PAROXETINE

Paroxetine is an orally administered selective serotonin reuptake inhibitor (SSRI) for the treatment of moderate to severe VMS associated with menopause. It is identified chemically as (-)- trans -4R- (4’-fluorophenyl) - 3S - [(3’,4’-methylenedioxyphenoxy) methyl] piperidine mesylate and has the empirical formula of C 19 H 20 FNO 3 •CH 3 SO 3 H. The molecular weight is 425.5 (329.4 as free base). The structural formula is: The mesylate salt of paroxetine is an odorless, off-white powder, having a melting point range of 147° to 150°C and a solubility of more than 1 g/mL in water. Each pink capsule contains 9.69 mg paroxetine mesylate equivalent to 7.5 mg paroxetine base. Inactive ingredients consist of: dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, gelatin, titanium dioxide, FD&C Yellow #6, FD&C Red #3, FD&C Red #40, shellac, and black iron oxide. chemical-structure

Paroxetine Capsules are indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. Limitation of Use: Paroxetine capsules are not indicated for the treatment of any psychiatric condition. Paroxetine capsules contain a lower dose of paroxetine than that used to treat depression, obsessive compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and post-traumatic stress disorder. The safety and efficacy of this lower dose of paroxetine in paroxetine capsules 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 medication that is indicated for such use. • Paroxetine capsules are a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause (VMS) ( 1 ) Limitation of Use: Paroxetine capsules are not indicated for the treatment of any psychiatric condition ( 1 )

• The recommended dosage of paroxetine capsules is 7.5 mg once daily, at bedtime (2.1) 2.1 Dosage Information The recommended dosage of paroxetine capsules for the treatment of moderate to severe VMS is 7.5 mg once daily, at bedtime, with or without food. 2.2 Use of Paroxetine Capsules Before or After a Monoamine Oxidase Inhibitor (MAOI) Wait at least 14 days after discontinuation of an 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)] .

• 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)].

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)] • Akathisia [see Warnings and Precautions (5.10)] • The most common adverse reactions (≥ 2%) reported in clinical trials were: headache, fatigue, and nausea/vomiting ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis at 1-866-634-9120 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 capsules in the one 8-week Phase 2 randomized, placebo-controlled trial and the two Phase 3 randomized, placebo-controlled, 12-week and 24-week trials for the treatment of moderate to severe VMS [see Clinical Studies (14)] . In these trials, a total of 635 women were exposed to paroxetine capsules 7.5 mg administered orally once daily and 641 women received placebo. The majority of paroxetine capsule-treated patients were Caucasian (68%) and African American (30%), with a mean age of 55 years (range 40 to 73 years). Women with a history of suicidal ideation or suicidal behavior were excluded from these studies. Adverse Reactions Leading to Study Discontinuation: A total of 4.7% of women taking paroxetine capsules discontinued from the clinical trials due to an adverse reaction, compared to 3.7% of women on placebo; the most frequent adverse reactions leading to discontinuation among paroxetine-treated women 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 women treated with paroxetine capsules reported at least 1 adverse reaction in the three controlled studies. The most common adverse reactions (≥ 2% and more common among paroxetine capsule-treated women) reported in these studies were headache, fatigue/malaise/lethargy, and nausea/vomiting. Of these commonly reported adverse reactions, nausea occurred primarily within the first 4 weeks of treatment and fatigue occurred primarily within the first week of treatment, and decreased in frequency with continued therapy. The adverse reactions that occurred in at least 2% of patients in the paroxetine capsule group and at a higher incidence than placebo are shown in Table 1 for the pooled Phase 2 and Phase 3 trials. Table 1 Frequency of Adverse Reactions in the Phase 2 and Phase 3 Trials (≥ 2% and at a higher incidence than placebo) Frequency n (%) Paroxetine Capsules (n = 635) Placebo (n = 641) Nervous system disorders Headache 40 (6.3) 31 (4.8) General disorders and administration site conditions Fatigue, malaise, lethargy 31 (4.9) 18 (2.8) Gastrointestinal disorders Nausea, vomiting 27 (4.3) 15 (2.3) Certain symptoms were seen more frequently in women at the time of discontinuation of paroxetine capsules compared to women discontinuing placebo, and have also been reported upon discontinuation of other formulations of paroxetine, particularly when abrupt. These include increased dreaming/nightmares, muscle cramps/spasms/twitching, headache, nervousness/anxiety, fatigue/tiredness, restless feeling in legs, and trouble sleeping/insomnia. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms with other formulations of paroxetine. Serious Adverse Reactions: In the pooled Phase 2 and Phase 3 trials, three paroxetine capsule-treated patients reported a serious adverse reaction of suicidal ideation and one paroxetine capsule-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. 6.2 Postmarketing Experience The following adverse reactions have been identified from clinical studies of paroxetine and during post-approval use of other formulations of paroxetine. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpura, Events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, agranulocytosis). Cardiac Disorders: Atrial fibrillation, Pulmonary edema, Ventricular fibrillation, Ventricular tachycardia (including torsades de pointes). Gastrointestinal Disorders: Pancreatitis, Pancreatitis hemorrhagic, Vomiting. General Disorders and Administration Site Conditions: Death, Drug withdrawal syndrome, Malaise. Hepatobiliary Disorders: Drug-induced liver injury, Hepatic failure, Jaundice. Immune System Disorders: Anaphylactoid reaction, Angioedema, Toxic epidermal necrolysis. Investigations: Elevated liver tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction). Metabolism and Nutrition Disorders: Diabetes mellitus inadequate control, Type 2 diabetes mellitus. Nervous System Disorders: Neuroleptic malignant syndrome, Paresthesia, Somnolence, Tremor, Anosmia, Hyposmia. Psychiatric Disorders: Aggression, Agitation, Anxiety, Confusional state, Depression, Disorientation, Homicidal ideation, Insomnia, Restlessness. Respiratory, Thoracic and Mediastinal Disorders: Pulmonary hypertension. Skin and Subcutaneous Tissue Disorders: Hyperhidrosis, Stevens-Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS).

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, in patients started on an SSRI who recently received an MAOI and in patients started on an MAOI who recently received an SSRI. Therefore, concomitant use of MAOIs with paroxetine capsules or use of paroxetine capsules and an MAOI within 14 days of each other is contraindicated [see Dosage and Administration (2.2), Contraindications (4.1) and Warnings and Precautions (5.2)] . Serotonergic Drugs If concomitant use of paroxetine capsules with other serotonergic drugs (e.g., other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) is clinically warranted, consider the increased risk of serotonin syndrome and carefully observe the patient, particularly during treatment initiation [see Warnings and Precautions (5.2)] . An interaction between paroxetine and tryptophan may occur when they are co-administered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine capsules with tryptophan is not recommended. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are co-administered with NSAIDs, aspirin, and warfarin or other drugs that affect coagulation. There may be a pharmacodynamic interaction between paroxetine and warfarin that causes an increased bleeding diathesis despite unaltered prothrombin time. Carefully monitor patients receiving warfarin therapy when paroxetine capsules is initiated or discontinued [see Warnings and Precautions (5.4)] .