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Paxil-CR

Paxil-CR

SIDE EFFECTS

The information included under the "Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With PAXIL CR" 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 PAXIL CR 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 PAXIL CR

Adverse Events Associated With Discontinuation of Treatment

Major Depressive Disorder: Ten percent (21/212) of patients treated with PAXIL CR 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 PAXIL CR compared to placebo) included the following:

  PAXIL CR
(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 PAXIL CR discontinued due to an adverse event. Events meeting the above criteria included the following:

  PAXIL CR
(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 PAXIL CR in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

  PAXILCR
(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 PAXIL CR in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

  PAXILCR
(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 PAXIL CR 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 PAXIL CR 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 PAXIL CR 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 PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the placebo group).

  PAXILCR
25 mg
(n = 348)
PAXILCR
12.5 mg
(n = 333)
Placebo
(n = 349)
TOTAL 15% 9.9% 6.3%
Nauseaa 6.0% 2.4% 0.9%
Asthenia 4.9% 3.0% 1.4%
Somnolencea 4.3% 1.8% 0.3%
Insomnia 2.3% 1.5% 0.0%
Concentration Impaireda 2.0% 0.6% 0.3%
Dry moutha 2.0% 0.6% 0.3%
Dizzinessa 1.7% 0.6% 0.6%
Decreased Appetitea 1.4% 0.6% 0.0%
Sweatinga 1.4% 0.0% 0.3%
Tremora 1.4% 0.3% 0.0%
Yawna 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 PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the placebo group).

Commonly Observed Adverse Events

Major Depressive Disorder: The most commonly observed adverse events associated with the use of PAXIL CR in a pool of 2 trials (incidence of 5.0% or greater and incidence for PAXIL CR 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 PAXIL CR 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 PAXIL CR either during continuous dosing or luteal phase dosing (incidence of 5% or greater and incidence for PAXIL CR 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 PAXIL CR 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 PAXIL CR 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 PAXIL CR, 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 PAXIL CR 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 PAXIL CR 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 PAXIL CR 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 PAXIL CR 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 PAXIL CR in a Pool of 2 Studies in Major Depressive Disordera,b

Body System/Adverse Event % Reporting Event
PAXIL CR
(n = 212)
Placebo
(n = 211)
Body as a Whole
  Headache 27% 20%
  Asthenia 14% 9%
  Infectionc 8% 5%
  Abdominal Pain 7% 4%
  Back Pain 5% 3%
  Traumad 5% 1%
  Paine 3% 1%
  Allergic Reactionf 2% 1%
Cardiovascular System
  Tachycardia 1% 0%
  Vasodilatationg 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 Visionh 5% 1%
  Taste Perversion 2% 0%
Urogenital System
  Abnormal Ejaculationi,j 26% 1%
  Female Genital Disorderi,k 10% < 1%
  Impotencei 5% 3%
  Urinary Tract Infection 3% 1%
  Menstrual Disorderi 2% < 1%
  Vaginitisi 2% 0%
a. Adverse events for which the PAXIL CR 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 PAXIL CR in a Study of Elderly Patients With Major Depressive Disordera,b

Body System/Adverse Event % Reporting Event
PAXIL CR
(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 Ejaculationc,d 17% 3%
  Impotencec 9% 3%
a. Adverse events for which the PAXIL CR 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 PAXIL CR in a Pool of 3 Panic Disorder Studiesa,b

Body System/Adverse Event % Reporting Event
PAXIL CR
(n = 444)
Placebo
(n = 445)
Body as a Whole
  Asthenia 15% 10%
  Abdominal Pain 6% 4%
  Traumac 5% 4%
Cardiovascular System
  Vasodilationd 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%
  Hypertoniae 2% < 1%
  Myoclonus 2% < 1%
Respiratory System
  Sinusitis 8% 5%
  Yawn 3% 0%
Skin and Appendages
  Sweating 7% 2%
Special Senses
  Abnormal Visionf 3% < 1%
Urogenital System
  Abnormal Ejaculationg,h 27% 3%
  Impotenceg 10% 1%
  Female Genital Disordersi,j 7% 1%
  Urinary Frequency 2% < 1%
  Urination Impaired 2% < 1%
  Vaginitisi 1% < 1%
a. Adverse events for which the reporting rate for PAXIL CR 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 PAXIL CR in a Social Anxiety Disorder Studya,b

Body System/Adverse Event % Reporting Event
PAXIL CR
(n = 186)
Placebo
(n = 184)
Body as a Whole
  Headache 23% 17%
  Asthenia 18% 7%
  Abdominal Pain 5% 4%
  Back Pain 4% 1%
  Traumac 3% < 1%
  Allergic Reactiond 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 Visione 2% 0%
  Abnormality of Accommodation 2% 0%
Urogenital System
  Abnormal Ejaculationf,g 15% 1%
  Impotencef 9% 0%
  Female Genital Disordersh,i 3% 0%
a. Adverse events for which the reporting rate for PAXIL CR 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 PAXIL CR in a Pool of 3 Premenstrual Dysphoric Disorder Studies With Continuous Dosing or in 1 Premenstrual Dysphoric Disorder Study With Luteal Phase Dosinea,b,c

Body System/Adverse Event % Reporting Event
Continuous Dosing Luteal Phase Dosing
PAXIL CR
(n = 681)
Placebo
(n = 349)
PAXIL CR
(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 Disordersd 8% 1% 2% 0%
  Menorrhagia 1% < 1% - -
  Vaginal Moniliasis 1% < 1% - -
  Menstrual Disorder - - 1% 0%
a. Adverse events for which the reporting rate of PAXIL CR 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, pruritis, 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 PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR and with placebo.

Table 7. Incidence of Common Adverse Events in Placebo, 12.5 mg, and 25 mg of PAXIL CR in a Pool of 3 Fixed-Dose PMDD Trials

  PAXILCR
25 mg
(n = 348)
PAXIL CR
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
  PAXIL CR Placebo PAXIL CR Placebo PAXIL CR Placebo PAXIL CR Placebo PAXIL CR 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 PAXIL CR or the immediate-release formulation, 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 PAXIL CR, 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 PAXIL CR 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 PAXIL CR and none of 109 placebo patients experienced liver transaminase elevations of potential clinical concern.

Two of the patients treated with PAXIL CR 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 PAXIL CR and none of 445 placebo patients experienced liver transaminase elevations of potential clinical concern. Elevations in all 4 patients decreased substantially after discontinuation of PAXIL CR. 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 PAXIL CR 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 PAXIL CR 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 PAXIL CR who experienced an event of the type cited on at least 1 occasion while receiving PAXIL CR. 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 PAXIL CR 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-Barre 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-Schonlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of immediate-release paroxetine andphenytoin coadministration. There has been a case report of severe hypotension when immediate-release paroxetine was added to chronic metoprolol treatment.

Drug Abuse And Dependence

Controlled Substance Class

PAXIL CR is not a controlled substance.

Physical and Psychologic Dependence

PAXIL CR 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 misuse or abuse of PAXIL CR (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

Read the Paxil-CR (paroxetine hydrochloride) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Tryptophan: As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking immediate-release paroxetine. Consequently, concomitant use of PAXIL CR with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions).

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.

Pimozide: In a controlled study of healthy volunteers, after immediate-release paroxetine hydrochloride was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and PAXIL CR is contraindicated (see CONTRAINDICATIONS).

Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when PAXIL CR is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions). The concomitant use of PAXIL CR with MAOIs (including linezolid and methylene blue) is contraindicated (see CONTRAINDICATIONS). The concomitant use of PAXIL CR with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: DRUG INTERACTIONS, Tryptophari).

Thioridazine: See CONTRAINDICATIONS and WARNINGS.

Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of PAXIL CR and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere With Hemostasis).

Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of PAXIL CR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions).

Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.

Cimetidine: Cimetidine inhibits many cytochrome P4so (oxidative) enzymes. In a study where immediate-release paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral Cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of PAXIL CR after the starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine's pharmacokinetics was not studied.

Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30-mg dose of immediate-release paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment with PAXIL CR is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Phenytoin: When a single oral 30-mg dose of immediate-release paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to immediate-release paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when PAXIL CR is coadministered with phenytoin; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports).

Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs, and many tricyclics), are metabolized by the cytochrome P4so isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients ( > 90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In 1 study, daily dosing of immediate-release paroxetine (20 mg once daily) under steady-state conditions increased single-dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when given with paroxetine.

Concomitant use of PAXIL CR with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either PAXIL CR or the other drug.

Therefore, coadministration of PAXIL CR with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.

However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS).

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS).

At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Tricyclic Antidepressants [TCAs]).

Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine's in vitro Kj and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of TCAs with PAXIL CR, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with PAXIL CR (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6).

Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of PAXIL CR to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.

Alcohol: Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL CR.

Lithium: A multiple-dose study with immediate-release paroxetine hydrochloride has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when immediate-release paroxetine hydrochloride is coadministered with lithium.

Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of PAXIL CR and digoxin should be undertaken with caution.

Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.

Procyclidine: Daily oral dosing of immediate-release paroxetine (30 mg once daily) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.

Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with immediate-release paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing Reports).

Theophylline: Reports of elevated theophylline levels associated with immediate-release paroxetine treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.

Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECTandPAXILCR.

Read the Paxil-CR Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 7/29/2011
This monograph has been modified to include the generic and brand name in many instances.

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