Paroxetine

RECENT MAJOR CHANGES Warnings and Precautions, Sexual Dysfunction( 5.13 ) 9/2021

1 INDICATIONS AND USAGE Paroxetine extended-release tablets 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 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 ) Ind ication St a rting Dose M a x imum 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 M aximum 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 an 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.

3 DOSAGE FORMS AND STRENGTHS Paroxetine extended-release tablets are available as: • 12.5 mg yellow, biconvex, enteric film-coated, extended release, round tablets, debossed with “X1” on one side and plain on the other side. The tablets should be free from all physical defects. • 25 mg pink, biconvex, enteric film-coated, extended release, round tablets debossed with "X2" on one side and plain on the other side. The tablets should be free from all physical defects. • 37.5 mg blue, biconvex, enteric film-coated, extended release, round tablets debossed with "X3" on one side and plain on the other side. The tablets should be free from all physical defects. Extended-release tablets: 12.5 mg, 25 mg, and 37.5 mg tablets. ( 3 )

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 )

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 and Neonatal 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 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 patients); and im …

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 M onoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including paroxetine extended-release tablets, and MAOIs increases the risk of serotonin syndrome. I ntervention 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 )]. Ex amples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue P i m o z ide 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. I ntervention 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. I ntervention 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 )]. Ex amples Other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, St. John’s Wort Dr ugs 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. I ntervention 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 )]. Ex amples aspirin, clopidogrel, heparin, warfarin Dr ugs 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. I ntervention Monitor for adverse reactions and reduce dosage of paroxetine extended-release tablets or other protein-bound drugs as warranted. Ex amples warfarin Dr ugs 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. Ex amples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risp …

8 USE IN SPECIFIC POPULATIONS Pregnancy: SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability) in the neonate. ( 5.4 , 8.1 ) Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother. ( 8.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online At https://womens mental health.org/clinical-and-research programs/pregnancyregistry/antidepressants/. 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 is 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/m2 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/m2 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 exp …

12.1 Mechanism of Action The mechanism of action of paroxetine in the treatment of major depressive disorder (MDD), panic disorder (PD), social anxiety disorder (SAD), and premenstrual dysphoric disorder (PMDD) 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-HT).

11 DESCRIPTION Paroxetine extended-release tablets, contains paroxetine hydrochloride hemihydrate, USP an SSRI. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (3S,4R)-3-[(1,3 benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl) piperidine hydrochloride hemihydrate or Piperidine, 3-[(1,3-benzodioxol-5-yloxy)methyl]- 4-( 4-fluorophenyl)-, hydrochloride, (3S-trans)- and has the empirical formula of C 19 H 20 FNO 3 •HCl• 1 / 2 H 2 O. The molecular weight is 374.8 g/mol (329.4 g/mol as free base). The structural formula of paroxetine hydrochloride is: Paroxetine hydrochloride hemihydrate, USP is a white to off white solid (or) powder, having a melting point range of 120°C to 142°C and soluble in methanol and in alcohol; slightly soluble in water. Paroxetine extended-release tablets are intended for oral administration. Each film-coated, extended-release tablet contains paroxetine hydrochloride USP equivalent to paroxetine 12.5 mg, 25 mg and 37.5 mg. One layer of the tablet consists of a degradable barrier layer and the other contains the active material in a hydrophilic matrix. Inactive ingredients consist of ferric oxide yellow, glyceryl behenate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid – ethyl acrylate copolymer (1:1) type A, polyethylene glycols, polysorbate 80, polyvinylpyrrolidone, silicon dioxide, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, film-coating material contains - FD&C Yellow #6/sunset yellow FCF aluminum lake, FD&C blue #2/Indigo carmine AL 3% to 5% and D&C Yellow #10 aluminum lake for 12.5 mg; D&C Red #30/Helendon pink aluminum lake for 25 mg and FD&C blue #2/Indigo carmine AL 3% to 5% and FD&C blue #2 Indigo carmine aluminum lake for 37.5 mg. paroxetine-structure.jpg

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Paroxetine extended-release tablets USP, 12.5 mg are supplied as yellow colored, round shaped, biconvex, film coated tablets imprinted with "L067" on one side and plain on other side. They are available as follows: Bottle of 30 tablets (NDC 68180-647-06) Bottle of 100 tablets (NDC 68180-647-01) Bottle of 500 tablets (NDC 68180-647-02) Bottle of 1000 tablets (NDC 68180-647-03) Paroxetine extended-release tablets USP, 25 mg are supplied as pink colored, round shaped, biconvex, film coated tablets imprinted with "L068" on one side and plain on other side. They are available as follows: Bottle of 30 tablets (NDC 68180-646-06) Bottle of 100 tablets (NDC 68180-646-01) Bottle of 500 tablets (NDC 68180-646-02) Bottle of 1000 tablets (NDC 68180-646-03) Paroxetine extended-release tablets USP, 37.5 mg are supplied as blue colored, round shaped, biconvex tablets imprinted with "L069" on one side and plain on other side. They are available as follows: Bottle of 30 tablets (NDC 68180-645-06) Bottle of 100 tablets (NDC 68180-645-01) Bottle of 500 tablets (NDC 68180-645-02) Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].