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Paroxetine MesylateASIMIATM Brand of PAROXETINE (as mesylate) tablets DESCRIPTIONASIMIATM (paroxetine mesylate) is an orally administered psychotropic drug with a chemical structure related to paroxetine hydrochloride (Paxil®). 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 19H20FNO3 CH3SO3H. The molecular weight is 425.5 (329.4 as free base). 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. Tablets Each oval, film coated tablet contains paroxetine mesylate equivalent to paroxetine as follows: 10 mg (white); 20 mg (scored, dark orange); 30 mg (yellow); 40 mg (rose). 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). CLINICAL PHARMACOLOGYPharmacodynamics The efficacy of paroxetine in the treatment of major depressive disorder, obsessive compulsive disorder (OCD), and panic disorder (PD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). 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. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2- and histamine (H1)-receptors; antagonism of muscarinic, histaminergic and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative and cardiovascular effects for other psychotropic drugs. Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent compound, they are essentially inactive. Pharmacokinetics 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. 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. 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 P450IID6. 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 PRECAUTIONS). 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. Distribution: Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Protein Binding: 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. Renal and Liver Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 ml/min was approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 ml/min and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, Cmax). The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION). Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30 and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced. (See DOSAGE AND ADMINISTRATION). Clinical Trials Major Depressive Disorder The efficacy of paroxetine as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (ages 18 to 73). In these studies paroxetine was shown to be significantly more effective than placebo in treating major depressive disorder 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 significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor and anxiety factor. A study of outpatients with major depressive disorder who had responded to paroxetine (HDRS total score <8) during an initial 8-week open–treatment phase and were then randomized to continuation on paroxetine or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. Obsessive Compulsive Disorder The effectiveness of paroxetine in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12–week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies 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. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40 or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was 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 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in the placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impressions (CGI) scale for Study 1.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term maintenance effects of paroxetine in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3–month double-blind phase and a 6–month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6–month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Panic Disorder The effectiveness of paroxetine in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1–3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown to be significantly more effective than placebo in treating panic disorder 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 were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12–week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine 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 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 patients. In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. Long-term maintenance effects of paroxetine in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10–week double-blind phase and during a 3–month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3–month double-blind relapse prevention phase. Patients randomized to paroxetine were 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. INDICATIONSAND USAGEMajor Depressive Disorder ASIMIATM (paroxetine mesylate) is indicated for the treatment of major depressive disorder. The efficacy of paroxetine in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (See CLINICAL PHARMACOLOGY). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The effects of paroxetine in hospitalized depressed patients has not been adequately studied. The efficacy of paroxetine in maintaining a response in major depressive disorder for up to 1 year was demonstrated in a placebo–controlled trial (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ASIMIATM for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Obsessive Compulsive Disorder ASIMIATM (paroxetine mesylate) is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of paroxetine was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see CLINICAL PHARMACOLOGY-Clinical Trials). Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. Long-term maintenance of efficacy was demonstrated in a 6–month relapse prevention trial. In this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ASIMIATM for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Panic Disorder ASIMIATM is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of paroxetine was established in three 10- to 12–week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY-Clinical Trials). Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Long-term maintenance of efficacy was demonstrated in a 3–month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who prescribes ASIMIATM for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
NDC 63672-2010-1 Bottles of 30 20 mg dark orange tablets with the inscription POT 20 on one side . The tablets are scored on both sides. NDC 63672-2020-1 Bottles of 30 NDC 63672-2020-2 Bottles of 100 NDC 63672-2020-4 Bottles of 500 30 mg yellow tablets with the inscription POT 30 on one side. NDC 63672-2030-1 Bottles of 30 40 mg rose tablets with the inscription POT 40 on one side. NDC 63672-2040-1 Bottles of 30 Store tablets between 15° and 30°C (59° and 86°F). DATE OF ISSUANCE Month/Year © Synthon Pharmaceuticals, Ltd. Synthon Pharmaceuticals, Ltd. Rx only Chapel Hill, North Carolina 27517
Where numbers are not provided the incidence of the adverse events in paroxetine patients was not >1% or was not greater than or equal to two times the incidence of placebo. 1. Incidence corrected for gender. Commonly Observed Adverse Events Major Depressive Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 1 below) were: asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance and other male genital disorders. Obsessive Compulsive Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that of placebo, derived from Table 2 below) were: nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence and abnormal ejaculation. Panic Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 2 below) were: asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders and impotence. Incidence in Controlled Clinical Trials The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied. Major Depressive Disorder Table 1 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
1. Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence of placebo paroxetine: abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly "cold symptoms" or "URI"), trauma and vomiting. 2. Includes mostly "lump in throat" and "tightness in throat." 3. Percentage corrected for gender. 4. Mostly "ejaculatory delay." 5. Includes "anorgasmia", "erectile difficulties", "delayed ejaculation/orgasm", and "sexual dysfunction", and "impotence". 6. Includes mostly "difficulty with micturition" and "urinary hesitancy." 7. Includes mostly "anorgasmia" and "difficulty reaching climax/orgasm." Obsessive Compulsive Disorder and Panic Disorder Table 2 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine who participated in placebo-controlled trials of 12–weeks duration in which patients were dosed in a range of 20 to 60 mg/day or among patients with panic disorder on paroxetine who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 to 60 mg/day.
1. Events reported by at least 2% of OCD or panic disorder paroxetine-treated patients are included, except the following events which had an incidence on placebo ³ paroxetine [OCD]: abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis and sinusitis. [panic disorder]: abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired and vasodilation. 2. Percentage corrected for gender. Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose study comparing paroxetine 10, 20, 30 and 40 mg/day with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with paroxetine use, as shown in the following table:
*Rule for including adverse events in table: incidence at least 5% for one of paroxetine groups and ³ twice the placebo incidence for at least one paroxetine group. 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 events and the dose of paroxetine to which patients were assigned. No new adverse events 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 panic disorder, there was no clear relationship between adverse events 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 events were observed in patients receiving paroxetine 60 mg compared to any of the other treatment groups. Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence and asthenia). Male and Female Sexual Dysfunction with SSRIs: 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 pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians 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. In placebo-controlled clinical trials involving more than 1,800 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD and panic disorder are displayed in Table 4 below.
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 sequelea. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss vs. smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine in controlled clinical trials. ECG Changes: In an analysis of ECGs obtained in 682 patients treated with paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. Liver Function Tests: In placebo-controlled clinical trials, patients treated with paroxetine exhibited abnormal values on liver function tests at no greater rate than that seen in placebo–treated patients. In particular, the paroxetine-vs.-placebo comparisons for alkaline phosphatase, SGOT, SGPT and bilirubin revealed no differences in the percentage of patients with marked abnormalities. Other Events Observed During the Premarketing Evaluation of Paroxetine During its premarketing assessment in major depressive disorder, multiple doses of paroxetine were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine varied greatly and included (in overlapping categories) open and double blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. During premarketing clinical trials in OCD and panic disorder, 542 and 469 patients, respectively, received multiple doses of paroxetine. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine who experienced an event of the type cited on at least one occasion while receiving paroxetine. All reported events are included except those already listed in Tables 1 and 2, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section. 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, syncope; rare: angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, 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, liver function tests abnormal, 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, non-protein nitrogen (NPN) increased. Musculoskeletal System: frequent: arthralgia; infrequent: arthritis, arthrosis; rare: bursitis, myositis, osteoporosis, generalised spasm, tenosynovitis, tetany. Nervous System: frequent: emotional lability, vertigo; infrequent: abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, 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, 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. Postmarketing Reports Voluntary reports of adverse events in patients taking paroxetine that have been received since market introduction and not listed above that may have no causal relationship with the drug include 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, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea, neuroleptic malignant syndrome-like events; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide, tremor and trismus; serotonin syndrome, associated in some cases with concomitant use of serotonergic drugs and with drugs which may have impaired paroxetine metabolism (symptoms have included agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor), status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, and events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis). There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin co–administration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment. DRUG ABUSE AND DEPENDENCE Controlled Substance Class: Paroxetine is not a controlled substance. Physical and Psychologic Dependence: Paroxetine has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of ASIMIATM misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
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