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adverse reactions
ADVERSE REACTIONS The information included under the “Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paroxetine Hydrochloride Controlled-Release Tablets” subsection of ADVERSE REACTIONS is based on data from 11 placebo-controlled clinical trials. Three of these studies were conducted in patients with major depressive disorder, 3 studies were done in patients with panic disorder, 1 study was conducted in patients with social anxiety disorder, and 4 studies were done in female patients with PMDD. Two of the studies in major depressive disorder, which enrolled patients in the age range 18 to 65 years, are pooled. Information from a third study of major depressive disorder, which focused on elderly patients (60 to 88 years), is presented separately as is the information from the panic disorder studies and the information from the PMDD studies. Information on additional adverse events associated with Paroxetine Hydrochloride Controlled-Release Tablets and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During the Clinical Development of Paroxetine). Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paroxetine Hydrochloride Controlled-Release Tablets: Adverse Events Associated With Discontinuation of Treatment Major Depressive Disorder Ten percent (21/212) of patients treated with Paroxetine Hydrochloride Controlled-Release Tablets discontinued treatment due to an adverse event in a pool of 2 studies of patients with major depressive disorder. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for Paroxetine Hydrochloride Controlled-Release Tablets compared to placebo) included the following: Paroxetine Hydrochloride Controlled-Release Tablets (n = 212) Placebo (n = 211) Nausea 3.7% 0.5% Asthenia 1.9% 0.5% Dizziness 1.4% 0.0% Somnolence 1.4% 0.0% In a placebo-controlled study of elderly patients with major depressive disorder, 13% (13/104) of patients treated with Paroxetine Hydrochloride Controlled-Release Tablets discontinued due to an adverse event. Events meeting the above criteria included the following: Paroxetine Hydrochloride Controlled-Release Tablets (n = 104) Placebo (n = 109) Nausea 2.9% 0.0% Headache 1.9% 0.9% Depression 1.9% 0.0% LFT’s abnormal 1.9% 0.0% Panic Disorder Eleven percent (50/444) of patients treated with Paroxetine Hydrochloride Controlled-Release Tablets in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following: Paroxetine Hydrochloride Controlled-Release Tablets (n = 444) Placebo (n = 445) Nausea 2.9% 0.4% Insomnia 1.8% 0.0% Headache 1.4% 0.2% Asthenia 1.1% 0.0% Social Anxiety Disorder Three percent (5/186) of patients treated with Paroxetine Hydrochloride Controlled-Release Tablets in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following: Paroxetine Hydrochloride Controlled-Release Tablets (n = 186) Placebo (n = 184) Nausea 2.2% 0.5% Headache 1.6% 0.5% Diarrhea 1.1% 0.5% Premenstrual Dysphoric Disorder Spontaneously reported adverse events were monitored in studies of both continuous and intermittent dosing of Paroxetine Hydrochloride Controlled-Release Tablets in the treatment of PMDD. Generally, there were few differences in the adverse event profiles of the 2 dosing regimens. Thirteen percent (88/681) of patients treated with Paroxetine Hydrochloride Controlled-Release Tablets in PMDD studies of continuous dosing discontinued treatment due to an adverse event. The most common events (≥1%) associated with discontinuation in either group treated with Paroxetine Hydrochloride Controlled-Release Tablets with an incidence rate that is at least twice that of placebo in PMDD trials that employed a continuous dosing regimen are shown in the following table. This table also shows those events that were dose dependent (indicated with an asterisk) as defined as events having an incidence rate with 25 mg of Paroxetine Hydrochloride Controlled-Release Tablets that was at least twice that with 12.5 mg of Paroxetine Hydrochloride Controlled-Release Tablets (as well as the placebo group). Paroxetine Hydrochloride Controlled-Release Tablets 25 mg (n = 348) Paroxetine Hydrochloride Controlled-Release Tablets 12.5 mg (n = 333) Placebo (n = 349) TOTAL 15% 9.9% 6.3% Nausea a 6.0% 2.4% 0.9% Asthenia 4.9% 3.0% 1.4% Somnolence a 4.3% 1.8% 0.3% Insomnia 2.3% 1.5% 0.0% Concentration Impaired a 2.0% 0.6% 0.3% Dry mouth a 2.0% 0.6% 0.3% Dizziness a 1.7% 0.6% 0.6% Decreased Appetite a 1.4% 0.6% 0.0% Sweating a 1.4% 0.0% 0.3% Tremor a 1.4% 0.3% 0.0% Yawn a 1.1% 0.0% 0.0% Diarrhea 0.9% 1.2% 0.0% a Events considered to be dose dependent are defined as events having an incidence rate with 25 mg of Paroxetine Hydrochloride Controlled-Release Tablets that was at least twice that with 12.5 mg of Paroxetine Hydrochloride Controlled-Release Tablets (as well as the placebo group). Commonly Observed Adverse Events Major Depressive Disorder The most commonly observed adverse events associated with the use of Paroxetine Hydrochloride Controlled-Release Tablets in a pool of 2 trials (incidence of 5.0% or greater and incidence for Paroxetine Hydrochloride Controlled-Release Tablets at least twice that for placebo, derived from Table 2) were: Abnormal ejaculation, abnormal vision, constipation, decreased libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma, tremor, and yawning. Using the same criteria, the adverse events associated with the use of Paroxetine Hydrochloride Controlled-Release Tablets in a study of elderly patients with major depressive disorder were: Abnormal ejaculation, constipation, decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor. Panic Disorder In the pool of panic disorder studies, the adverse events meeting these criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating, and female genital disorders (generally anorgasmia or difficulty achieving orgasm). Social Anxiety Disorder In the social anxiety disorder study, the adverse events meeting these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence, insomnia, and libido decreased. Premenstrual Dysphoric Disorder The most commonly observed adverse events associated with the use of Paroxetine Hydrochloride Controlled-Release Tablets either during continuous dosing or luteal phase dosing (incidence of 5% or greater and incidence for Paroxetine Hydrochloride Controlled-Release Tablets at least twice that for placebo, derived from Table 6) were: Nausea, asthenia, libido decreased, somnolence, insomnia, female genital disorders, sweating, dizziness, diarrhea, and constipation. In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day of Paroxetine Hydrochloride Controlled-Release Tablets limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the 3 off-drug phases were combined, the following adverse events were reported at an incidence of 2% or greater for Paroxetine Hydrochloride Controlled-Release Tablets and were at least twice the rate of that reported for placebo: Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%), sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%). Incidence in Controlled Clinical Trials Table 2 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with Paroxetine Hydrochloride Controlled-Release Tablets, aged 18 to 65, who participated in 2 short-term (12-week) placebo-controlled trials in major depressive disorder in which patients were dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse events reported at an incidence of 5% or greater among elderly patients (ages 60 to 88) treated with Paroxetine Hydrochloride Controlled-Release Tablets who participated in a short-term (12-week) placebo-controlled trial in major depressive disorder in which patients were dosed in a range of 12.5 mg to 50 mg/day. Table 4 enumerates adverse events reported at an incidence of 1% or greater among patients (19 to 72 years) treated with Paroxetine Hydrochloride Controlled-Release Tablets who participated in short-term (10-week) placebo-controlled trials in panic disorder in which patients were dosed in a range of 12.5 mg to 75 mg/day. Table 5 enumerates adverse events reported at an incidence of 1% or greater among adult patients treated with Paroxetine Hydrochloride Controlled-Release Tablets who participated in a short-term (12-week), double-blind, placebo-controlled trial in social anxiety disorder in which patients were dosed in a range of 12.5 to 37.5 mg/day. Table 6 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with Paroxetine Hydrochloride Controlled-Release Tablets who participated in three, 12-week, placebo-controlled trials in PMDD in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses (luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures 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 that 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 population studied. Table 2. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine Hydrochloride Controlled-Release Tablets in a Pool of 2 Studies in Major Depressive Disorder a,b Body System/Adverse Event % Reporting Event Paroxetine Hydrochloride Controlled-Release Tablets (n = 212) Placebo (n = 211) Body as a Whole Headache 27% 20% Asthenia 14% 9% Infection c 8% 5% Abdominal Pain 7% 4% Back Pain 5% 3% Trauma d 5% 1% Pain e 3% 1% Allergic Reaction f 2% 1% Cardiovascular System Tachycardia 1% 0% Vasodilatation g 2% 0% Digestive System Nausea 22% 10% Diarrhea 18% 7% Dry Mouth 15% 8% Constipation 10% 4% Flatulence 6% 4% Decreased Appetite 4% 2% Vomiting 2% 1% Nervous System Somnolence 22% 8% Insomnia 17% 9% Dizziness 14% 4% Libido Decreased 7% 3% Tremor 7% 1% Hypertonia 3% 1% Paresthesia 3% 1% Agitation 2% 1% Confusion 1% 0% Respiratory System Yawn 5% 0% Rhinitis 4% 1% Cough Increased 2% 1% Bronchitis 1% 0% Skin and Appendages Sweating 6% 2% Photosensitivity 2% 0% Special Senses Abnormal Vision h 5% 1% Taste Perversion 2% 0% Urogenital System Abnormal Ejaculation i,j 26% 1% Female Genital Disorder i,k 10% <1% Impotence i 5% 3% Urinary Tract Infection 3% 1% Menstrual Disorder i 2% <1% Vaginitis i 2% 0% a Adverse events for which the Paroxetine Hydrochloride Controlled-Release Tablets reporting incidence was less than or equal to the placebo incidence are not included. These events are: Abnormal dreams, anxiety, arthralgia, depersonalization, dysmenorrhea, dyspepsia, hyperkinesia, increased appetite, myalgia, nervousness, pharyngitis, purpura, rash, respiratory disorder, sinusitis, urinary frequency, and weight gain. b <1% means greater than zero and less than 1%. c Mostly flu. d A wide variety of injuries with no obvious pattern. e Pain in a variety of locations with no obvious pattern. f Most frequently seasonal allergic symptoms. g Usually flushing. h Mostly blurred vision. i Based on the number of males or females. j Mostly anorgasmia or delayed ejaculation. k Mostly anorgasmia or delayed orgasm. Table 3. Treatment-Emergent Adverse Events Occurring in ≥5% of Patients Treated With Paroxetine Hydrochloride Controlled-Release Tablets in a Study of Elderly Patients With Major Depressive Disorder a,b Body System/Adverse Event % Reporting Event Paroxetine Hydrochloride Controlled-Release Tablets (n = 104) Placebo (n = 109) Body as a Whole Headache 17% 13% Asthenia 15% 14% Trauma 8% 5% Infection 6% 2% Digestive System Dry Mouth 18% 7% Diarrhea 15% 9% Constipation 13% 5% Dyspepsia 13% 10% Decreased Appetite 12% 5% Flatulence 8% 7% Nervous System Somnolence 21% 12% Insomnia 10% 8% Dizziness 9% 5% Libido Decreased 8% <1% Tremor 7% 0% Skin and Appendages Sweating 10% <1% Urogenital System Abnormal Ejaculation c,d 17% 3% Impotence c 9% 3% a Adverse events for which the Paroxetine Hydrochloride Controlled-Release Tablets reporting incidence was less than or equal to the placebo incidence are not included. These events are nausea and respiratory disorder. b <1% means greater than zero and less than 1%. c Based on the number of males. d Mostly anorgasmia or delayed ejaculation. Table 4. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine Hydrochloride Controlled-Release Tablets in a Pool of 3 Panic Disorder Studies a,b Body System/Adverse Event % Reporting Event Paroxetine Hydrochloride Controlled-Release Tablets (n = 444) Placebo (n = 445) Body as a Whole Asthenia 15% 10% Abdominal Pain 6% 4% Trauma c 5% 4% Cardiovascular System Vasodilation d 3% 2% Digestive System Nausea 23% 17% Dry Mouth 13% 9% Diarrhea 12% 9% Constipation 9% 6% Decreased Appetite 8% 6% Metabolic/Nutritional Disorders Weight Loss 1% 0% Musculoskeletal System Myalgia 5% 3% Nervous System Insomnia 20% 11% Somnolence 20% 9% Libido Decreased 9% 4% Nervousness 8% 7% Tremor 8% 2% Anxiety 5% 4% Agitation 3% 2% Hypertonia e 2% <1% Myoclonus 2% <1% Respiratory System Sinusitis 8% 5% Yawn 3% 0% Skin and Appendages Sweating 7% 2% Special Senses Abnormal Vision f 3% <1% Urogenital System Abnormal Ejaculation g,h 27% 3% Impotence g 10% 1% Female Genital Disorders i,j 7% 1% Urinary Frequency 2% <1% Urination Impaired 2% <1% Vaginitis i 1% <1% a Adverse events for which the reporting rate for Paroxetine Hydrochloride Controlled-Release Tablets was less than or equal to the placebo rate are not included. These events are: Abnormal dreams, allergic reaction, back pain, bronchitis, chest pain, concentration impaired, confusion, cough increased, depression, dizziness, dysmenorrhea, dyspepsia, fever, flatulence, headache, increased appetite, infection, menstrual disorder, migraine, pain, paresthesia, pharyngitis, respiratory disorder, rhinitis, tachycardia, taste perversion, thinking abnormal, urinary tract infection, and vomiting. b <1% means greater than zero and less than 1%. c Various physical injuries. d Mostly flushing. e Mostly muscle tightness or stiffness. f Mostly blurred vision. g Based on the number of male patients. h Mostly anorgasmia or delayed ejaculation. i Based on the number of female patients. j Mostly anorgasmia or difficulty achieving orgasm. Table 5. Treatment-Emergent Adverse Effects Occurring in ≥1% of Patients Treated With Paroxetine Hydrochloride Controlled-Release Tablets in a Social Anxiety Disorder Study a,b Body System/Adverse Event % Reporting Event Paroxetine Hydrochloride Controlled-Release Tablets (n = 186) Placebo (n = 184) Body as a Whole Headache 23% 17% Asthenia 18% 7% Abdominal Pain 5% 4% Back Pain 4% 1% Trauma c 3% <1% Allergic Reaction d 2% <1% Chest Pain 1% <1% Cardiovascular System Hypertension 2% 0% Migraine 2% 1% Tachycardia 2% 1% Digestive System Nausea 22% 6% Diarrhea 9% 8% Constipation 5% 2% Dry Mouth 3% 2% Dyspepsia 2% <1% Decreased Appetite 1% <1% Tooth Disorder 1% 0% Metabolic/Nutritional Disorders Weight Gain 3% 1% Weight Loss 1% 0% Nervous System Insomnia 9% 4% Somnolence 9% 4% Libido Decreased 8% 1% Dizziness 7% 4% Tremor 4% 2% Anxiety 2% 1% Concentration Impaired 2% 0% Depression 2% 1% Myoclonus 1% <1% Paresthesia 1% <1% Respiratory System Yawn 2% 0% Skin and Appendages Sweating 14% 3% Eczema 1% 0% Special Senses Abnormal Vision e 2% 0% Abnormality of Accommodation 2% 0% Urogenital System Abnormal Ejaculation f,g 15% 1% Impotence f 9% 0% Female Genital Disorders h,i 3% 0% a Adverse events for which the reporting rate for Paroxetine Hydrochloride Controlled-Release Tablets was less than or equal to the placebo rate are not included. These events are: Dysmenorrhea, flatulence, gastroenteritis, hypertonia, infection, pain, pharyngitis, rash, respiratory disorder, rhinitis, and vomiting. b <1% means greater than zero and less than 1%. c Various physical injuries. d Most frequently seasonal allergic symptoms. e Mostly blurred vision. f Based on the number of male patients. g Mostly anorgasmia or delayed ejaculation. h Based on the number of female patients. i Mostly anorgasmia or difficulty achieving orgasm. Table 6. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine Hydrochloride Controlled-Release Tablets in a Pool of 3 Premenstrual Dysphoric Disorder Studies With Continuous Dosing or in 1 Premenstrual Dysphoric Disorder Study With Luteal Phase Dosing a,b,c Body System/Adverse Event % Reporting Event Continuous Dosing Luteal Phase Dosing Paroxetine Hydrochloride Controlled-Release Tablets (n = 681) Placebo (n = 349) Paroxetine Hydrochloride Controlled-Release Tablets (n = 246) Placebo (n = 120) Body as a Whole Asthenia 17% 6% 15% 4% Headache 15% 12% - - Infection 6% 4% - - Abdominal pain - - 3% 0% Cardiovascular System Migraine 1% <1% - - Digestive System Nausea 17% 7% 18% 2% Diarrhea 6% 2% 6% 0% Constipation 5% 1% 2% <1% Dry Mouth 4% 2% 2% <1% Increased Appetite 3% <1% - - Decreased Appetite 2% <1% 2% 0% Dyspepsia 2% 1% 2% 2% Gingivitis - - 1% 0% Metabolic and Nutritional Disorders Generalized Edema - - 1% <1% Weight Gain - - 1% <1% Musculoskeletal System Arthralgia 2% 1% - - Nervous System Libido Decreased 12% 5% 9% 6% Somnolence 9% 2% 3% <1% Insomnia 8% 2% 7% 3% Dizziness 7% 3% 6% 3% Tremor 4% <1% 5% 0% Concentration Impaired 3% <1% 1% 0% Nervousness 2% <1% 3% 2% Anxiety 2% 1% - - Lack of Emotion 2% <1% - - Depression - - 2% <1% Vertigo - - 2% <1% Abnormal Dreams 1% <1% - - Amnesia - - 1% 0% Respiratory System Sinusitis - - 4% 2% Yawn 2% <1% - - Bronchitis - - 2% 0% Cough Increased 1% <1% - - Skin and Appendages Sweating 7% <1% 6% <1% Special Senses Abnormal Vision - - 1% 0% Urogenital System Female Genital Disorders d 8% 1% 2% 0% Menorrhagia 1% <1% - - Vaginal Moniliasis 1% <1% - - Menstrual Disorder - - 1% 0% a Adverse events for which the reporting rate of Paroxetine Hydrochloride Controlled-Release Tablets was less than or equal to the placebo rate are not included. These events for continuous dosing are: Abdominal pain, back pain, pain, trauma, weight gain, myalgia, pharyngitis, respiratory disorder, rhinitis, sinusitis, pruritus, dysmenorrhea, menstrual disorder, urinary tract infection, and vomiting. The events for luteal phase dosing are: Allergic reaction, back pain, headache, infection, pain, trauma, myalgia, anxiety, pharyngitis, respiratory disorder, cystitis, and dysmenorrhea. b <1% means greater than zero and less than 1%. c The luteal phase and continuous dosing PMDD trials were not designed for making direct comparisons between the 2 dosing regimens. Therefore, a comparison between the 2 dosing regimens of the PMDD trials of incidence rates shown in Table 6 should be avoided. d Mostly anorgasmia or difficulty achieving orgasm. Dose Dependency of Adverse Events Table 7 shows results in PMDD trials of common adverse events, defined as events with an incidence of ≥1% with 25 mg of Paroxetine Hydrochloride Controlled-Release Tablets that was at least twice that with 12.5 mg of Paroxetine Hydrochloride Controlled-Release Tablets and with placebo. Table 7. Incidence of Common Adverse Events in Placebo, 12.5 mg and 25 mg of Paroxetine Hydrochloride Controlled-Release Tablets in a Pool of 3 Fixed-Dose PMDD Trials Paroxetine Hydrochloride Controlled-Release Tablets 25 mg (n = 348) Paroxetine Hydrochloride Controlled-Release Tablets 12.5 mg (n = 333) Placebo (n = 349) Common Adverse Event Sweating 8.9% 4.2% 0.9% Tremor 6.0% 1.5% 0.3% Concentration Impaired 4.3% 1.5% 0.6% Yawn 3.2% 0.9% 0.3% Paresthesia 1.4% 0.3% 0.3% Hyperkinesia 1.1% 0.3% 0.0% Vaginitis 1.1% 0.3% 0.3% A comparison of adverse event rates in a fixed-dose study comparing immediate-release paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with the use of immediate-release paroxetine. 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 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. The percentage of patients reporting symptoms of sexual dysfunction in the pool of 2 placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of 3 placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients with social anxiety disorder, and in the intermittent dosing and the pool of 3 placebo-controlled continuous dosing trials in female patients with PMDD are as follows: Major Depressive Disorder Panic Disorder Social Anxiety Disorder PMDD Continuous Dosing PMDD Luteal Phase Dosing Controlled-Release Paroxetine Placebo Controlled-Release Paroxetine Placebo Controlled-Release Paroxetine Placebo Controlled-Release Paroxetine Placebo Controlled-Release Paroxetine Placebo n (males) 78 78 162 194 88 97 n/a n/a n/a n/a Decreased Libido 10% 5% 9% 6% 13% 1% n/a n/a n/a n/a Ejaculatory Disturbance 26% 1% 27% 3% 15% 1% n/a n/a n/a n/a Impotence 5% 3% 10% 1% 9% 0% n/a n/a n/a n/a n (females) 134 133 282 251 98 87 681 349 246 120 Decreased Libido 4% 2% 8% 2% 4% 1% 12% 5% 9% 6% Orgasmic Disturbance 10% <1% 7% 1% 3% 0% 8% 1% 2% 0% There are no adequate, 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, 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 with Paroxetine Hydrochloride Controlled-Release Tablets or the immediate-release formulation of paroxetine hydrochloride, had minimal weight loss (about 1 pound). No significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature) were observed in patients treated with Paroxetine Hydrochloride Controlled-Release Tablets, or immediate-release paroxetine hydrochloride, in controlled clinical trials. ECG Changes In an analysis of ECGs obtained in 682 patients treated with immediate-release 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 a pool of 2 placebo-controlled clinical trials, patients treated with Paroxetine Hydrochloride Controlled-Release Tablets or placebo exhibited abnormal values on liver function tests at comparable rates. In particular, the controlled-release paroxetine-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities. In a study of elderly patients with major depressive disorder, 3 of 104 patients treated with Paroxetine Hydrochloride Controlled-Release Tablets and none of 109 placebo patients experienced liver transaminase elevations of potential clinical concern. Two of the patients treated with Paroxetine Hydrochloride Controlled-Release Tablets dropped out of the study due to abnormal liver function tests; the third patient experienced normalization of transaminase levels with continued treatment. Also, in the pool of 3 studies of patients with panic disorder, 4 of 444 patients treated with Paroxetine Hydrochloride Controlled-Release Tablets and none of 445 placebo patients experienced liver transaminase elevations of potential clinical concern. Elevations in all 4 patients decreased substantially after discontinuation of Paroxetine Hydrochloride Controlled-Release Tablets. The clinical significance of these findings is unknown. In placebo-controlled clinical trials with the immediate-release formulation of paroxetine, patients exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. Hallucinations In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving drug and in 4 of 3,187 patients receiving placebo. Other Events Observed During the Clinical Development of Paroxetine The following adverse events were reported during the clinical development of Paroxetine Hydrochloride Controlled-Release Tablets and/or the clinical development of the immediate-release formulation of paroxetine. Adverse events for which frequencies are provided below occurred in clinical trials with the controlled-release formulation of paroxetine. During its premarketing assessment in major depressive disorder, panic disorder, social anxiety disorder, and PMDD, multiple doses of Paroxetine Hydrochloride Controlled-Release Tablets were administered to 1,627 patients in phase 3 double-blind, controlled, outpatient studies. 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 COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of the 1,627 patients exposed to Paroxetine Hydrochloride Controlled-Release Tablets who experienced an event of the type cited on at least 1 occasion while receiving Paroxetine Hydrochloride Controlled-Release Tablets. All reported events are included except those already listed in Tables 2 through 7 and those events where a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was deleted or, when possible, replaced with a more informative term. 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 1 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 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Adverse events for which frequencies are not provided occurred during the premarketing assessment of immediate-release paroxetine in phase 2 and 3 studies of major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to immediate-release 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. Only those events not previously listed for controlled-release paroxetine are included. The extent to which these events may be associated with Paroxetine Hydrochloride Controlled-Release Tablets is unknown. Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in the PRECAUTIONS section. Body as a Whole Infrequent were chills, face edema, fever, flu syndrome, malaise; rare were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed were adrenergic syndrome, neck rigidity, sepsis. Cardiovascular System Infrequent were angina pectoris, bradycardia, hematoma, hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia, syncope; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation, cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles. Digestive System Infrequent were bruxism, dysphagia, eructation, gastritis, gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function test abnormal, melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis, glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction, peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue edema. Endocrine System Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus, hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis. Hemic and Lymphatic System Infrequent were anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis, lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia. Metabolic and Nutritional Disorders Infrequent were generalized edema, hyperglycemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare were bilirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperphosphatemia, hypocalcemia, hypoglycemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased. Musculoskeletal System Infrequent were arthritis, bursitis, tendonitis; rare were myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis, tenosynovitis, tetany. Nervous System Frequent were depression; infrequent were amnesia, convulsion, depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis, vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis, withdrawal syndrome; also observed were abnormal gait, akathisia, akinesia, aphasia, choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction, manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus. Respiratory System Frequent were pharyngitis; infrequent were asthma, dyspnea, epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema, hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum increased. Skin and Appendages Frequent were rash; infrequent were acne, alopecia, dry skin, eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash, seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis, photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss. Urogenital System Frequent were dysmenorrhea * ; infrequent were albuminuria, amenorrhea * , breast pain * , cystitis, dysuria, prostatitis * , urinary retention; rare were breast enlargement * , breast neoplasm * , female lactation, hematuria, kidney calculus, metrorrhagia * , nephritis, nocturia, pregnancy and puerperal disorders * , salpingitis, urinary incontinence, uterine fibroids enlarged * ; also observed were breast atrophy, ejaculatory disturbance, endometrial disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria, urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage. * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of adverse events in patients taking immediate-release paroxetine hydrochloride 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, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of 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; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, 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 an elevated phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when immediate-release paroxetine was added to chronic metoprolol treatment.