PAROXETINE

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nonclinical studies have shown that paroxetine is an SSRI. Paroxetine is not an estrogen, and its mechanism of action for the treatment of VMS is unknown. 12.2 Pharmacodynamics Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a selective inhibitor of neuronal serotonin reuptake and has weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic alpha 1 -, alpha 2 -, beta-adrenergic-, dopamine (D 2 )-, 5-HT 1 -, 5-HT 2 -, and histamine (H 1 )-receptors. 12.3 Pharmacokinetics Absorption, Distribution, Metabolism and Excretion Absorption Paroxetine is completely absorbed after oral dosing of the mesylate salt. In a study in which healthy postmenopausal women (n=24) received Paroxetine Capsules 7.5 mg capsules as a daily dose 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 dose, indicating non-linear pharmacokinetics. Steady-state C max values were approximately 5 times greater than those attained after a single 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. The effects of food on the bioavailability of paroxetine were studied with paroxetine tablets at higher strength. AUC was only slightly increased (6%) when drug was administered with food but 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. Paroxetine Capsules can be taken with or without food. 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. Under clinical conditions, paroxetine concentrations would normally be less than 100 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. 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. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-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 paroxetine 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 feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period. Specific Populations Renal and Liver Impairment Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentration in patients with creatinine clearance below 30 mL/min was approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min and patients with hepatic impairment had about a 2-fold increase in plasma concentrations (AUC, C max ). No Paroxetine Capsules dose adjustment is considered necessary in patients with renal or hepatic impairment. Elderly Patients In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30, and 40 mg, C min concentrations were about 70% to 80% greater than the respective C min concentrations in nonelderly subjects. No Paroxetine Capsules dose adjustment is considered necessary in elderly patients. Drug Interaction Studies Potential Effect of Paroxetine Capsules on Other Drugs Drugs Metabolized by CYP3A4 An in vivo drug interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for CYP3A4, including astemizole, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Drugs Metabolized by CYP2D6 Many drugs are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. Specific studies investigating the effect of paroxetine on drugs metabolized by CYP2D6 are listed below: Pimozide: Higher doses of paroxetine have been shown to elevate plasma levels of pimozide. In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C max of 62%, compared to pimozide administered alone [see Drug Interactions ( 7.1 )] . Tamoxifen: It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6. However, other studies have failed to demonstrate such a risk [see Warnings and Precautions ( 5.3 ) and Drug Interactions ( 7.1 )] . Desipramine: In one study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C max , AUC, and T 1/2 by an average of approximately 2-, 5-, and 3-fold, respectively [see Drug Interactions ( 7.1 )] . Risperidone: Daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day), a CYP2D6 substrate, increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold [see Drug Interactions ( 7.1 )] . Atomoxetine: The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady-state atomoxetine AUC values that were 6-to 8-fold greater and in atomoxetine C max values that were 3-to 4-fold greater than when atomoxetine was given alone [see Drug Interactions ( 7.1 )] . Digoxin: Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine [see Drug Interactions ( 7.1 )] . Beta Blockers: In a study in which propranolol (80 mg twice daily) was dosed orally for 18 days, the steady-state plasma concentrations of propranolol were unaltered during co-administration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated. Potential Effect of Other Drugs on Paroxetine Capsules Concomitant use of paroxetine with other drugs that alter CYP enzymes activities including CYP2D6 may affect the plasma concentrations of paroxetine. Specific studies investigating the effect of other drugs on paroxetine are listed below: Cimetidine: Cimetidine inhibits many cytochrome P450 enzymes. In a study in which paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during co-administration with oral cimetidine (300 mg three times daily) for the final week [see Drug Interactions ( 7.2 )] . Phenobarbital: Phenobarbital induces many cytochrome P450 enzymes. When a single oral 30 mg dose of paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T 1/2 were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Because paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed [see Drug Interactions ( 7.2 )] . Phenytoin: When a single oral 30 mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T 1/2 were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Because both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed [see Drug Interactions ( 7.2 )] . Digoxin: A clinical drug interaction study showed that concurrent use of digoxin did not affect paroxetine exposure. Diazepam: A clinical drug interaction study showed that concurrent use of diazepam did not affect paroxetine exposure.

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 is 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 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 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 Capsules-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 Capsules-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 Capsules 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 Capsules-treated patients reported a serious adverse reaction of suicidal ideation and one Paroxetine Capsules-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. 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.

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 Antidepressant (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 Phenytoin Decreased paroxetine exposure No dose adjustment for Paroxetine Capsules. Monitor clinical effect of Paroxetine Capsules. 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., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, 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. If concomitant use of Paroxetine Capsules with a serotonergic drug is warranted, carefully observe the patient, particularly during treatment initiation. There have been postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. Paroxetine Capsules contain paroxetine, which is also the active ingredient in other drugs. The concomitant use of Paroxetine Capsules with other paroxetine products is not recommended [see Indications and Usage ( 1 )] . 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 are initiated or discontinued [see Warnings and Precautions ( 5.4 )] .