paroxetine

Warnings and Precautions, Sexual Dysfunction ( 5.12 ) 09/2023

1 INDICATIONS AND USAGE Paroxetine capsules are indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. Limitations of Use : Paroxetine capsules are not indicated for the treatment of any psychiatric condition. Paroxetine capsules have a lower recommended paroxetine dosage than that used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and post-traumatic stress disorder. The safety and effectiveness of the lower paroxetine capsules dosage have not been established for any psychiatric condition. Patients who require paroxetine for treatment of a psychiatric condition should discontinue paroxetine capsules and initiate a paroxetine-containing product that is indicated for such use. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause (VMS) ( 1 ) Limitations of Use : Paroxetine capsules are not indicated for the treatment of any psychiatric condition ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dosage of paroxetine capsules is 7.5 mg once daily, at bedtime ( 2.1 ) 2.1 Recommended Dosage The recommended oral dosage of paroxetine capsules for the treatment of moderate to severe VMS associated with menopause is 7.5 mg once daily, at bedtime, with or without food [see Clinical Pharmacology ( 12.3 )] . 2.2 Use of Paroxetine Capsules Before or After a Monoamine Oxidase Inhibitor Wait at least 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI) before initiating therapy with paroxetine capsules. Conversely, allow at least 14 days after stopping paroxetine capsules before starting an MAOI [see Contraindications ( 4.1 ), Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.3 )] .

3 DOSAGE FORMS AND STRENGTHS Paroxetine capsules are available as 7.5 mg white opaque capsules printed with “544” in black ink on the cap and “7.5 mg” in black ink on the body. Each capsule contains 9.69 mg of paroxetine mesylate equivalent to 7.5 mg paroxetine base. Capsules: 7.5 mg ( 3 )

4 CONTRAINDICATIONS • Concurrent use with monoamine oxidase inhibitors (MAOI) or use within 14 days of MAOI use ( 2.2 , 4.1 , 5.2 , 7.3 ) • Use with thioridazine ( 4.2 , 7.1 ) • Use with pimozide ( 4.3 , 7.1 ) • Hypersensitivity to any ingredient in paroxetine capsules ( 4.4 ) • Pregnancy ( 4.5 , 8.1 ) 4.1 Monoamine Oxidase Inhibitors Concomitant use of an MAOI with paroxetine capsules or within 14 days of stopping treatment with paroxetine capsules is contraindicated because of an increased risk of serotonin syndrome. The use of paroxetine capsules within 14 days of stopping an MAOI is also contraindicated [see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Drug Interactions (7.3)] . Starting paroxetine capsules in a patient who is being treated with linezolid or intravenous methylene blue, both of which inhibit monoamine oxidase, is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Drug Interactions (7.3)] . 4.2 Thioridazine Concomitant use of paroxetine capsules with thioridazine is contraindicated, because thioridazine prolongs the QT interval, and paroxetine can increase thioridazine levels [see Drug Interactions (7.1)] . 4.3 Pimozide Concomitant use of paroxetine capsules with pimozide is contraindicated because pimozide prolongs the QT interval, and paroxetine increases pimozide levels [see Drug Interactions (7.1)] . 4.4 Hypersensitivity to any Ingredient in Paroxetine Capsules Paroxetine capsules are contraindicated in patients with a history of hypersensitivity to paroxetine or any of the other ingredients in paroxetine capsules. 4.5 Pregnancy Menopausal VMS does not occur during pregnancy and paroxetine capsules may cause fetal harm [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: • Suicidality [see Warnings and Precautions ( 5.1 )] • Serotonin syndrome [see Warnings and Precautions ( 5.2 )] • Abnormal bleeding [see Warnings and Precautions ( 5.4 )] • Angle-Closure Glaucoma [see Warnings and Precautions ( 5.5 )] • Hyponatremia [see Warnings and Precautions ( 5.6 )] • Bone Fracture [see Warnings and Precautions ( 5.7 )] • Mania/Hypomania [see Warnings and Precautions ( 5.8 )] • Seizure [see Warnings and Precautions ( 5.9 )] The most common adverse reactions (≥ 2%) reported in clinical trials were: headache, fatigue, and nausea/vomiting (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare LLC at 1-866-257-2597 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 directly be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to paroxetine in the following randomized, placebo-controlled trials for the treatment of moderate to severe VMS associated with menopause [see Clinical Studies ( 14 )]: (1) one 8-week Phase 2 trial, (2) one 12-week Phase 3 trial and (3) one 24-week Phase 3 trial. In these trials, a total of 635 postmenopausal females received paroxetine 7.5 mg administered orally once daily and 641 postmenopausal females received placebo. In these trials, 68% were White, 30% were Black or African American (30%), and 2% were other races, with a mean age of 55 years (range 40 to 73 years). Postmenopausal females with a history of suicidal ideation or suicidal behavior were excluded from these trials. Serious Adverse Reactions: In the pooled Phase 2 and Phase 3 trials, three paroxetine-treated patients reported a serious adverse reaction of suicidal ideation and one paroxetine-treated patient reported a serious adverse reaction of suicide attempt. There were no serious adverse reactions of suicidal ideation or suicide attempt reported among the placebo-treated patients. Adverse Reactions Leading to Study Discontinuation : A total of 4.7% of females taking paroxetine capsules discontinued from the clinical trials due to an adverse reaction, compared to 3.7% of females on placebo; the most frequent adverse reactions leading to discontinuation among paroxetine-treated females were: abdominal pain (0.3%), attention disturbances (0.3%), headache (0.3%), and suicidal ideation (0.3%). Common Adverse Reactions : Overall, based on investigators’ determinations about what events were likely to be drug-related, about 20% of postmenopausal females treated with paroxetine capsules reported at least 1 adverse reaction in the three controlled trials. The most common adverse reactions (≥ 2% and at a higher incidence in paroxetine capsules-treated females compared to placebo-treated females) reported in these trials were headache, fatigue/malaise/lethargy, and nausea/vomiting. Of these commonly reported adverse reactions, nausea occurred primarily within the first 4 weeks of paroxetine treatment and fatigue occurred primarily within the first week of paroxetine treatment, and decreased in frequency with continued therapy. The adverse reactions that occurred in ≥ 2% of paroxetine-treated patients and at a higher incidence in paroxetine-treated females compared to placebo-treated females are shown in Table 1 for the pooled Phase 2 and Phase 3 trials. Table 1: Incidence of Common Adverse Reactions in the Phase 2 and Phase 3 Trials of Postmenopausal Females with Moderate to Severe VMS 1 Incidence n (%) Paroxetine Capsules (n = 635) Placebo (n = 641) Headache 40 (6.3) 31 (4.8) Fatigue, malaise, lethargy 31 (4.9) 18 (2.8) Nausea, vomiting 27 (4.3) 15 (2.3) 1 ≥ 2% Paroxetine-treated patients and at a higher incidence in paroxetine-treated females com …

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with paroxetine capsules. Paroxetine is a strong CYP2D6 inhibitor. Co-administration of paroxetine capsules can alter concentrations of other drugs that are metabolized by CYP2D6. Consider potential drug interactions prior to and during therapy ( 5.3 , 7.1 , 7.3 ). See Full Prescribing Information for a list of clinically significant drug interactions ( 7.1 , 7.2 , 7.3 ) 7.1 Potential for Paroxetine Capsules to Affect Other Drugs Paroxetine is a strong CYP2D6 inhibitor. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 [see Clinical Pharmacology (12.3)] . Table 2 contains examples of drugs with a metabolism that may be affected by co-administration with paroxetine capsules. Table 2 Effects of Paroxetine on Other Drugs Concomitant Drug Name Effect of Paroxetine on Other Drugs Clinical Recommendations Thioridazine Increased plasma concentrations of thioridazine Potential QTc prolongation Concomitant use of thioridazine and paroxetine capsules is contraindicated. Pimozide Increased plasma concentrations of pimozide. Potential QTc prolongation Concomitant use of pimozide and paroxetine capsules is contraindicated. Tamoxifen Reduced plasma concentrations of active tamoxifen metabolite Consider avoiding concomitant use of tamoxifen and paroxetine capsules. Tricyclic Antidepressants (TCA) (e.g., Desipramine) Increased plasma concentrations and elimination half-life Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced if a TCA is co-administered with paroxetine capsules. Monitor tolerability. Risperidone Increased plasma concentrations of risperidone A lower dosage of risperidone may be necessary (see the Full Prescribing Information for risperidone). Monitor tolerability. Atomoxetine Increased exposure of atomoxetine A lower dosage of atomoxetine may be necessary (see Full Prescribing Information for atomoxetine). Monitor tolerability. Drugs Highly Bound to Plasma Protein (e.g., Warfarin) Increased free plasma concentrations The dosage of warfarin may need to be reduced. Monitor tolerability and the International Normalized Ratio. Digoxin Decreased plasma concentrations of digoxin Dosage of digoxin may need to be increased. Monitor digoxin concentrations and clinical effect. Theophylline Increased plasma concentrations of theophylline Dosage of theophylline may need to be decreased. Monitor theophylline concentrations and tolerability. Use caution if co-administering paroxetine capsules with other drugs that are metabolized by CYP2D6, including nortriptyline, amitriptyline, imipramine, desipramine, fluoxetine, phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide). 7.2 Potential for Other Drugs to Affect Paroxetine Capsules The metabolism and pharmacokinetics of paroxetine may be affected by the induction and inhibition of drug metabolizing enzymes such as CYP2D6. Table 3 contains a list of drugs that may affect the pharmacokinetics of paroxetine capsules when administered concomitantly [see Clinical Pharmacology (12.3)] . Table 3 Effects of Other Drugs on Paroxetine Concomitant Drug Name Effect of Concomitant Drug on Paroxetine Clinical Recommendations Phenobarbital Decreased paroxetine exposure No dose adjustment for paroxetine capsules. Monitor clinical effect of paroxetine capsules. Phenytoin Decreased paroxetine exposure Fosamprenavir/Ritonavir Decreased plasma concentration of paroxetine Cimetidine Increased plasma concentration of paroxetine Use caution if co-administering paroxetine capsules with other drugs that inhibit CYP2D6 (e.g., quinidine). 7.3 Other Potentially Significant Drug Interactions Monoamine Oxidase Inhibitors (MAOIs) Serious adverse reactions such as serotonin syndrome have been reported in patients receiving a concomitant SSRI and MAOI, …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X Risk Summary Paroxetine capsules are contraindicated in pregnant women because menopausal VMS does not occur during pregnancy and paroxetine can cause fetal harm. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy may have an increased risk of cardiovascular malformations. Cardiac malformations are a common congenital abnormality. These data would suggest that the risk of a cardiac abnormality following paroxetine exposure in the first trimester may increase the risk from 1% to 2%. Exposure to SSRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). No teratogenicity was seen in reproductive development studies conducted in rats and rabbits. However, an increase in rat pup deaths was seen during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation, at a dose approximately equal to the maximum recommended human dose (MRHD) for VMS (7.5 mg) on an mg/m 2 basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Human Data First-Trimester Pregnancy Exposure • Epidemiologic studies which include data from the Swedish National Registry, a retrospective cohort study using United Healthcare data and a meta-analysis of studies (1992-2008) have shown a less than 2-fold increased risk of cardiac malformations, primarily ventricular septal and atrial septal defects, with first-trimester paroxetine exposure. Two case-control studies using separate databases with > 9000 birth defect cases and > 4000 controls showed 7 and 6 paroxetine-exposed infants respectively, with right ventricular outflow tract obstructions, a 2- to 3-fold increased risk. An increase in overall congenital malformations with first-trimester paroxetine use was not observed in all studies. Third-Trimester Pregnancy Exposure • Neonates exposed to 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, tremor, jitteriness, irritability, and constant crying. These features 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 (5.2)] . • Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1000 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 6-fold higher for infants exposed to SSRIs after the 20 th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. Animal Data 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 approximat …

12.1 Mechanism of Action Nonclinical studies have shown that paroxetine is an SSRI. Paroxetine capsules are not an estrogen, and its mechanism of action for the treatment of VMS is unknown.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nonclinical studies have shown that paroxetine is an SSRI; paroxetine is not an estrogen. The mechanism of action of paroxetine for the treatment of moderate to severe VMS associated with menopause is unknown. Studies at clinically relevant paroxetine doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. Paroxetine is a neuronal serotonin reuptake inhibitor with weak effects on norepinephrine and dopamine neuronal reuptake in vitro. Paroxetine also has low affinity for muscarinic alpha 1 -, alpha 2 -, beta-adrenergic, dopamine (D 2 )-, 5-HT 1 -, 5-HT 2 -, and histamine (H 1 )-receptors. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of paroxetine for the treatment of moderate to severe VMS associated with menopause have not been fully characterized. 12.3 Pharmacokinetics Absorption Paroxetine is completely absorbed after oral dosing. In a study in which healthy postmenopausal females (n=24) received paroxetine capsules 7.5 mg once daily for 14 days, steady-state paroxetine concentrations were achieved by approximately 12 days of dosing for most subjects, although it may take substantially longer in an occasional patient. Peak concentrations were reached at a median of 6 hours (3 to 8 hours range). Steady-state mean values of C max , C min , and AUC 0-last were 13.10 ng/mL (CV 91%), 7.17 ng/mL (CV 99%), and 237 hr * ng/mL (CV 94%), respectively. Steady-state AUC 0-24 values were about 3 times those of AUC 0-inf following a single paroxetine dose, indicating non-linear pharmacokinetics. Steady-state C max values were approximately 5 times greater than those attained after a single paroxetine dose and steady-state exposure based on AUC 0-24 was about 10 times greater than AUC 0-24 after a single dose. The nonlinear kinetics and excess accumulation are due to the fact that CYP2D6, an enzyme that is in part responsible for paroxetine metabolism, is readily saturable. Effect of Food: The effects of food on the bioavailability of paroxetine were studied after administration of another paroxetine product with a dosage higher than paroxetine. AUC was slightly increased (6%) when paroxetine was administered with food and the C max was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. These changes are not clinically significant [see Dosage and Administration ( 2.1 )] . Distribution Paroxetine distributes throughout the body, including the central nervous system, 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. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Elimination Metabolism: 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 cytochrome CYP2D6. The role of this enzyme in paroxetine metabolism also suggests potential drug interactions [see Drug Interactions ( 7 )] . At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes, which, unlike CYP2D6, show no evidence of saturation. Excretion: Approximately 64% of a 30 mg oral solution of another paroxetine product (four times the recommended paroxetine capsules dosage) was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% of the dose was excreted in the fece …

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 pro-serotonergic 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 (1-800-221-2222) or a medical toxicologist for overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Paroxetine capsules are available as 7.5 mg white opaque capsules printed with “544” in black ink on the cap and “7.5 mg” in black ink on the body. NDC 43547-409-03, bottle of 30 Store at 20 o C to 25 o C (68 o F to 77 o F); excursions permitted to 15 o C to 30 o C (59 o F to 86 o F) [See USP Controlled Room Temperature]. Protect from light and humidity.