BRISDELLE

BRISDELLE (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 of 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. image description

BRISDELLE is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. Limitations of Use: BRISDELLE is not indicated for the treatment of any psychiatric condition. BRISDELLE has 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 BRISDELLE dosage has not been established for any psychiatric condition. Patients who require paroxetine for treatment of a psychiatric condition should discontinue BRISDELLE and initiate a paroxetine-containing product that is indicated for such use. BRISDELLE 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 : BRISDELLE is not indicated for the treatment of any psychiatric condition ( 1 )

The recommended dosage of BRISDELLE is 7.5 mg once daily, at bedtime ( 2.1 ) 2.1 Recommended Dosage The recommended oral dosage of BRISDELLE 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 BRISDELLE Before or After a Monoamine Oxidase Inhibitor Wait at least 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI) before initiating therapy with BRISDELLE. Conversely, allow at least 14 days after stopping BRISDELLE before starting an MAOI [see Contraindications ( 4.1 ), Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.3 )] .

BRISDELLE 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 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 BRISDELLE [see Adverse Reactions ( 6.2 )] Who are or become pregnant because menopausal VMS does not occur during pregnancy and BRISDELLE 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 BRISDELLE ( 4.4 ) Pregnancy ( 4.5 , 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 )] The most common adverse reactions (≥ 2%) reported in clinical trials were: headache, fatigue, and nausea/vomiting ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Legacy Pharma Inc. at 1-800-727-7151 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 BRISDELLE 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 BRISDELLE 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 BRISDELLE-treated patients reported a serious adverse reaction of suicidal ideation and one BRISDELLE-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 BRISDELLE 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 BRISDELLE reported at least 1 adverse reaction in the three controlled trials. The most common adverse reactions (≥ 2% and at a higher incidence in BRISDELLE-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 BRISDELLE treatment and fatigue occurred primarily within the first week of BRISDELLE treatment, and decreased in frequency with continued therapy. The adverse reactions that occurred in ≥ 2% of BRISDELLE-treated patients and at a higher incidence in BRISDELLE-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 (%) BRISDELLE (n = 635) BRISDELLE (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% BRISDELLE-treated patients and at a higher incidence in BRISDELLE-treated females compared to placebo-treated females. Adverse Reactions After Discontinuing BRISDELLE Certain symptoms were seen more frequently in postmenopausal females at the time of discontinuation of BRISDELLE compared to discontinuation of placebo and have also been reported upon discontinuation of other paroxetine products, particularly after abrupt discontinuation. Adverse reactions reported after discontinuation of BRISDELLE included increased dreaming/nightmares, muscle cramps/spasms/twitching, headache, nervousness/anxiety, fatigue/tiredness, restless feeling in legs, and trouble sleeping/insomnia. While these adverse reactions were generally self-limiting, there have been reports of serious discontinuation symptoms with other paroxetine products. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of this and other paroxetine products. 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: Anaphylaxis, 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).

Paroxetine is a strong CYP2D6 inhibitor. Co-administration of BRISDELLE 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 BRISDELLE 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 BRISDELLE. 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 BRISDELLE is contraindicated. Pimozide Increased plasma concentrations of pimozide. Potential QTc prolongation Concomitant use of pimozide and BRISDELLE is contraindicated. Tamoxifen Reduced plasma concentrations of active tamoxifen metabolite Consider avoiding concomitant use of tamoxifen and BRISDELLE. 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 BRISDELLE. 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 BRISDELLE 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 BRISDELLE 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 BRISDELLE 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 Fosamprenavir/Ritonavir Decreased plasma concentration of paroxetine Monitor clinical effect of BRISDELLE. No BRISDELLE dosage adjustment is needed. Cimetidine Increased plasma concentration of paroxetine Use caution if BRISDELLE is 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 recently received an MAOI and in patients started on an MAOI who recently received an SSRI. Therefore, concomitant use of MAOIs with BRISDELLE or use of BRISDELLE 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 BRISDELLE 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 reactions, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of BRISDELLE 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 concomitantly administered with NSAIDs, aspirin, 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 BRISDELLE is initiated or discontinued [see Warnings and Precautions ( 5.4 )] .