to 46 years old who received Paroxetine Extended-Release Tablets at doses of 12.5 mg or 25 mg once daily. Study 11 was a 12-week placebo-controlled trial in patients 18 to 46 years old who received Paroxetine Extended-Release Tablets 2 weeks prior to the onset of menses (luteal phase dosing) at doses of 12.5 mg or 25 mg once daily. Adverse Reactions Leading to Discontinuation in Patients with MDD, PD, SAD, and PMDD In pooled studies in patients with MDD, PD and SAD, the most common adverse reactions leading to study withdrawal were: nausea (up to 4% of patients), asthenia, headache, depression, insomnia, and abnormal liver function tests (each occurring in up to 2% of patients), and dizziness, somnolence, and diarrhea (each occurring in up to 1% of patients). In pooled studies for PMDD, the most common adverse reactions leading to study withdrawal were: nausea (occurring in up to 6% of patients), asthenia (occurring in up to 5% of patients), somnolence (occurring in up to 4% of patients), insomnia (occurring in approximately 2% of pa…