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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.