Paroxetine Hydrochloride

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

1 INDICATIONS AND USAGE Paroxetine is indicated in adults for the treatment of: Major depressive disorder (MDD) Panic disorder (PD) Social anxiety disorder (SAD) Premenstrual dysphoric disorder (PMDD) Paroxetine is 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, reduce dose gradually. ( 2.7 ) 2.1 Important Administration Instructions Administer Paroxetine 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 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 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 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 Prior to initiating treatment with Paroxetine 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 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. In addition, at least 14 days must elapse after stopping Paroxetine before starting an MAOI antidepressant [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . 2.7 Discontinuation of Treatment with Paroxetine Adverse reactions may occur upon discontinuation of Paroxetine [see Warnings and Precautions ( 5.7 )] . Gradually reduce the dosage rather than stopping Paroxetine abruptly whenever possible.

3 DOSAGE FORMS AND STRENGTHS Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows: 12.5 mg white tablets (debossed with “KU” on one side and “470” on the other) 25 mg pink tablets (debossed with “KU” on one side and “471” on the other) 37.5 mg blue tablets (debossed with “KU” on one side and “472” on the other) Extended-release tablets: 12.5 mg, 25 mg, and 37.5 mg tablets. ( 3 )

4 CONTRAINDICATIONS Paroxetine is 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 [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. ( 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 Lannett Company, Inc. at 1-844-834-0530 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 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. Studies 1 and 2 were 12-week studies that enrolled patients 18 to 65 years old who received Paroxetine 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 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 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 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 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 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 impaired concentration, dry mouth, dizziness, decreased appetite, sweating, tremor, yawn and diarrhea (occurring in less than or equal to 2% of patients). Adverse …

7 DRUG INTERACTIONS Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of Paroxetine 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 Table 6 includes clinically significant drug interactions with Paroxetine. Table 6: Clinically Significant Drug Interactions with Paroxetine Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including Paroxetine, and MAOIs increases the risk of serotonin syndrome. Intervention Paroxetine is 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 is contraindicated in patients taking pimozide or thioridazine [see Contraindications ( 4 )] . Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with Paroxetine 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 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 may potentiate the risk of bleeding. Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of Paroxetine 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 is highly bound to plasma protein. The concomitant use of Paroxetine with another drug that is highly bound to plasma protein may increase free concentrations of Paroxetine or other tightly-bound drugs in plasma . Intervention Monitor for adverse reactions and reduce dosage of Paroxetine or other protein-bound drugs as warranted. Examples warfarin Drugs Metabolized by CYP2D6 Clinical Impact Paroxetine is a CYP2D6 inhibitor [see Clinical Pharmacology ( 12.3 )] . The concomitant use of Paroxetine 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 use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if Paroxetine is discontinued. Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone. Tamoxifen Clinical Impact Concomitant use of tamoxifen with Paroxetine may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen Intervention Consider use of an alternative antidepressant little or no CYP2D6 inhibition [see Warnings and Precautions ( 5.11 )] . Fosamprenavir/Ritonavir Clinical Impact Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Intervention Any dose …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. ( 5.4 , 8.1 ) Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother. ( 8.3 ) 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions ( 5.4 )] 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. 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. 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). 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 be …

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, USP contain paroxetine hydrochloride, an SSRI. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)- trans -4 R- (4'-fluorophenyl)-3 S -[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of C 19 H 20 FNO 3 •HCl•1/2H 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 is an odorless, off-white powder, having a melting point range of 120° C to 138°C and a solubility of 5.4 mg/mL in water. Paroxetine Extended-Release Tablets, USP are intended for oral administration. Each enteric, film-coated, extended-release tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 12.5 mg–white, 25 mg–pink and 37.5 mg–blue. Inactive ingredients consist of hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid and ethyl acrylate copolymer dispersion, polyethylene glycols, polyvinyl alcohol, povidone, silicon dioxide, talc, titanium dioxide, triethyl citrate. In addition, the 25 mg and 37.5 mg colorant contains FD&C Blue No. 2 aluminum lake. In addition, the 25 mg colorant also contains carmine. Paroxetine meets USP Dissolution Test 3. Formula

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 are supplied as film-coated, extended-release, round convex tablets, as follows: 12.5 mg white tablets (debossed with “KU” on one side and “470” on the other) NDC 62175-470-32 Bottles of 30 NDC 62175-470-41 Bottles of 500 25 mg pink tablets (debossed with “KU” on one side and “471” on the other) NDC 62175-471-32 Bottles of 30 NDC 62175-471-41 Bottles of 500 37.5 mg blue tablets (debossed with “KU” on one side and “472” on the other) NDC 62175-472-32 Bottles of 30 NDC 62175-472-41 Bottles of 500 Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].