CLINICAL PHARMACOLOGY
Pharmacodynamics
The efficacy of paroxetine in the treatment of major depressive disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) 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, alpha
1-, alpha
2-, beta-adrenergic-, dopamine (D
2)-, 5-HT
1-, 5-HT
2-, and histamine (H
1)-receptors; antagonism of muscarinic, histaminergic, and alpha
1-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 hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).
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 C
max or AUC than females.
Absorption and Distribution
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C
max, T
max,
C
min, and T
½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21 hours (CV 32%), respectively. The steady-state C
max and C
min values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC
0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.
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 C
max was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.
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.
Metabolism and Excretion
The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to C
min values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.
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 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
PRECAUTIONS: Drugs Metabolized by CYP2D6).
Other Clinical Pharmacology Information
Specific Populations
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. were 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, C
max).
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, C
min concentrations were about 70% to 80% greater than the respective C
min concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see
DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions
In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see
PRECAUTIONS: Drug Interactions).
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 (aged 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 placebo-treated patients.
The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1 |
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 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 to 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.
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 Generalized Anxiety Disorder (DSM-IV).
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine were both demonstrated to be 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 40 mg/day dose compared to the 20 mg/day 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, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), 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 longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine, 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 receiving continued paroxetine experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.
ADVERSE REACTIONS
Associated With Discontinuation of Treatment
Twenty percent (1,199/6,145) of patients treated with paroxetine in worldwide clinical trials in major depressive disorder and 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine in worldwide trials in OCD, panic disorder, and GAD, respectively, discontinued treatment due to an adverse event. 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 compared to placebo) included the following:
| Major Depressive Disorder | OCD | Panic Disorder | Generalized Anxiety Disorder |
Paroxetine | Placebo | Paroxetine | Placebo | Paroxetine | Placebo | Paroxetine | Placebo |
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 2 times the incidence of placebo. 1. Incidence corrected for gender.
|
CNS
| | | | | | | | |
Somnolence
| 2.3%
| 0.7%
| —
| | 1.9%
| 0.3%
| 2%
| 0.2%
|
Insomnia
| —
| —
| 1.7%
| 0%
| 1.3%
| 0.3%
| | |
Agitation
| 1.1%
| 0.5%
| —
| | | | | |
Tremor
| 1.1%
| 0.3%
| —
| | | | | |
Anxiety
| —
| —
| —
| | | | | |
Dizziness
| —
| —
| 1.5%
| 0%
| | | 1%
| 0.2%
|
Gastrointestinal
| | | | | | | | |
Constipation
| —
| | 1.1%
| 0%
| | | | |
Nausea
| 3.2%
| 1.1%
| 1.9%
| 0%
| 3.2%
| 1.2%
| 2%
| 0.2%
|
Diarrhea
| 1%
| 0.3%
| —
| | | | | |
Dry mouth
| 1%
| 0.3%
| —
| | | | | |
Vomiting
| 1%
| 0.3%
| —
| | | | | |
Flatulence
| | | | | | | | |
Other
| | | | | | | | |
Asthenia
| 1.6%
| 0.4%
| 1.9%
| 0.4%
| | | 1.8%
| 0.2%
|
Abnormal Ejaculation1
| 1.6%
| 0%
| 2.1%
| 0%
| | | 2.5%
| 0.5%
|
Sweating
| 1%
| 0.3%
| —
| | | | 1.1%
| 0.2%
|
Impotence1
| —
| | 1.5%
| 0%
| | | | |
Libido Decreased
| | | | | | | | |
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 2) 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 3) 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 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.
Generalized Anxiety 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 4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.
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 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 populations studied.
Major Depressive Disorder
Table 2 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 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder1
Body System | Preferred Term | Paroxetine (n=421) | Placebo (n=421) |
1. Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on 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.”
|
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 Disorder2
| 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 Disturbance3,4
| 13%
| 0%
|
Other Male Genital Disorders3,5
| 10%
| 0%
|
Urinary Frequency
| 3%
| 1%
|
Urination Disorder6
| 3%
| 0%
|
Female Genital Disorders3,7
| 2%
| 0%
|
Obsessive Compulsive Disorder and Panic Disorder
Table 3 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 mg 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 mg to 60 mg/day.
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder and Panic Disorder1
Body System | Preferred Term | Obsessive Compulsive Disorder | Panic Disorder |
Paroxetine (n = 542) | Placebo (n = 265) | Paroxetine (n = 469) | Placebo (n = 324) |
1. Events reported by at least 2% of OCD and panic disorder in patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ 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.
|
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%
|
Trauma
| —
| —
| —
| —
|
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%
|
Dyspepsia
| —
| —
| —
| —
|
Flatulence
| —
| —
| —
| —
|
Increased Appetite
| 4%
| 3%
| 2%
| 1%
|
Vomiting
| —
| —
| —
| —
|
Musculoskeletal
| Myalgia
| —
| —
| —
|
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%
|
Pharyngitis
| —
| —
| —
| —
|
Yawn
| —
| —
| —
| —
|
Special Senses
| Abnormal Vision
| 4%
| 2%
| —
| —
|
Taste Perversion
| 2%
| 0%
| —
| —
|
Urogenital System
| Abnormal Ejaculation2
| 23%
| 1%
| 21%
| 1%
|
Dysmenorrhea
| —
| —
| —
| —
|
Female Genital Disorder2
| 3%
| 0%
| 9%
| 1%
|
Impotence2
| 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 4 enumerates adverse events 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.
Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized Anxiety Disorder1
Body System | Preferred Term | Generalized Anxiety Disorder |
Paroxetine (n=735) | Placebo (n=529) |
1. Events reported by at least 2% of GAD in patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis.
2. Percentage corrected for gender.
|
Body as a Whole
| Asthenia
| 14%
| 6%
|
Headache
| 17%
| 14%
|
Infection
| 6%
| 3%
|
Abdominal Pain
| | |
Trauma
| | |
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%
|
Dyspepsia
| —
| —
|
Nervous System
| Insomnia
| 11%
| 8%
|
Somnolence
| 15%
| 5%
|
Dizziness
| 6%
| 5%
|
Tremor
| 5%
| 1%
|
Nervousness
| 4%
| 3%
|
Libido Decreased
| 9%
| 2%
|
Abnormal Dreams
| | |
Respiratory System
| Respiratory Disorder
| 7%
| 5%
|
Sinusitis
| 4%
| 3%
|
Yawn
| 4%
| —
|
Special Senses
| Abnormal Vision
| 2%
| 1%
|
Urogenital System
| Abnormal Ejaculation2
| 25%
| 2%
|
Female Genital Disorder2
| 4%
| 1%
|
Impotence2
| 4%
| 3%
|
Dose Dependency of Adverse Events
A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of 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 use of paroxetine, as shown in Table 5:
Table 5. Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder*
Body System/Preferred Term | Placebo | Paroxetine |
n = 51 | 10 mg n = 102 | 20 mg n = 104 | 30 mg n = 101 | 40 mg n = 102 |
* Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups and ≥ twice the placebo incidence for at least 1 paroxetine group.
|
Body as a Whole
| | | | | |
Asthenia
| 0%
| 2.9%
| 10.6%
| 13.9%
| 12.7%
|
Dermatology
| | | | | |
Sweating
| 2%
| 1%
| 6.7%
| 8.9%
| 11.8%
|
Gastrointestinal
| | | | | |
Constipation
| 5.9%
| 4.9%
| 7.7%
| 9.9%
| 12.7%
|
Decreased Appetite
| 2%
| 2%
| 5.8%
| 4%
| 4.9%
|
Diarrhea
| 7.8%
| 9.8%
| 19.2%
| 7.9%
| 14.7%
|
Dry Mouth
| 2%
| 10.8%
| 18.3%
| 15.8%
| 20.6%
|
Nausea
| 13.7%
| 14.7%
| 26.9%
| 34.7%
| 36.3%
|
Nervous System
| | | | | |
Anxiety
| 0%
| 2%
| 5.8%
| 5.9%
| 5.9%
|
Dizziness
| 3.9%
| 6.9%
| 6.7%
| 8.9%
| 12.7%
|
Nervousness
| 0%
| 5.9%
| 5.8%
| 4%
| 2.9%
|
Paresthesia
| 0%
| 2.9%
| 1%
| 5%
| 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%
| 2.9%
| 2.9%
| 2%
| 7.8%
|
Urogenital System
| | | | | |
Abnormal Ejaculation
| 0%
| 5.8%
| 6.5%
| 10.6%
| 13%
|
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 20, 40, and 60 mg of paroxetine 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 group treated with 60 mg of paroxetine compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine 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 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 generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation.
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 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, and GAD are displayed in Table 6.
Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials
| Paroxetine | Placebo |
n (males) | 1446 | 1042 |
Decreased Libido
| 6-15%
| 0-5%
|
Ejaculatory Disturbance
| 13-28%
| 0-2%
|
Impotence
| 2-9%
| 0-3%
|
n (females)
| 1822
| 1340
|
Decreased Libido
| 0-9%
| 0-2%
|
Orgasmic Disturbance
| 2-9%
| 0-1%
|
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, 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 versus 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-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities.
Hallucinations
In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo.
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, panic disorder and generalized anxiety disorder, 542, 469, and 735 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 1 occasion while receiving paroxetine. All reported events are included except those already listed in Tables 2 to 5, 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 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. 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, 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 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, cholelithiasis, 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, generalized 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, pyuria, 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, 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), and vasculitic syndromes (such as Henoch-Schönlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.