This site is intended for healthcare professionals
FDA Hero  Banner - Multi-coloured pills and tablets
  • Home
  • /
  • Drugs
  • /
  • P
  • /
  • PEXEVA
  • /
  • PEXEVA PAROXETINE MESYLATE 40 mg/1 Sebela Pharmaceuticals Inc.
FDA Drug information

PEXEVA

Read time: 1 mins
Marketing start date: 28 May 2024

Summary of product characteristics


Adverse Reactions

6 ADVERSE REACTIONS The following adverse reactions are included in more detail in other sections of the prescribing information: Hypersensitivity reactions to paroxetine [see Contraindications ( 4 )] Suicidal Thoughts and Behaviors [see Warnings and Precautions ( 5.1 )] Serotonin syndrome [see Warnings and Precautions ( 5.2 )] Embryofetal Toxicity [see Warnings and Precautions ( 5.4 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.5 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.6 )] Discontinuation Syndrome [see Warnings and Precautions ( 5.7 )] Seizure [see Warnings and Precautions ( 5.8 )] Angle-closure Glaucoma [see Warnings and Precautions ( 5.9 )] Hyponatremia [see Warnings and Precautions ( 5.10 )] Bone Fracture [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (≥5% and at least twice placebo): asthenia, sweating, nausea, decreased appetite, dry mouth, constipation, somnolence, dizziness, insomnia, tremor, nervousness, libido decreased, female genital disorders, impotence, ejaculatory disturbance, other male genital disorders, orgasmic disturbance, and infection ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sebela Pharmaceuticals Inc. at 1-844-732-3521 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 safety data for paroxetine are from: 6-week clinical trials in MDD patients who received paroxetine 20 mg to 50 mg once daily 12-week clinical trials in OCD patients who received paroxetine 20 mg to 60 mg once daily 10- to 12-week clinical trials in PD patients who received paroxetine 10 mg to 60 mg once daily 8-week clinical trials in GAD patients who received paroxetine 10 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1199/6145) of patients treated with paroxetine in clinical trials in MDD and 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine in clinical trials in OCD, PD, and GAD, respectively, discontinued treatment due to an adverse reaction. Table 3 shows the most common reactions (≥1%) associated with discontinuation and considered to be drug related (i.e., those reactions associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo). TABLE 3: Adverse Reactions Reported as Leading to Discontinuation (≥1% of Paroxetine-Treated Patients and (≥2% Placebo) in MDD, OCD, PD, and GAD Trials Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not >1% or was not greater than or equal to two times the incidence of placebo. 1 Incidence corrected for gender. MDD OCD PD GAD Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % CNS Somnolence 2.3% 0.7% - - 1.9% 0.3% 2.0% 0.2% Insomnia - - 1.7% 0% 1.3% 0.3% - - Agitation 1.1% 0.5% - - - - - - Tremor 1.1% 0.3% - Dizziness - - 1.5% 0% - - 1.0% 0.2% Gastrointestinal Constipation - - 1.1% 0% - - - - Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 2.0% 0.2% Diarrhea 1.0% 0.3% - - - - - - Dry mouth 1.0% 0.3% - - - - - - Vomiting 1.0% 0.3% - - - - - - Other Asthenia 1.6% 0.4% 1.9% 0.4% - - 1.8% 0.2% Abnormal Ejaculation 1 1.6% 0% 2.1% 0% - - 2.5% 0.5% Sweating 1.0% 0.3% - - - - 1.1% 0.2% Impotence 1 - - 1.5% 0% - - - - Most Common Adverse Reactions in MDD, OCD, PD, and GAD The most commonly observed adverse reactions associated with the use of PEXEVA (incidence of 5% or greater and at least twice that for placebo) were: Major Depressive Disorder: asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. Obsessive Compulsive Disorder: nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. Panic Disorder: asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. Generalized Anxiety Disorder: asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. Adverse Reactions Occurring at an Incidence of 1% or More in Paroxetine Treated Patients Major Depressive Disorder: Table 4 enumerates adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine-treated patients with MDD. TABLE 4: Adverse Reactions (≥1% of Paroxetine-treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD 1 Includes mostly “lump in throat” and “tightness in throat.” 2 Percentage corrected for gender. 3 Mostly “ejaculatory delay.” 4 Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction” and “impotence.” 5 Includes mostly “difficulty with micturition” and “urinary hesitancy.” 6 Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” Body System Preferred Term Paroxetine (n=421) % Placebo (n=421) % Body as a Whole Headache 18 17 Asthenia 15 6 Cardiovascular Palpitation 3 1 Vasodilation 3 1 Dermatologic Sweating 11 2 Rash 2 1 Gastrointestinal Nausea 26 9 Dry Mouth 18 12 Constipation 14 9 Diarrhea 12 8 Decreased Appetite 6 2 Flatulence 4 2 Oropharynx Disorder 1 2 0 Dyspepsia 2 1 Musculoskeletal Myopathy 2 1 Myalgia 2 1 Myasthenia 1 0 Nervous System Somnolence 23 9 Dizziness 13 6 Insomnia 13 6 Tremor 8 2 Nervousness 5 3 Anxiety 5 3 Paresthesia 4 2 Libido Decreased 3 0 Drugged Feeling 2 1 Confusion 1 0 Respiration Yawn 4 0 Special Senses Blurred Vision 4 1 Taste Perversion 2 0 Urogenital System Ejaculatory Disturbance 2,3 13 0 Other Male Genital Disorders 2,4 10 0 Urinary Frequency 3 1 Urination Disorder 5 3 0 Female Genital Disorders 2,6 2 0 Obsessive Compulsive Disorder and Panic Disorder: Table 5 enumerates adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD and PD. 1 Percentage corrected for gender. TABLE 5: Adverse Reactions (≥2% of Paroxetine-Treated Patients and Greater than Placebo) in 10- to 12-Week Clinical Trials for OCD and PD Obsessive Compulsive Disorder Panic Disorder Body System Preferred Term Paroxetine (n=542) % Placebo (n=265) % Paroxetine (n=469) % Placebo (n=324) % Body as a Whole Asthenia 22 14 14 5 Abdominal Pain - - 4 3 Chest Pain 3 2 - - Back Pain - - 3 2 Chills 2 1 2 1 Cardiovascular Vasodilation 4 1 - - Palpitation 2 0 - - Dermatologic Sweating 9 3 14 6 Rash 3 2% - - Gastrointestinal Nausea 23 10 23 17 Dry Mouth 18 9 18 11 Constipation 16 6 8 5 Diarrhea 10 10 12 7 Decreased Appetite 9 3 7 3 Increased Appetite 4 3 2 1 Nervous System Insomnia 24 13 18 10 Somnolence 24 7 19 11 Dizziness 12 6 14 10 Tremor 11 1 9 1 Nervousness 9 8 - - Libido Decreased 7 4 9 1 Agitation - - 5 4 Anxiety - - 5 4 Abnormal Dreams 4 1 - - Concentration Impaired 3 2 - - Depersonalization 3 0 - - Myoclonus 3 0 3 2 Amnesia 2 1 - - Respiratory System Rhinitis - - 3 0 Special Senses Abnormal Vision 4 2 - - Taste Perversion 2 0 - - Urogenital System Abnormal Ejaculation 1 23 1 21 1 Female Genital Disorder 1 3 0 9 1 Impotence 1 8 1 5 0 Urinary Frequency 3 1 2 0 Urination Impaired 3 0 - - Urinary Tract Infection 2 1 2 1 Generalized Anxiety Disorder: Table 6 enumerates adverse reactions that occurred at a frequency of 2% or more among GAD patients on paroxetine who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day. 1 Percentage corrected for gender. TABLE 6: Adverse Reactions (≥2% of Paroxetine-Treated Patients and Greater than Placebo) in 8-Week Clinical Trials for GAD Body System Preferred Term Paroxetine (n=735) % Placebo (n=529) % Body as a Whole Asthenia 14 6 Headache 17 14 Infection 6 3 Cardiovascular Vasodilation 3 1 Dermatologic Sweating 6 2 Gastrointestinal Nausea 20 5 Dry Mouth 11 5 Constipation 10 2 Diarrhea 9 7 Decreased Appetite 5 1 Vomiting 3 2 Nervous System Insomnia 11 8 Somnolence 15 5 Dizziness 6 5 Tremor 5 1 Nervousness 4 3 Libido Decreased 9 2 Respiratory System Respiratory Disorder 7 5 Sinusitis 4 3 Yawn 4 - Special Senses Abnormal Vision 2 1 Urogenital System Abnormal Ejaculation 1 25 2 Female Genital Disorder 1 4 1 Impotence 1 4 3 Dose Dependency of Adverse Reactions: A comparison of adverse reaction rates in a fixed-dose study comparing paroxetine 10, 20, 30, and 40 mg/day with placebo in the treatment of MDD revealed a clear dose dependency for some of the more common adverse reactions associated with paroxetine use, as shown in Table 7: TABLE 7: Adverse Reactions (≥5% of Paroxetine-Treated Patients and Twice that of Placebo) in a Dose-Comparison Trial in the Treatment of MDD* Body System/ Preferred Term Placebo Paroxetine n=51 % 10 mg n=102 % 20 mg n=104 % 30 mg n=101 % 40 mg n=102 % Body as a Whole Asthenia 0 2.9 10.6 13.9 12.7 Dermatology Sweating 2.0 1.0 6.7 8.9 11.8 Gastrointestinal Constipation 5.9 4.9 7.7 9.9 12.7 Decreased Appetite 2.0 2.0 5.8 4.0 4.9 Diarrhea 7.8 9.8 19.2 7.9 14.7 Dry Mouth 2.0 10.8 18.3 15.8 20.6 Nausea 13.7 14.7 26.9 34.7 36.3 Nervous System Anxiety 0 2.0 5.8 5.9 5.9 Dizziness 3.9 6.9 6.7 8.9 12.7 Nervousness 0.0 5.9 5.8 4.0 2.9 Paresthesia 0.0 2.9 1.0 5.0 5.9 Somnolence 7.8 12.7 18.3% 20.8 21.6 Tremor 0 0 7.7 7.9 14.7 Special Senses Blurred Vision 2.0 2.9 2.9 2.0 7.8 Urogenital System Abnormal Ejaculation 0 5.8 6.5 10.6 13.0 Impotence 0 1.9 4.3 6.4 1.9 Male Genital Disorders 0 3.8 8.7 6.4 3.7 In a fixed-dose study comparing placebo and paroxetine 20, 40, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned. No new adverse reactions were observed in the paroxetine 60 mg dose group compared to any of the other treatment groups. In a fixed-dose study comparing placebo and paroxetine 10, 20, and 40 mg in the treatment of PD, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse reactions were observed in patients receiving 60 mg of paroxetine compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of GAD, for most of the adverse reactions, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned, except for the following adverse reactions: asthenia, constipation, and abnormal ejaculation. Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, , GAD, and two other indications are displayed in Table 8. Table 8: Incidence of Sexual Adverse Reactions in Controlled Clinical Trials Paroxetine Placebo n (males) 1446 1042 % % Decreased Libido 6 to 15 0 to 5 Ejaculatory Disturbance 13 to 28 0 to 2 Impotence 2 to 9 0 to 3 n (females) 1822 1340 % % Decreased Libido 0 to 9 0 to 2 Orgasmic Disturbance 2 to 9 0 to 1 There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment. Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, healthcare providers should routinely inquire about such possible side effects. Hallucinations : In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 0.2% of paroxetine-treated patients compared to 0.1% of patients receiving placebo. 6.2 Other Reactions Observed During the Premarketing Evaluation of Paroxetine Less Common Adverse Reactions The following adverse reactions occurred during the clinical studies of paroxetine and are not included elsewhere in the labeling. Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients. Body as a Whole: infrequent : allergic reaction, chills, face edema, malaise, neck pain; rare: adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System: frequent: hypertension, tachycardia; infrequent : bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarction, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles. Digestive System: infrequent: bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests , rectal hemorrhage, ulcerative stomatitis; rare: aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, chlolelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System: rare: diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems: infrequent: anemia, leukopenia, lymphadenopathy, purpura; rare: abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional: frequent : weight gain; infrequent: edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, nonprotein nitrogen (NPN) increased. Musculoskeletal System: frequent: arthralgia; infrequent: arthritis, arthrosis; rare: bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System: frequent: emotional lability, vertigo; infrequent: abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome. Respiratory System: infrequent: asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages: frequent: pruritus; infrequent: acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis, herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses: frequent: tinnitus; infrequent: abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect. Urogenital System: infrequent: amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, pyuria, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis. 6.3 Postmarketing Experience The following reactions have been identified during post approval use of paroxetine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), priapism, syndrome of inappropriate ADH secretion (SIADH), prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura) and premature births in pregnant women. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

Contraindications

4 CONTRAINDICATIONS PEXEVA 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 PEXEVA [see Adverse Reactions ( 6.2 , 6.3 )] Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing a MAOIs use ( 4 , 5.2 , 7 ) Concomitant use of pimozide or thioridazine ( 4 , 5.3 , 7 ) Known hypersensitivity to paroxetine or to any of the inactive ingredients in PEXEVA ( 4 )

Description

11 DESCRIPTION PEXEVA contains paroxetine mesylate, an SSRI. It is the mesylate salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine mesylate and has the empirical formula of C 19 H 2 0FNO 3 •CH 3 SO 3 H. The molecular weight is 425.5 (329.4 as free base). The structural formula is: Paroxetine mesylate 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. PEXEVA tablets are intended for oral administration. Each oval, film-coated tablet contains 10 mg, 20 mg, 30 mg, or 40 mg paroxetine equivalent to 12.9 mg, 25.8 mg, 38.8 mg, or 51.7 mg paroxetine mesylate, respectively. Inactive ingredients consist of dibasic calcium phosphate, hydroxypropyl methylcellulose, hydroxypropylcellulose, magnesium stearate, sodium starch glycolate, titanium dioxide, ferric oxide red (C.I. 77491) (20 mg and 40 mg only) and ferric oxide yellow (C.I. 77492) (20 mg, 30 mg, and 40 mg only). Paroxetine Mesylate

Dosage And Administration

2 DOSAGE AND ADMINISTRATION Recommended starting and maximum daily dosage: ( 2.2 , 2.3 , 2.4 , 2.5 ) Indication Starting Daily Dose Maximum Daily Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg GAD 20 mg 50 mg Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dosage is 10mg/day. Maximum dosage is 40mg/day. When discontinuing PEXEVA, reduce dosage gradually ( 2.6 ) 2.1 Administration Information Administer PEXEVA as a single daily dose in the morning, with or without food. 2.2 Recommended Dosage The recommended initial dosage and maximum dosage of PEXEVA in patients with MDD, OCD, PD, and GAD are presented in Table 1. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability. TABLE 1: Recommended Daily Dosage of PEXEVA in Patients with MDD, OCD, PD, and GAD Indication Starting Dose Maximum Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg GAD 20 mg 50 mg 2.3 Screen for Bipolar Disorder Prior to Starting PEXEVA Prior to initiating treatment with PEXEVA or other antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.6 )] . 2.4 Recommended Dosage Modifications for Elderly Patients, Patients with Severe Renal Impairment and Patients with Severe Hepatic Impairment The recommended initial dose is 10 mg/day for elderly patients, patients with severe renal impairment and patients with severe hepatic impairment. Dosage should not exceed 40 mg/day [see Use in Specific Populations ( 8.5 , 8.6 )] 2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of PEXEVA. In addition, at least 14 days must elapse after stopping PEXEVA before starting an MAOI antidepressant [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . 2.6 Discontinuation of Treatment with PEXEVA Adverse reactions may occur upon discontinuation of PEXEVA [see Warnings and Precaution ( 5.7 )] . Gradually reduce the dosage rather than stopping PEXEVA abruptly whenever possible.

Indications And Usage

1 INDICATIONS AND USAGE PEXEVA is indicated in adults for the treatment of: Major depressive disorder (MDD) Obsessive-compulsive disorder (OCD) Panic disorder (PD) Generalized anxiety disorder (GAD) PEXEVA is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of: Major Depressive Disorder (MDD) Obsessive Compulsive Disorder (OCD) Panic Disorder (PD) Generalized Anxiety Disorder (GAD)

Overdosage

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.

Adverse Reactions Table

TABLE 3: Adverse Reactions Reported as Leading to Discontinuation (≥1% of Paroxetine-Treated Patients and (≥2% Placebo) in MDD, OCD, PD, and GAD Trials

Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not >1% or was not greater than or equal to two times the incidence of placebo.

1Incidence corrected for gender.

MDDOCDPDGAD
Paroxetine %Placebo %Paroxetine %Placebo %Paroxetine %Placebo %Paroxetine %Placebo %
CNS
Somnolence2.3%0.7%--1.9%0.3%2.0%0.2%
Insomnia--1.7%0%1.3%0.3%--
Agitation1.1%0.5%------
Tremor1.1%0.3%-
Dizziness--1.5%0%--1.0%0.2%
Gastrointestinal
Constipation--1.1%0%----
Nausea3.2%1.1%1.9%0%3.2%1.2%2.0%0.2%
Diarrhea1.0%0.3%------
Dry mouth1.0%0.3%------
Vomiting1.0%0.3%------
Other
Asthenia1.6%0.4%1.9%0.4%--1.8%0.2%
Abnormal Ejaculation 11.6%0%2.1%0%--2.5%0.5%
Sweating1.0%0.3%----1.1%0.2%
Impotence 1--1.5%0%----

Drug Interactions

7 DRUG INTERACTIONS Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of PEXEVA or other protein-bound drugs (e.g., warfarin) as warranted ( 7 ) Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. ( 7 ) Concomitant use with Tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. ( 5.11 , 7 ) 7.1 Clinically Significant Drug Interactions Table 9: Clinically Significant Drug Interactions with PEXEVA Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including PEXEVA, and MAOIs increases the risk of serotonin Intervention PEXEVA is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Pimozide and Thioridizine Clinical Impact Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias. Intervention PEXEVA is contraindicated in patients taking pimozide or thioridazine [see Contraindications ( 4 )]. Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with PEXEVA increases the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of PEXEVA and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2 )] . Examples other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact The concurrent use of an antiplatelet agent or anticoagulant with PEXEVA may potentiate the risk of bleeding. Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of PEXEVA and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions ( 5.5 )]. Examples aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact PEXEVA is highly bound to plasma protein. The concomitant use of PEXEVA with another drug that is highly bound to plasma protein may increase free concentrations of PEXEVA or other tightly-bound drugs in plasma. Intervention Monitor for adverse reactions and reduce dosage of PEXEVA or other protein-bound drugs as warranted. Examples warfarin Drugs Metabolized by CYP25D6 Clinical Impact PEXEVA is a CYP2D6 inhibitor [see Clinical Pharmacology ( 12.3 )] . The concomitant use of PEXEVA with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention Decrease the dosage of a CYP2D6 substrate if needed with concomitant PEXEVA use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if PEXEVA is discontinued. Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone. Tamoxifen Clinical Impact Concomitant use of tamoxifen with PEXEVA may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen Intervention Consider use of an alternative antidepressant with little or no CYP2D6 inhibition [see Warnings and Precautions ( 5.11 )]. Fosamprenavir/Ritonavir Clinical Impact Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Intervention Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Drug Interactions Table

Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact The concomitant use of SSRIs, including PEXEVA, and MAOIs increases the risk of serotonin
Intervention PEXEVA is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2), Contraindications ( 4), Warnings and Precautions ( 5.2)] .
Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide and Thioridizine
Clinical Impact Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias.
Intervention PEXEVA is contraindicated in patients taking pimozide or thioridazine [see Contraindications ( 4)].
Other Serotonergic Drugs
Clinical Impact The concomitant use of serotonergic drugs with PEXEVA increases the risk of serotonin syndrome.
Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of PEXEVA and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2)] .
Examples other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact The concurrent use of an antiplatelet agent or anticoagulant with PEXEVA may potentiate the risk of bleeding.
Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of PEXEVA and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions ( 5.5)].
Examples aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact PEXEVA is highly bound to plasma protein. The concomitant use of PEXEVA with another drug that is highly bound to plasma protein may increase free concentrations of PEXEVA or other tightly-bound drugs in plasma.
Intervention Monitor for adverse reactions and reduce dosage of PEXEVA or other protein-bound drugs as warranted.
Examples warfarin
Drugs Metabolized by CYP25D6
Clinical Impact PEXEVA is a CYP2D6 inhibitor [see Clinical Pharmacology ( 12.3)] . The concomitant use of PEXEVA with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention Decrease the dosage of a CYP2D6 substrate if needed with concomitant PEXEVA use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if PEXEVA is discontinued.
Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone.
Tamoxifen
Clinical Impact Concomitant use of tamoxifen with PEXEVA may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen
Intervention Consider use of an alternative antidepressant with little or no CYP2D6 inhibition [see Warnings and Precautions ( 5.11)].
Fosamprenavir/Ritonavir
Clinical Impact Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine.
Intervention Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Clinical Pharmacology

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of paroxetine in the treatment of major depressive disorder (MDD), obsessive compulsive disorder (OCD), panic disorder (PD), and general anxiety disorder (GAD) is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-HT). 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 potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. 12.3 Pharmacodynamics Absorption Paroxetine mesylate is completely absorbed after oral dosing of the mesylate salt. In a study in which normal male subjects (n=25) received paroxetine 30 mg tablets daily for 24 days, steady-state paroxetine concentrations were achieved by approximately 13 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T1/2 were 81.3 ng/ml (CV 41%), 8.1 hr. (CV 56%), 43.2 ng/ml (CV 52%), and 33.2 hr. (CV 52%), respectively. The steady-state Cmax and Cmin values were about 7 and 10 times what would be predicted from single dose studies. Steady-state drug exposure based on AUC0-24 was about 10 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 to 40 mg daily for the elderly and 20 to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg were only about 2 to 3 times greater than doubled. In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females. Effect of Food The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Distribution Paroxetine distributes throughout the body, including the CNS, 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 400 ng/ml. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Elimination Metabolism The elimination half-life is approximately 15 to 20 hours after a single dose of PEXEVA. 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 )] . Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). Excretion Approximately 64% of a 30 mg oral solution dose 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% 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. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Drug Interaction Studies: There are clinically significant drug interactions between paroxetine and other drugs [see Drug Interactions ( 7 )]. Potential Effect of PEXEVA 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 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 Cmax 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 ( 5.11 ) 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) Cmax, AUC, and T1/2 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 Cmax 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 PEXEVA 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 T1/2 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 T1/2 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.

Effective Time

20230831

Version

10

Dosage And Administration Table

IndicationStarting Daily DoseMaximum Daily Dose
MDD20 mg50 mg
OCD20 mg60 mg
PD10 mg60 mg
GAD20 mg50 mg

Dosage Forms And Strengths

3 DOSAGE FORMS AND STRENGTHS PEXEVA is available as oval, film-coated tablets which contains paroxetine mesylate equivalent to paroxetine as follows: 10 mg tablets : white, oval, film-coated tablets, with the inscription “POT 10” on one side. 20 mg tablets : dark orange, oval, film-coated tablets, with the inscription “POT 20” on one side. The tablets are scored on both sides. 30 mg tablets : yellow, oval, film-coated tablets, with the inscription “POT 30” on one side. 40 mg tablets : rose, oval, film-coated tablets, with the inscription “POT 40” on one side. Tablets: 10 mg, 20 mg, 30 mg, 40 mg ( 3 )

Spl Product Data Elements

PEXEVA paroxetine mesylate ANHYDROUS DIBASIC CALCIUM PHOSPHATE HYPROMELLOSE 2910 (50 MPA.S) HYDROXYPROPYL CELLULOSE MAGNESIUM STEARATE SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE PAROXETINE MESYLATE PAROXETINE white OVAL 10mg;POT10 PEXEVA paroxetine mesylate ANHYDROUS DIBASIC CALCIUM PHOSPHATE HYPROMELLOSE 2910 (50 MPA.S) HYDROXYPROPYL CELLULOSE MAGNESIUM STEARATE SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE FERRIC OXIDE YELLOW PAROXETINE MESYLATE PAROXETINE orange OVAL 20mg;POT20 PEXEVA paroxetine mesylate ANHYDROUS DIBASIC CALCIUM PHOSPHATE HYPROMELLOSE 2910 (50 MPA.S) HYDROXYPROPYL CELLULOSE MAGNESIUM STEARATE SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE FERRIC OXIDE YELLOW PAROXETINE MESYLATE PAROXETINE yellow OVAL 30mg;POT30 PEXEVA paroxetine mesylate TITANIUM DIOXIDE FERRIC OXIDE YELLOW ANHYDROUS DIBASIC CALCIUM PHOSPHATE HYPROMELLOSE 2910 (50 MPA.S) HYDROXYPROPYL CELLULOSE MAGNESIUM STEARATE SODIUM STARCH GLYCOLATE TYPE A POTATO PAROXETINE MESYLATE PAROXETINE red OVAL 40mg;POT40

Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are 2.0 (mouse) and 3 (rat) times the maximum recommended human dose (MRHD) of 60 mg on a mg/m2 basis. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Impairment of Fertility: Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2 times the MRHD of 60 mg on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (8 and 4 times the MRHD of 60 mg on a mg/m2 basis).

Application Number

NDA021299

Brand Name

PEXEVA

Generic Name

paroxetine mesylate

Product Ndc

54766-204

Product Type

HUMAN PRESCRIPTION DRUG

Route

ORAL

Package Label Principal Display Panel

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 10 MG LABEL NDC 54766-201-01 30 Tablets PEXEVA® (paroxetine mesylate) Tablets Equivalent to 10 mg paroxetine base 10 mg Rx only Sebela Pharmaceuticals Inc 10 mg label

Recent Major Changes

Warnings and Precautions ( 5.2 , 5.4 , 5.5 ) 8/2023

Information For Patients

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of PEXEVA with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also other, such as linezolid). Instruct patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )]. Concomitant Medications Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.1 )]. Increased Risk of Bleeding Inform patients about the concomitant use of PEXEVA with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their healthcare providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions ( 5.5 )]. Activation of Mania/Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions ( 5.6 )]. Discontinuation Syndrome Advise patients not to abruptly discontinue PEXEVA and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur with PEXEVA is discontinued [see Warnings and Precautions ( 5.7 )]. Sexual Dysfunction Advise patients that use of PEXEVA may cause symptoms of sexual dysfunction in female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions ( 5.13 )] . Pregnancy Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with PEXEVA. Advise women of risks associated with first trimester use of PEXEVA and that use later in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] . Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] . Lactation Advise breastfeeding women using PEXEVA to to monitor infants for agitation, irritability, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )]. Females and Males of Reproductive Potential Advise men that PEXEVA may affect sperm quality, which may impair fertility; it is unknown if this effect is reversible [see Use in Specific Populations ( 8.3 )] . Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions ( 6 )]. Distributed By Sebela Pharmaceuticals Inc. 645 Hembree Parkway, Suite I Roswell, GA 30076 www.sebelapharma.com Toll Free 1-844-732-3521 ©2023 Sebela Pharmaceuticals Inc. All rights reserved.

Spl Medguide

MEDICATION GUIDE PEXEVA® (pex-EE-va) (paroxetine mesylate) tablets What is the most important information I should know about PEXEVA? PEXEVA can cause serious side effects, including: Increased risk of suicidal thoughts or actions. PEXEVA and other antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. PEXEVA is not for use in children. How can I watch for or try to prevent suicidal thoughts and actions? o Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions. o Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. o Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you: o attempts to commit suicide o acting on dangerous impulses o acting aggressive or violent o thoughts about suicide or dying o new or worse depression o new or worse anxiety or panic attacks o feeling agitated, restless, angry, or irritable o trouble sleeping o an increase in activity and talking more than what is normal for you o other unusual changes in behavior or mood What is PEXEVA? PEXEVA is a prescription medicine used in adults to treat: A certain type of depression called Major Depressive Disorder (MDD) Obsessive Compulsive Disorder (OCD) Panic Disorder (PD) Generalized Anxiety Disorder (GAD) Do not take PEXEVA if you: take a monoamine oxidase inhibitor (MAOI) have stopped taking an MAOI in the last 14 days are being treated with the antibiotic linezolid or intravenous methylene blue are taking thioridazine are taking pimozide are allergic to paroxetine or any of the ingredients in PEXEVA. See the end of this Medication Guide for a complete list of ingredients in PEXEVA. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI or one of these medicines, including intravenous methylene blue. Do not start taking an MAOI for at least 14 days after you stop treatment with PEXEVA. Before taking PEXEVA, tell your healthcare provider about all your medical conditions, including if you: have heart problems have or had bleeding problems have, or have a family history of bipolar disorder, mania or hypomania have or had seizures or convulsions have glaucoma (high pressure in the eye) have low sodium levels in your blood have bone problems have kidney or liver problems are pregnant or plan to become pregnant. PEXEVA may harm your unborn baby. o Taking PEXEVA during your first trimester of pregnancy may cause your baby to be at an increased risk of having a heart problem (cardiac malformations) at birth. o Taking PEXEVA during your third trimester of pregnancy may cause your baby to have breathing, temperature, and feeding problems, low muscle tone (floppy baby syndrome), and irritability after birth and may cause your baby to be at an increased risk of a serious lung problem at birth. Talk to your healthcare provider about the risk to your unborn baby if you take PEXEVA during pregnancy. o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with PEXEVA. o There is a pregnancy registry for females who are exposed to PEXEVA during pregnancy. The purpose of the registry is to collect information about the health of females exposed to PEVEXA and their baby. If you become pregnant during treatment with PEVEXA talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. are breastfeeding or plan to breastfeed. PEXEVA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with PEXEVA. Tell your healthcare provider about all the medicines you take, including prescription and over-the -counter medicines, vitamins, and herbal supplements. PEXEVA and some other medicines may affect each other causing possible side effects. PEXEVA may affect the way other medicines work and other medicines may affect the way PEXEVA works. Especially tell your healthcare provider if you take: medicines used to treat migraine headaches called triptans tricyclic antidepressants lithium tramadol, fentanyl, meperidine, methadone, or other opioids tryptophan buspirone amphetamines St John’s Wort medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or warfarin diuretics tamoxifen Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take PEXEVA with your other medicines. Do not start or stop any other medicines during treatment with PEXEVA without talking to your healthcare provider first. Stopping PEXEVA suddenly may cause you to have serious side effects. See, “What are the possible side effects of PEXEVA?” Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How should I take PEXEVA? Take PEXEVA exactly as your healthcare provider tell you to. Your healthcare provider may need to change the dose of PEXEVA until it is the right dose for you. Take PEXEVA 1 time each day in the morning PEXEVA may be taken with or without food. If you take too much PEXEVA, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of PEXEVA? PEXEVA can cause serious side effects, including: • See, “What is the most important information I should know about PEXEVA?” • Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take PEXEVA with certain other medicines. See, “Who should not take PEXEVA?” Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome: o Agitation o sweating o seeing or hearing things that are not real o flushing (hallucinations) o high body temperature (hyperthermia) o confusion o loss of coordination o coma o shaking (tremors), stiff muscles, or muscle o fast heart beat twitching o changes in blood pressure o seizures o dizziness o nausea, vomiting, diarrhea • Medicine interactions. Taking PEXEVA with certain other medicines including thioridazine and pimozide may increase the risk of developing a serious heart problem called QT prolongation. • Abnormal bleeding. Taking PEXEVA with aspirin, NSAIDs, or blood thinners may add to this risk. Tell your healthcare provider about any unusual bleeding or bruising. • Manic episodes. Manic episodes may happen in people with bipolar disorder who take PEXEVA. Symptoms may include: o greatly increased energy o severe problems sleeping o racing thoughts o reckless behavior o unusually grand ideas o excessive happiness or irritability o talking more or faster than usual • Discontinuation syndrome. Suddenly stopping PEXEVA may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: o nausea o electric shock feeling (paresthesia) o tiredness o sweating o tremor o problems sleeping o changes in your mood o anxiety o hypomania o irritability and agitation o confusion o ringing in your ears (tinnitus) o dizziness o headache o seizures • Seizures (convulsions). • Eye problems (angle-closure glaucoma). PEXEVA may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. • Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with PEXEVA. Elderly people and people who take certain medicines may be at a greater risk for developing low sodium levels in your blood. Signs and symptoms may include: o headache o difficulty concentrating o memory changes o confusion o weakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include: o seeing or hearing things that are not real (hallucinations) o fainting o seizures o coma o stopping breathing (respiratory arrest) • Bone fractures. Sexual Problems (Dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including PEXEVA, may cause sexual problems. Symptoms in males may include: • Delayed ejaculation or inability to have an ejaculation • Decreased sex drive • Delayed orgasm or inability to have an orgasm Symptoms in females may include: • Decreased sex drive • Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with PEXEVA. There may be treatments your healthcare provider can suggest. The most common side effects of PEXEVA include: • weakness (asthenia) • sweating • nausea • decreased appetite • dry mouth • constipation • sleepiness • dizziness • problems sleeping • shaking (tremor) • nervousness • male and female sexual function problems • infection These are not all the possible side effects of PEXEVA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PEXEVA? Store PEXEVA at room temperature between 59°F to 86°F (15°C to 30°C). Keep PEXEVA bottle closed tightly. Keep PEXEVA and all medicines out of reach of children. General information about the safe and effective use of PEXEVA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take PEXEVA for a condition for which it was not prescribed. Do not give PEXEVA to other people, even if they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or pharmacist for information about PEXEVA that is written for healthcare professionals. What are the ingredients in PEXEVA? Active ingredient: paroxetine mesylate Inactive ingredients: dibasic calcium phosphate, hydroxypropyl methylcellulose, hydroxypropylcellulose, magnesium stearate, sodium starch glycolate, titanium dioxide, and iron oxide(s). Distributed by: Sebela Pharmaceuticals Inc., 645 Hembree Parkway, Suite I, Roswell, GA 30076 For more information about PEXEVA call (1-844-732-3521) or go to www.PEXEVA.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 08/2023

Spl Medguide Table

MEDICATION GUIDE

PEXEVA® (pex-EE-va) (paroxetine mesylate) tablets

What is the most important information I should know about PEXEVA? PEXEVA can cause serious side effects, including:

  • Increased risk of suicidal thoughts or actions.PEXEVA and other antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. PEXEVA is not for use in children. How can I watch for or try to prevent suicidal thoughts and actions?
  • o Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions. o Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. o Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you: o attempts to commit suicide o acting on dangerous impulses o acting aggressive or violent o thoughts about suicide or dying o new or worse depression o new or worse anxiety or panic attacks o feeling agitated, restless, angry, or irritable o trouble sleeping o an increase in activity and talking more than what is normal for you o other unusual changes in behavior or mood

    What is PEXEVA?

    PEXEVA is a prescription medicine used in adults to treat:

  • A certain type of depression called Major Depressive Disorder (MDD)
  • Obsessive Compulsive Disorder (OCD)
  • Panic Disorder (PD)
  • Generalized Anxiety Disorder (GAD)
  • Do not take PEXEVA if you:

  • take a monoamine oxidase inhibitor (MAOI)
  • have stopped taking an MAOI in the last 14 days
  • are being treated with the antibiotic linezolid or intravenous methylene blue
  • are taking thioridazine
  • are taking pimozide
  • are allergic to paroxetine or any of the ingredients in PEXEVA. See the end of this Medication Guide for a complete list of ingredients in PEXEVA.
  • Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI or one of these medicines, including intravenous methylene blue.

    Do not start taking an MAOI for at least 14 days after you stop treatment with PEXEVA.

    Before taking PEXEVA, tell your healthcare provider about all your medical conditions, including if you:

  • have heart problems
  • have or had bleeding problems
  • have, or have a family history of bipolar disorder, mania or hypomania
  • have or had seizures or convulsions
  • have glaucoma (high pressure in the eye)
  • have low sodium levels in your blood
  • have bone problems
  • have kidney or liver problems
  • are pregnant or plan to become pregnant. PEXEVA may harm your unborn baby.
  • o Taking PEXEVA during your first trimester of pregnancy may cause your baby to be at an increased risk of having a heart problem (cardiac malformations) at birth. o Taking PEXEVA during your third trimester of pregnancy may cause your baby to have breathing, temperature, and feeding problems, low muscle tone (floppy baby syndrome), and irritability after birth and may cause your baby to be at an increased risk of a serious lung problem at birth. Talk to your healthcare provider about the risk to your unborn baby if you take PEXEVA during pregnancy. o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with PEXEVA. o There is a pregnancy registry for females who are exposed to PEXEVA during pregnancy. The purpose of the registry is to collect information about the health of females exposed to PEVEXA and their baby. If you become pregnant during treatment with PEVEXA talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
  • are breastfeeding or plan to breastfeed. PEXEVA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with PEXEVA.
  • Tell your healthcare provider about all the medicines you take,including prescription and over-the -counter medicines, vitamins, and herbal supplements.

    PEXEVA and some other medicines may affect each other causing possible side effects. PEXEVA may affect the way other medicines work and other medicines may affect the way PEXEVA works.

    Especially tell your healthcare provider if you take:

  • medicines used to treat migraine headaches called triptans
  • tricyclic antidepressants
  • lithium
  • tramadol, fentanyl, meperidine, methadone, or other opioids
  • tryptophan
  • buspirone
  • amphetamines
  • St John’s Wort
  • medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or warfarin
  • diuretics
  • tamoxifen
  • Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take PEXEVA with your other medicines.

    Do not start or stop any other medicines during treatment with PEXEVA without talking to your healthcare provider first. Stopping PEXEVA suddenly may cause you to have serious side effects. See, “What are the possible side effects of PEXEVA?”

    Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

    How should I take PEXEVA?

  • Take PEXEVA exactly as your healthcare provider tell you to. Your healthcare provider may need to change the dose of PEXEVA until it is the right dose for you.
  • Take PEXEVA 1 time each day in the morning
  • PEXEVA may be taken with or without food.
  • If you take too much PEXEVA, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.
  • What are the possible side effects of PEXEVA?

    PEXEVA can cause serious side effects, including:

    • See, “What is the most important information I should know about PEXEVA?”Serotonin syndrome.A potentially life-threatening problem called serotonin syndrome can happen when you take PEXEVA with certain other medicines. See, “Who should not take PEXEVA?” Call your healthcare provider or go to the nearest hospital emergency room right awayif you have any of the following signs and symptoms of serotonin syndrome: o Agitation o sweating o seeing or hearing things that are not real o flushing (hallucinations) o high body temperature (hyperthermia) o confusion o loss of coordination o coma o shaking (tremors), stiff muscles, or muscle

    o fast heart beat twitching o changes in blood pressure o seizures

    o dizziness o nausea, vomiting, diarrhea

    Medicine interactions.Taking PEXEVA with certain other medicines including thioridazine and pimozide may increase the risk of developing a serious heart problem called QT prolongation.

    Abnormal bleeding.Taking PEXEVA with aspirin, NSAIDs, or blood thinners may add to this risk. Tell your healthcare provider about any unusual bleeding or bruising.

    Manic episodes.Manic episodes may happen in people with bipolar disorder who take PEXEVA. Symptoms may include: o greatly increased energy o severe problems sleeping o racing thoughts o reckless behavior o unusually grand ideas o excessive happiness or irritability o talking more or faster than usual

    Discontinuation syndrome.Suddenly stopping PEXEVA may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: o nausea o electric shock feeling (paresthesia) o tiredness o sweating o tremor o problems sleeping o changes in your mood o anxiety o hypomania o irritability and agitation o confusion o ringing in your ears (tinnitus) o dizziness o headache o seizures

    Seizures (convulsions).

    Eye problems (angle-closure glaucoma).PEXEVA may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye.

    Low sodium levels in your blood (hyponatremia).Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with PEXEVA. Elderly people and people who take certain medicines may be at a greater risk for developing low sodium levels in your blood. Signs and symptoms may include: o headache o difficulty concentrating o memory changes o confusion o weakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include: o seeing or hearing things that are not real (hallucinations) o fainting o seizures o coma o stopping breathing (respiratory arrest)

    Bone fractures.

  • Sexual Problems (Dysfunction).
  • Taking selective serotonin reuptake inhibitors (SSRIs), including PEXEVA, may cause sexual problems.

    Symptoms in males may include:

    • Delayed ejaculation or inability to have an ejaculation

    • Decreased sex drive

    • Delayed orgasm or inability to have an orgasm

    Symptoms in females may include:

    • Decreased sex drive • Delayed orgasm or inability to have an orgasm

    Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with PEXEVA. There may be treatments your healthcare provider can suggest.

    The most common side effects of PEXEVA include: • weakness (asthenia) • sweating • nausea • decreased appetite • dry mouth • constipation • sleepiness • dizziness • problems sleeping • shaking (tremor) • nervousness • male and female sexual function problems • infection

    These are not all the possible side effects of PEXEVA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store PEXEVA?

  • Store PEXEVA at room temperature between 59°F to 86°F (15°C to 30°C).
  • Keep PEXEVA bottle closed tightly.
  • Keep PEXEVA and all medicines out of reach of children.
  • General information about the safe and effective use of PEXEVA.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take PEXEVA for a condition for which it was not prescribed. Do not give PEXEVA to other people, even if they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or pharmacist for information about PEXEVA that is written for healthcare professionals.

    What are the ingredients in PEXEVA?

    Active ingredient:paroxetine mesylate

    Inactive ingredients:dibasic calcium phosphate, hydroxypropyl methylcellulose, hydroxypropylcellulose, magnesium stearate, sodium starch glycolate, titanium dioxide, and iron oxide(s).

    Distributed by: Sebela Pharmaceuticals Inc., 645 Hembree Parkway, Suite I, Roswell, GA 30076

    For more information about PEXEVA call (1-844-732-3521) or go to www.PEXEVA.com.

    Clinical Studies

    14 CLINICAL STUDIES 14.1 Major Depressive Disorder The efficacy of paroxetine as a treatment for MDD has been established in 6 placebo-controlled studies of patients with MDD (ages 18 to 73). In these studies, paroxetine was shown to be statistically significantly more effective than placebo in treating MDD by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine was statistically significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. Long-term efficacy of paroxetine for treatment of MDD in outpatients was demonstrated in a randomized withdrawal study. Patients who responded to paroxetine (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue paroxetine or placebo, for up to 1 year. Patients treated with paroxetine demonstrated a statistically significant lower relapse rate during the withdrawal phase (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. 14.2 Obsessive Compulsive Disorder The effectiveness of paroxetine in the treatment OCD was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. In study 1, a dose-range finding study, patients received fixed daily doses of paroxetine 20 mg, 40 mg, or 60 mg. Study 1 demonstrated that daily doses of paroxetine 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving paroxetine 40 mg and 60 mg To experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was statistically significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible dose study comparing paroxetine (20 mg to 60 mg daily) with clomipramine (25 mg to 250 mg daily or placebo). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was statistically significantly greater than the mean reduction of approximately 4 points in the placebo-treated patients. Table 10 provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impressions (CGI) scale for Study 1. Table 10: Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1 in Patients with OCD Outcome Classification Placebo (N=74) % Paroxetine 20 mg (N=75) % Paroxetine 40 mg (N=66) % Paroxetine 60 mg (N=66) % Worse 14 7 7 3 No Change 44 35 22 19 Minimally Improved 24 33 29 34 Much Improved 11 18 22 24 Very Much Improved 7 7 20 20 Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term efficacy of paroxetine for the treatment of OCD was demonstrated in a long-term extension to Study 1. Patients who responded to paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 mg to 60 mg daily) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were statistically significantly less likely to relapse than comparably treated patients who were randomized to placebo. 14.3 Panic Disorder The effectiveness of paroxetine in the treatment of panic disorder (PD) was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had PD (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown to be statistically significantly more effective than placebo in treating PD by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10-week dose-range finding study: patients received fixed doses of paroxetine doses of 10 mg, 20 mg, or 40 mg daily or placebo. A statistically significant difference from placebo was observed only for the paroxetine 40 mg daily group. At endpoint, 76% of patients receiving paroxetine 40 mg daily were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing paroxetine 10 mg to 60 mg daily and placebo. At endpoint, 51% of paroxetine-treated patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing paroxetine 10 mg to 60 mg daily to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo-treated patients. In Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg daily. Long-term maintenance efficacy of paroxetine in PD was demonstrated in an extension to Study 1. Patients who responded to paroxetine during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine 10 mg, 20 mg, or 40 mg daily or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were statistically significantly less likely to relapse than comparably treated patients who were randomized to placebo. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. 14.4 Generalized Anxiety Disorder The effectiveness of paroxetine in the treatment of generalized anxiety disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with GAD (DSM-IV). Study 1 was an 8-week study comparing fixed doses of paroxetine 20 mg or 40 mg daily with placebo. Doses of paroxetine 20 mg or 40 mg were both demonstrated to be statistically significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the paroxetine 40 mg daily dose compared to the 20 mg daily dose. Study 2 was a flexible-dose study comparing paroxetine 20 mg to 50 mg daily and placebo. Paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, a flexible-dose study comparing paroxetine 20 mg to 50 mg daily to placebo, did not demonstrate statistically significant superiority of paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a long-term trial, 566 patients meeting DSM-IV criteria for GAD, who had responded during a single-blind, 8-week acute treatment phase with paroxetine 20 mg to 50 mg daily , were randomized to continuation of paroxetine at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or withdrawal due to lack of efficacy. Patients continuing to receive paroxetine experienced a statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.

    Clinical Studies Table

    Table 10: Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1 in Patients with OCD
    Outcome Classification

    Placebo

    (N=74)

    %

    Paroxetine

    20 mg

    (N=75)

    %

    Paroxetine

    40 mg

    (N=66)

    %

    Paroxetine

    60 mg

    (N=66)

    %

    Worse14773
    No Change44352219
    Minimally Improved24332934
    Much Improved11182224
    Very Much Improved772020

    Use In Specific Populations

    8 USE IN SPECIFIC POPULATIONS Pregnancy: SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability) in the neonate ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.5 ) and Clinical Considerations] . PEXEVA is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. While individual epidemiological studies on the association between paroxetine use and cardiovascular malformations have reported inconsistent findings, some meta-analyses of epidemiological studies have identified an increased risk of cardiovascular malformations (see Data) . There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including PEXEVA, during pregnancy. There also are risks associated with untreated depression in pregnancy (see Clinical Considerations). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options. No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD - 60 mg) on an mg/m2 basis. When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis (see Data) . The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of PEXEVA in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.5 )] . Fetal/Neonatal adverse reactions Neonates exposed to PEXEVA and other 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, tremors, jitteriness, irritability, and constant crying. These findings 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 )] . Data Human Data Published epidemiological studies on the association between first trimester paroxetine use and cardiovascular malformations have reported inconsistent results; however, meta-analyses of population-based cohort studies published between 1996-2017 indicate a less than 2-fold increased risk for overall cardiovascular malformations. Specific cardiac malformations identified in two meta-analyses include approximately 2 to 2.5-fold increased risk for right ventricular outflow tract defects. One meta-analysis also identified an increased risk (less than 2-fold) for bulbus cordis anomalies and anomalies of cardiac septal closure, and an increased risk for atrial septal defects (pooled OR 2.38, 95% CI 1.14-4.97). Important limitations of the studies included in these meta-analyses include potential confounding by indication, depression severity, and potential exposure misclassification. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. 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 approximately 8 (rat) and less than 2 (rabbit) times (MRHD - 60 mg) on an mg/m2 basis. These studies have revealed no evidence of malformations. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis. The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known. 8.2 Lactation Risk Summary Data from the published literature report the presence of paroxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to paroxetine through breast milk (see Clinical Considerations). There are no data on the effects of paroxetine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PEXEVA and any potential adverse effects on the breastfed infant from PEXEVA or the underlying maternal condition. Clinical Considerations Infants exposed to PEXEVA should be monitored for agitation, irritability, poor feeding and poor weight gain. Data Published literature suggests the presence of paroxetine in human milk with relative infant doses ranging between 0.4% to 2.2%, and a milk: plasma ratio of <1. No significant amounts were detected in the plasma of an infants after breastfeeding. 8.3 Females and Males of Reporductive Potential Infertility Male Based on findings from clinical studies, paroxetine may affect sperm quality which may impair fertility; it is not known if this effect is reversible [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of PEXEVA in pediatric patients have not been established [see Boxed Warning] . Effectiveness was not demonstrated in three placebo-controlled trials in 752 paroxetine-treated pediatric patients with MDD. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Decreased appetite and weight loss have been observed in association with the use of SSRIs. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with paroxetine and at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Adverse reactions upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain. 8.5 Geriatric Use In premarketing clinical trials with immediate-release paroxetine, 17% of paroxetine-treated patients (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; however, no overall differences in safety or effectiveness were observed between these subjects and younger subjects [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]. SSRIs, including PEXEVA, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5.10 )] . 8.6 Renal and/or Hepatic Impairment Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage of PEXEVA should be reduced in patients with severe renal impairment and patients with severe hepatic impairment [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )].

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Tablets: Pexeva (paroxetine mesylate) tablets are oval, film-coated tablets supplied as follows: PEXEVA 10 mg white tablets with the inscription POT 10 on one side. NDC 54766-201-01 Bottles of 30 PEXEVA 20 mg dark orange tablets with the inscription POT 20 on one side. The tablets are scored on both sides. NDC 54766-202-01 Bottles of 30 30 mg yellow tablets with the inscription POT 30 on one side. NDC 54766-203-01 Bottles of 30 40 mg rose tablets with the inscription POT 40 on one side. NDC 54766-204-01 Bottles of 30 Protect from Humidity. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature)

    Boxed Warning

    WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. PEXEVA is not approved for use in pediatric patients ( 5.1 , 8.4 ). WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all anti-depressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions ( 5.1 )] . PEXEVA is not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] .

    Learning Zones

    The Learning Zones are an educational resource for healthcare professionals that provide medical information on the epidemiology, pathophysiology and burden of disease, as well as diagnostic techniques and treatment regimens.

    Disclaimer

    The drug Prescribing Information (PI), including indications, contra-indications, interactions, etc, has been developed using the U.S. Food & Drug Administration (FDA) as a source (www.fda.gov).

    Medthority offers the whole library of PI documents from the FDA. Medthority will not be held liable for explicit or implicit errors, or missing data.

    Drugs appearing in this section are approved by the FDA. For regions outside of the United States, this content is for informational purposes only and may not be aligned with local regulatory approvals or guidance.