PAROXETINE

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 )] .

5 WARNINGS AND PRECAUTIONS • Suicidality: Monitor for suicidality or unusual changes in behavior ( 5.1 ) • Serotonin Syndrome: Paroxetine capsules can cause serotonin syndrome with increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue paroxetine capsules and serotonergic agents and initiate supportive measures ( 5.2 , 7.3 ) • Tamoxifen: Efficacy of tamoxifen may be reduced when administered concomitantly with paroxetine capsules ( 5.3 , 7.1 ) • Abnormal Bleeding: Caution patients about the risk of bleeding associated with the concomitant use of paroxetine capsules and non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation ( 5.4 , 7.1 ) • Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients who have untreated anatomically narrow angles and who are treated with antidepressants. ( 5.5 ) • Hyponatremia: Can occur in association with syndrome of inappropriate antidiuretic hormone secretion (SIADH) (5.6) • Bone Fracture: Epidemiological studies have reported an association between SSRI treatment and fractures (5.7) • Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/ hypomania (5.8) • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.9) • Sexual Dysfunction: Paroxetine use may cause symptoms of sexual dysfunction. ( 5.10 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults SSRIs increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term trials for the treatment of major depressive disorder (MDD) and other psychiatric disorders - paroxetine capsules are not approved for use in any psychiatric condition or in pediatric and young adult patients [see Indications and Usage ( 1 ) and Use in Specific Populations ( 8.4 )] . There is limited information regarding suicidal thoughts and behaviors in females who use paroxetine capsules for treatment of moderate to severe VMS associated with menopause. The paroxetine capsules trials excluded females with a presence or history of previous psychiatric disorders. Monitor all paroxetine capsules-treated patients for any emergence of suicidal thoughts and behaviors, especially during the initial few months of paroxetine capsules therapy. Counsel family members to monitor for changes in behavior and to alert the health care provider if such changes occur. Consider discontinuing paroxetine capsules in patients who experience emergent suicidal thoughts or behaviors or symptoms that might be precursors to suicidal thoughts or behaviors, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. 5.2 Serotonin Syndrome Paroxetine capsules can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., monoamine oxidase inhibitors (MAOIs) [see Contraindications ( 4 ), Drug Interactions ( 7.3 )] . Serotonin syndrome can also occur when paroxetine capsules are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of paroxetine capsules with MAOIs is contraindicated. Do not start paroxetine capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports…

4 CONTRAINDICATIONS Paroxetine capsules 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 Interaction ( 7 )] . • Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions ( 5.3 ), Drug Interaction ( 7 )] . • Taking pimozide because of risk of QT prolongation [see Warnings and Precautions ( 5.3 ), Drug Interaction ( 7 )] . • With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in paroxetine capsules [see Adverse Reactions ( 6.2 )] . Who are or become pregnant because menopausal VMS does not occur during pregnancy and paroxetine capsules may cause fetal harm [see Use in Specific Populations ( 8.1 )] . • 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 )

7 DRUG INTERACTIONS 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 concomitant use 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 TCA dosage may need to be reduced if a TCA is used concomitantly with paroxetine capsules. Monitor tolerability. Risperidone Increased plasma concentrations of risperidone A lower risperidone dosage may be necessary (see the risperidone Prescribing Information for). Monitor tolerability. Atomoxetine Increased exposure of atomoxetine A lower atomoxetine dosage of may be necessary (see atomoxetine Prescribing Information for). Monitor tolerability. Drugs Highly Bound to Plasma Protein (e.g., Warfarin) Increased free plasma concentrations The warfarin dosage may need to be reduced. Monitor tolerability and the International Normalized Ratio. Digoxin Decreased plasma concentrations of digoxin The digoxin dosage of may need to be increased. Monitor digoxin concentrations and clinical effect. Theophylline Increased plasma concentrations of theophylline The theophylline dosage of may need to be decreased. Monitor theophylline concentrations and tolerability. Use caution with concomitant use of 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 Monitor clinical effect of paroxetine capsules. No paroxetine capsules dosage adjustment is needed. Phenytoin Decreased paroxetine exposure Fosamprenavir/ Ritonavir Decreased plasma concentration of paroxetine Cimetidine Increased plasma concentration of paroxetine Use caution if paroxetine capsules are used concomitantly with other drugs that inhibit CYP2D6 (e.g., quinidine). 7.3 Other Potentially Significant Drug Interactions Monoamine Oxidase Inhibitors Serious adverse reactions such as serotonin syndrome have been reported in patients treated with a SSRI and a concomitant monoamine oxidase inhibitor (MAOI), in patients started on an SSRI who re…

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…