SIDE EFFECTS
Immediate-Release Tablets and Oral Suspension
Associated with Discontinuation of Treatment
Twenty percent (1199/6145) of paroxetine HCl patients in
worldwide clinical trials in depression and 16.1% (84/522),
11.8% (64/542) and 9.4% (44/469) of paroxetine HCl patients
in worldwide trials in social anxiety disorder, OCD and
panic disorder, respectively, discontinued treatment due
to an adverse event. The most common events (³1%) 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 HCl compared to placebo)
are included in TABLE 2A and TABLE 2B.
| TABLE
2A Depression and Social Anxiety Disorder |
| |
Depression |
Social Anxiety
Disorder |
| |
Paroxetine HCl |
Placebo |
Paroxetine HCl |
Placebo |
| CNS |
| Somnolence |
2.3% |
0.7% |
3.4% |
0.3% |
| Insomnia |
¾ |
¾ |
3.1% |
0% |
| Agitation |
1.1% |
0.5% |
|
|
| Tremor |
1.1% |
0.3% |
1.7% |
0% |
| Anxiety |
¾ |
¾ |
1.1% |
0% |
| Dizziness |
¾ |
¾ |
1.9% |
0% |
| Gastrointestinal |
| Constipation |
¾ |
|
|
|
| Nausea |
3.2% |
1.1% |
4.0% |
0.3% |
| Diarrhea |
1.0% |
0.3% |
|
|
| Dry
mouth |
1.0% |
0.3% |
|
|
| Vomiting |
1.0% |
0.3% |
1.0% |
0% |
| Flatulence |
|
|
1.0% |
0.3% |
| Other |
| Asthenia |
1.6% |
0.4% |
2.5% |
0.6% |
| Abnormal
ejaculation* |
1.6% |
0% |
4.9% |
0.6% |
| Sweating |
1.0% |
0.3% |
1.1% |
0% |
| Impotence* |
¾ |
|
|
|
| Libido
decreased |
|
|
1.0% |
0% |
| * Incidence
corrected for gender. |
| Where numbers
are not provided the incidence of the adverse events
in paroxetine HCl patients was not >1% or was not
greater than or equal to two times the incidence of
placebo. |
| TABLE 2B OCD
and Panic Disorder |
| |
OCD |
Panic Disorder |
| |
Paroxetine HCl |
Placebo |
Paroxetine HCl |
Placebo |
| CNS |
| Somnolence |
¾ |
|
1.9% |
0.3% |
| Insomnia |
1.7% |
0% |
1.3% |
0.3% |
| Agitation |
¾ |
|
|
|
| Tremor |
¾ |
|
|
|
| Anxiety |
¾ |
|
|
|
| Dizziness |
1.5% |
0% |
|
|
| Gastrointestinal |
| Constipation |
1.1% |
0% |
|
|
| Nausea |
1.9% |
0% |
3.2% |
1.2% |
| Diarrhea |
¾ |
|
|
|
| Dry
Mouth |
¾ |
|
|
|
| Vomiting |
¾ |
|
|
|
| Flatulence |
|
|
|
|
| Other |
| Asthenia |
1.9% |
0.4% |
|
|
| Abnormal
ejaculation* |
2.1% |
0% |
|
|
| Sweating |
¾ |
|
|
|
| Impotence* |
1.5% |
0% |
|
|
| Libido
Decreased |
|
|
|
|
| * Incidence
corrected for gender. |
| Where numbers
are not provided the incidence of the adverse events
in paroxetine HCl patients was not >1% or was not
greater than or equal to two times the incidence of
placebo. |
Commonly Observed Adverse Events
Depression: The most commonly
observed adverse events associated with the use of paroxetine
(incidence of 5% or greater and incidence for paroxetine
HCl at least twice that for placebo, derived from TABLE
3A and TABLE 3B) 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 HCl at least twice that of placebo,
derived from TABLE 4A, TABLE 4B, TABLE 4C, and TABLE 4D)
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
HCl at least twice that for placebo, derived from TABLE
4A, TABLE 4B, TABLE 4C, and TABLE 4D) were: asthenia,
sweating, decreased appetite, libido decreased, tremor,
abnormal ejaculation, female genital disorders, and impotence.
Social Anxiety Disorder: The
most commonly observed adverse events associated with
the use of paroxetine incidence of 5% or greater and (incidence
for paroxetine HCl at least twice that for placebo, derived
from TABLE 4A, TABLE 4B, TABLE 4C, and TABLE 4D) were:
sweating, nausea, dry mouth, constipation, decreased appetite,
somnolence, tremor, libido decreased, yawn, abnormal ejaculation,
female genital disorders, and impotence.
Incidence in Controlled Clinical Trials
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 which prevailed in
the clinical trials. Similarly, the cited frequencies
cannot be compared with figures obtained from other clinical
investigations involving different treatments, uses and
investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating
the relative contribution of drug and nondrug factors
to the side effect incidence rate in the population studied.
Depression: TABLE 3A and TABLE
3B enumerate adverse events that occurred at an incidence
of 1% or more among paroxetine-treated patients who participated
in short-term (6-week) placebo-controlled trials in which
patients were dosed in a range of 20 to 50 mg/day. Reported
adverse events were classified using a standard COSTART-based
Dictionary terminology.
| TABLE 3A Treatment-Emergent
Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Depression* |
| |
Paroxetine HCl |
Placebo |
| Body System & Preferred
Term |
(n=421) |
(n=421) |
| Body as
a Whole |
| Headache |
18% |
17% |
| Asthenia |
15% |
6% |
| Cardiovascular |
| Palpitation |
3% |
1% |
| Vasodilation |
3% |
1% |
| Dermatologic |
| Sweating |
11% |
2% |
| Rash |
2% |
1% |
| Gastrointestinal |
| Nausea |
26% |
9% |
| Dry
Mouth |
18% |
12% |
| Constipation |
14% |
9% |
| Diarrhea |
12% |
8% |
| Decreased
Appetite |
6% |
2% |
| Flatulence |
4% |
2% |
| Oropharynx
Disorder† |
2% |
0% |
| Dyspepsia |
2% |
1% |
| * Events
reported by at least 1% of patients treated with paroxetine
HCl are included, except the following events which
had an incidence on placebo ³
paroxetine HCl: 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. |
| † Includes
mostly "lump in throat" and "tightness
in throat." |
| TABLE 3B Treatment-Emergent
Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Depression* |
| Body System & Preferred
Term |
Paroxetine HCl |
Placebo |
| |
(n=421) |
(n=421) |
| 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
Disturbanceठ|
13% |
0% |
| Other
Male Genital |
|
|
| Disorders‡¤ |
10% |
0% |
| Urinary
Frequency |
3% |
1% |
| Urination
Disorder¶ |
3% |
0% |
| Female
Genital Disorders‡** |
2% |
0% |
| * Events
reported by at least 1% of patients treated with paroxetine
HCl are included, except the following events which
had an incidence on placebo ³
paroxetine HCl: 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. |
| † Includes
mostly "lump in throat" and "tightness
in throat." |
| ‡ Percentage
corrected for gender. |
| § Mostly
"ejaculatory delay." |
| ¤
Includes "anorgasmia", "erectile difficulties,"
"delayed ejaculation/orgasm," and "sexual
dysfunction," and "impotence." |
| ¶ Includes
mostly "difficulty with micturition" and
"urinary hesitancy." |
| ** Includes
mostly "anorgasmia" and "difficulty
reaching climax/orgasm." |
Obsessive Compulsive Disorder, Panic Disorder,
and Social Anxiety Disorder: TABLE 4A, TABLE
4B, TABLE 4C, and TABLE 4D enumerate adverse events that
occurred at a frequency of 2% or more among OCD patients
on paroxetine HCl who participated in placebo-controlled
trials of 12-weeks duration in which patients were dosed
in a range of 20 to 60 mg/day or among patients with panic
disorder on paroxetine HCl who participated in placebo-controlled
trials of 10- to 12-weeks duration in which patients were
dosed in a range of 10 to 60 mg/day or among patients with
social anxiety disorder on paroxetine HCl who participated
in placebo-controlled trials of 12-weeks duration in which
patients were dosed in a range of 20 to 50 mg/day.
| TABLE 4A Treatment-Emergent
Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Obsessive Compulsive Disorder
and Social Anxiety Disorder* |
| |
Obsessive Compulsive
Disorder |
Social Anxiety
Disorder |
| Body System & Preferred
Term |
Paroxetine HCl (n=542) |
Placebo (n=265) |
Paroxetine HCl (n=425) |
Placebo (n=339) |
| Body as
a Whole |
| Asthenia |
22% |
14% |
22% |
14% |
| Abdominal
Pain |
¾ |
¾ |
¾ |
¾ |
| Chest
Pain |
3% |
2% |
¾ |
¾ |
| Back
Pain |
¾ |
¾ |
¾ |
¾ |
| Chills |
2% |
1% |
¾ |
¾ |
| Trauma |
¾ |
¾ |
3% |
1% |
| Cardiovascular |
| Vasodilation |
4% |
1% |
¾ |
¾ |
| Palpitation |
2% |
0% |
¾ |
¾ |
| Dermatologic |
| Sweating |
9% |
3% |
9% |
2% |
| Rash |
3% |
2% |
¾ |
¾ |
| Gastrointestinal |
| Nausea |
23% |
10% |
25% |
7% |
| Dry
Mouth |
18% |
9% |
9% |
3% |
| Constipation |
16% |
6% |
5% |
2% |
| Diarrhea |
10% |
10% |
9% |
6% |
| Decreased
Appetite |
9% |
3% |
8% |
2% |
| Dyspepsia |
¾ |
¾ |
4% |
2% |
| Flatulence |
¾ |
¾ |
4% |
2% |
| Increased
Appetite |
4% |
3% |
¾ |
¾ |
| Vomiting |
¾ |
¾ |
2% |
1% |
| * Events
reported by at least 2% of OCD and social anxiety
disorder paroxetine HCl-treated patients are included,
except the following events which had an incidence
on placebo ³ paroxetine
HCl. (OCD): abdominal pain, agitation, anxiety, back
pain, cough increased, depression, headache, hyperkinesia,
infection, paresthesia, pharyngitis, respiratory disorder,
rhinitis, and sinusitis (social anxiety disorder):
abdominal pain, depression, headache, infection, respiratory
disorder, and sinusitis. |
| TABLE 4B Treatment-Emergent
Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Obsessive Compulsive Disorder
and Social Anxiety Disorder* |
| |
Obsessive Compusive
Disorder |
Social Anxiety
Disorder |
| Body System & Preferred
Term |
Paroxetine HCl (n=542) |
Placebo (n=265) |
Paroxetine HCl (n=425) |
Placebo (n=339) |
| Musculoskeletal |
| Myalgia |
¾ |
¾ |
4% |
3% |
| Nervous
System |
| Insomnia |
24% |
13% |
21% |
16% |
| Somnolence |
24% |
7% |
22% |
5% |
| Dizziness |
12% |
6% |
11% |
7% |
| Tremor |
11% |
1% |
9% |
1% |
| Nervousness |
9% |
8% |
8% |
7% |
| Libido
Decreased |
7% |
4% |
12% |
1% |
| Agitation |
¾ |
¾ |
3% |
1% |
| Anxiety |
¾ |
|
5% |
4% |
| Abnormal
Dreams |
4% |
1% |
¾ |
¾ |
| Concentration
Impaired |
3% |
2% |
4% |
1% |
| Depersonalization |
3% |
0% |
¾ |
¾ |
| Myoclonus |
3% |
0% |
2% |
1% |
| Amnesia |
2% |
1% |
¾ |
¾ |
| Respiratory
System |
| Rhinitis |
¾ |
¾ |
¾ |
¾ |
| Pharyngitis |
¾ |
¾ |
4% |
2% |
| Yawn |
¾ |
¾ |
5% |
1% |
| Special
Senses |
| Abnormal
Vision |
4% |
2% |
4% |
1% |
| Taste
Perversion |
2% |
0% |
¾ |
¾ |
| Urogenital
System |
| Abnormal
Ejaculation† |
23% |
1% |
28% |
1% |
| Dysmenorrhea |
¾ |
¾ |
5% |
4% |
| Female
Genital Disorder† |
3% |
0% |
9% |
1% |
| Impotence† |
8% |
1% |
5% |
1% |
| Urinary
Frequency |
3% |
1% |
¾ |
¾ |
| Urination
Impaired |
3% |
0% |
¾ |
¾ |
| Urinary
Tract Infection |
2% |
1% |
¾ |
¾ |
| * Events
reported by at least 2% of OCD and social anxiety
disorder paroxetine HCl-treated patients are included,
except the following events which had an incidence
on placebo ³ paroxetine
HCl. (OCD): abdominal pain, agitation, anxiety, back
pain, cough increased, depression, headache, hyperkinesia,
infection, paresthesia, pharyngitis, respiratory disorder,
rhinitis, and sinusitis. (social anxiety disorder):
abdominal pain, depression, headache, infection, respiratory
disorder, and sinusitis. |
| † Percentage
corrected for gender. |
| TABLE 4C Treatment-Emergent
Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Panic Disorder* |
| Body System & Preferred
Term |
Paroxetine HCl (n=469) |
Placebo (n=324) |
| Body as
a Whole |
| Asthenia |
14% |
5% |
| Abdominal
Pain |
4% |
3% |
| Back
Pain |
3% |
2% |
| Chills |
2% |
1% |
| Dermatologic |
| Sweating |
14% |
6% |
| Gastrointestinal |
| Nausea |
23% |
17% |
| Dry
Mouth |
18% |
11% |
| Constipation |
8% |
5% |
| Diarrhea |
12% |
7% |
| Decreased
Appetite |
7% |
3% |
| Flatulence |
¾ |
¾ |
| Increased
Appetite |
2% |
1% |
| Vomiting |
¾ |
¾ |
| * Events
reported by at least 2% of panic disorder paroxetine
HCl-treated patients are included, except the following
events which had an incidence on placebo ³
paroxetine HCl: 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. |
| TABLE 4D Treatment-Emergent
Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Panic Disorder* |
| Body System & Preferred
Term |
Paroxetine HCl (n=489) |
Placebo (n=324) |
| Nervous
System |
| Insomnia |
18% |
10% |
| Somnolence |
19% |
11% |
| Dizziness |
14% |
10% |
| Tremor |
9% |
1% |
| Libido
Decreased |
9% |
1% |
| Agitation |
5% |
4% |
| Anxiety |
5% |
4% |
| Concentration
Impaired |
¾ |
¾ |
| Myoclonus |
3% |
2% |
| Amnesia |
¾ |
¾ |
| Respiratory
System |
| Rhinitis |
3% |
0% |
| Yawn |
¾ |
¾ |
| Urogenital
System |
| Abnormal
Ejaculation† |
21% |
1% |
| Female
Genital Disorder† |
9% |
1% |
| Impotence† |
5% |
0% |
| Urinary
Frequency |
2% |
0% |
| Urinary
Tract Infection |
2% |
1% |
| * Events
reported by at least 2% of panic disorder paroxetine
HCl-treated patients are included, except the following
events which had an incidence on placebo ³
paroxetine HCl: 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. |
| †. Percentage
corrected for gender. |
Dose Dependency of Adverse Events: A comparison
of adverse event rates in a fixed-dose study comparing paroxetine
HCl 10, 20, 30, and 40 mg/day with placebo in the treatment
of depression revealed a clear dose dependency for some
of the more common adverse events associated with paroxetine
HCl use, as shown in TABLE 5.
| TABLE 5 Treatment-Emergent
Adverse Experience Incidence in a Depression Dose-Comparison
Trial* |
| |
Placebo |
Paroxetine HCl |
| Body System/Preferred Term |
|
10 mg |
20 mg |
30 mg |
40 mg |
| |
n=51 |
n=102 |
n=104 |
n=101 |
n=102 |
| Body as
a Whole |
| Asthenia |
0.0% |
2.9% |
10.6% |
13.9% |
12.7% |
| Dermatology |
| Sweating |
2.0% |
1.0% |
6.7% |
8.9% |
11.8% |
| Gastrointestinal |
| Constipation |
5.9% |
4.9% |
7.7% |
9.9% |
12.7% |
| Decreased
Appetite |
2.0% |
2.0% |
5.8% |
4.0% |
4.9% |
| Diarrhea |
7.8% |
9.8% |
19.2% |
7.9% |
14.7% |
| Dry
Mouth |
2.0% |
10.8% |
18.3% |
15.8% |
20.6% |
| Nausea |
13.7% |
14.7% |
26.9% |
34.7% |
36.3% |
| Nervous
System |
| Anxiety |
0.0% |
2.0% |
5.8% |
5.9% |
5.9% |
| Dizziness |
3.9% |
6.9% |
6.7% |
8.9% |
12.7% |
| Nervousness |
0.0% |
5.9% |
5.8% |
4.0% |
2.9% |
| Paresthesia |
0.0% |
2.9% |
1.0% |
5.0% |
5.9% |
| Somnolence |
7.8% |
12.7% |
18.3% |
20.8% |
21.6% |
| Tremor |
0.0% |
0.0% |
7.7% |
7.9% |
14.7% |
| Special
Senses |
| Blurred
Vision |
2.0% |
2.9% |
2.9% |
2.0% |
7.8% |
| Urogenital
System |
| Abnormal
Ejaculation |
0.0% |
5.8% |
6.5% |
10.6% |
13.0% |
| Impotence |
0.0% |
1.9% |
4.3% |
6.4% |
1.9% |
| Male
Genital Disorders |
0.0% |
3.8% |
8.7% |
6.4% |
3.7% |
| * Rule for
including adverse events in table: incidence at least
5% for one of paroxetine groups and ³
twice the placebo incidence for at least one paroxetine
group. |
In a fixed-dose study comparing placebo and paroxetine HCl
20, 40, and 60 mg in the treatment of OCD, there was no
clear relationship between adverse events and the dose of
paroxetine HCl to which patients were assigned. No new adverse
events were observed in the paroxetine HCl 60 mg dose group
compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and paroxetine
HCl 10, 20, and 40 mg in the treatment of panic disorder,
there was no clear relationship between adverse events
and the dose of paroxetine HCl to which patients were
assigned, except for asthenia, dry mouth, anxiety, libido
decreased, tremor, and abnormal ejaculation. In flexible
dose studies, no new adverse events were observed in patients
receiving paroxetine HCl 60 mg compared to any of the
other treatment groups.
In a fixed-dose study comparing placebo and paroxetine
HCl 20, 40, and 60 mg in the treatment of social anxiety
disorder, for most of the adverse events, there was no
clear relationship between adverse events and the dose
of paroxetine HCl to which patients were assigned.
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 party 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
1800 patients, the ranges for the reported incidence of
sexual side effects in males and females with depression,
OCD, panic disorder, and social anxiety disorder are displayed
in TABLE 6.
| TABLE
6 Incidence of Sexual Adverse Events in Controlled
Clinical Trials |
| |
Paroxetine HCl |
Placebo |
| n (males) |
925 |
655 |
| Decreased
libido |
6-14% |
0-5% |
| Ejaculatory
disturbance |
13-28% |
0-1% |
| Impotence |
2-8% |
0-1% |
| n (females) |
932 |
694 |
| Decreased
libido |
1-9% |
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.
Liver Function Tests: In placebo-controlled
clinical trials, patients treated with paroxetine HCl
exhibited abnormal values on liver function tests at no
greater rate than that seen in placebo-treated patients.
In particular, the paroxetine HCl-vs.-placebo comparison
for alkaline phosphatase, SGOT, SGPT and bilirubin revealed
no differences in the percentage of patients with marked
abnormalities.
Other Events Observed During the Premarketing
Evaluation of Paroxetine HCl
During its premarketing assessment in depression, multiple
doses of paroxetine HCl were administered to 6145 patients
in phase 2 and 3 studies. The conditions and duration
of exposure to paroxetine HCl 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
social anxiety disorder, 542, 469, and 522 patients, respectively,
received multiple doses of paroxetine HCl. 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 7678 patients exposed to multiple
doses of paroxetine HCl who experienced an event of the
type cited on at least one occasion while receiving paroxetine
HCl. All reported events are included except those already
listed in TABLE 2A, TABLE 2B, TABLE 3A, and TABLE 3B,
those reported in terms so general as to be uninformative
and those events where a drug cause was remote. It is
important to emphasize that although the events reported
occurred during treatment with paroxetine, they were not
necessarily caused by it.
Events are further categorized by body system and listed
in order of decreasing frequency according to the following
definitions: frequent adverse events are those occurring
on one or more occasions in at least 1/100 patients (only
those not already listed in the tabulated results from
placebo-controlled trials appear in this listing); infrequent
adverse events are those occurring in 1/100 to 1/1000
patients; rare events are those occurring in fewer than
1/1000 patients. Events of major clinical importance are
also described in PRECAUTIONS.
Body as a Whole: Frequent:
Chills, malaise; Infrequent: Allergic reaction, face edema,
neck pain; Rare: Adrenergic syndrome, cellulitis, moniliasis,
neck rigidity, pelvic pain, peritonitis, ulcer.
Cardiovascular System: Frequent:
Hypertension, syncope, tachycardia; Infrequent: Bradycardia,
hematoma, hypotension, migraine; 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, cholelithiasis,
duodenitis, enteritis, esophagitis, fecal impactions,
fecal incontinence, gum hemorrhage, hematemesis, hepatitis,
ileus, intestinal obstruction, jaundice, melena, mouth
ulceration, peptic ulcer, salivary gland enlargement,
stomach ulcer, stomatitis, tongue discoloration, tongue
edema, tooth caries.
Endocrine System: Rare: Diabetes
mellitus, hyperthyroidism, hypothyroidism, thyroiditis.
Hemic and Lymphatic Systems:
Infrequent: Anemia, eosinophilia, leukocytosis, leukopenia,
lymphadenopathy, purpura; Rare: Abnormal erythrocytes,
basophilia, hypochromic anemia, iron deficiency anemia,
lymphedema, abnormal lymphocytes, lymphocytosis, microcytic
anemia, monocytosis, normocytic anemia, thrombocythemia,
thrombocytopenia.
Metabolic and Nutritional: Frequent:
Weight gain, weight loss; Infrequent: Alkaline phosphatase
increased, edema, peripheral edema, SGOT increased, SGPT
increased, thirst; Rare: Bilirubinemia, BUN increased,
creatinine phosphokinase increased, dehydration, gamma
globulins increased, gout, hypercalcemia, hypercholesteremia,
hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia,
hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic
dehydrogenase increased.
Musculoskeletal System: Frequent:
Arthralgia; Infrequent: Arthritis; Rare: Arthrosis, bursitis,
myositis, osteoporosis, generalized spasm, tenosynovitis,
tetany.
Nervous System: Frequent: Amnesia,
CNS stimulation, concentration impaired, depression, emotional
lability, vertigo; Infrequent: Abnormal thinking, alcohol
abuse, ataxia, delirium, depersonalization, dystonia,
dyskinesia, euphoria, hallucinations, hostility, hyperkinesia,
hypertonia, hypesthesia, hypokinesia, incoordination,
lack of emotion, libido increased, manic reaction, neurosis,
paralysis, paranoid reaction, psychosis; Rare: Abnormal
gait, akinesia, antisocial reaction, aphasia, choreoathetosis,
circumoral parethesias, convulsion, 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, reflexes decreased, reflexes increased, stupor,
trismus, withdrawal syndrome.
Respiratory System: Frequent:
Cough increased, rhinitis, sinusitis; Infrequent: Asthma,
bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia,
respiratory flu; Rare: Emphysema, hemoptysis, hiccups,
lung fibrosis, pulmonary edema, sputum increased, voice
alteration.
Skin and Appendages: Frequent:
Pruritus; Infrequent: Acne, alopecia, contact dermatitis,
dry skin, ecchymosis, eczema, herpes simplex, maculopapular
rash, photosensitivity, urticaria; Rare: Angioedema, erythema
nodosum, erythema multiforme, fungal dermatitis, furunculosis
, herpes zoster, hirsutism, seborrhea, skin discoloration,
skin hypertrophy, skin ulcer, vesiculobullous rash.
Special Senses: Infrequent:
Abnormality of accommodation, conjunctivitis, ear pain,
eye pain, mydriasis, otitis media, photophobia, tinnitus;
Rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival
edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage,
glaucoma, hyperacusis, keratoconjunctivitis, night blindness,
otitis externa, parosmia, ptosis, retinal hemorrhage,
taste loss, visual field defect.
Urogenital System: Infrequent:
Abortion, amenorrhea, breast pain, cystitis, dysuria,
hematuria, menorrhagia, nocturia, polyuria, urinary incontinence,
urinary retention, urinary urgency, vaginal moniliasis
vaginitis; Rare: Breast atrophy, breast enlargement, epidiymitis,
female lactation, fibrocystic breast, kidney calculus,
kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis,
oliguria, pyuria, urethritis, uterine spasm, urolith,
vagina hemorrhage.
Controlled-Release Tablets
The information included in Adverse Findings Observed
in Short-Term, Placebo-Controlled Trials with Paroxetine
HCl Controlled-Release Tablets is based on data from three
placebo-controlled clinical trials in depressed patients.
Two studies, which are pooled in TABLE 7A, TABLE 7B, TABLE
8 , enrolled patients in the age range 18 to 65 years.
A third study, presented separately, focused on elderly
patients (ages 60 to 88) (see TABLE 9). Information on
additional adverse events associated with paroxetine HCl
controlled-release tablets and the immediate-release formulation
of paroxetine HCl 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 HCl Controlled-Release Tablets
Adverse Events Associated with Discontinuation
of Treatment
Ten percent (21/212) of paroxetine HCl controlled-release
tablets patients discontinued treatment due to an adverse
event in a pool of two studies of depressed patients. The
most common events (³1%) 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 HCl controlled-release tablets compared to placebo)
included those shown in TABLE 7A.
| TABLE 7A |
| |
Paroxetine HCl 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 depressed, elderly patients,
13% (13/104) of paroxetine HCl controlled-release tablets
patients discontinued due to an adverse event. Events meeting
the above criteria included those shown in TABLE 7B.
| TABLE 7B |
| |
Paroxetine HCl 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% |
Commonly Observed Adverse Events
The most commonly observed adverse events associated
with the use of paroxetine HCl controlled-release tablets
in a pool of two trials (incidence of 5.0% or greater
and incidence for paroxetine HCl controlled-release tablets
at least twice that for placebo, derived from TABLE 8)
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 HCl controlled-release tablets
in a study of elderly patients were: abnormal ejaculation,
constipation, decreased appetite, dry mouth, impotence,
infection, libido decreased, sweating, and tremor.
Incidence in Controlled Clinical Trials
TABLE 8 enumerates adverse events that occurred at an
incidence of 1% or more among paroxetine HCl controlled-release
tablets-treated patients, aged 18-65, who participated
in two short-term (12-week) placebo-controlled trials
in depression in which patients were dosed in a range
of 25 to 62.5 mg/day. TABLE 9 enumerates adverse events
reported at an incidence of 5% or greater among elderly
paroxetine HCl controlled-release tablets-treated patients
(ages 60-88) who participated in a short-term (12-week)
placebo-controlled trial in depression in which patients
were dosed in a range of 12.5 to 50 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 which prevailed in the
clinical trials. Similarly, the cited frequencies cannot
be compared with figures obtained from other clinical investigations
involving different treatments, uses and investigators.
The cited figures, however, do provide the prescribing physician
with some basis for estimating the relative contribution
of drug and nondrug factors to the side effect incidence
rate in the population studied.
| TABLE 8 Treatment
Emergent Adverse Events Occurring in ³1%
of Paroxetine Controlled-Release Tablets Patients
in a Pool of Two Studies *† |
| Body System/Adverse Event |
% Reporting Event |
| |
Paroxetine Controlled-Release
Tablets(N=212) |
Placebo (N=211) |
| Body as
a Whole |
| Headache |
27% |
20% |
| Asthenia |
14% |
9% |
| Infection‡ |
8% |
5% |
| Abdominal
Pain |
7% |
4% |
| Back
Pain |
5% |
3% |
| Trauma§ |
5% |
1% |
| Pain¤ |
3% |
1% |
| Allergic
Reaction¶ |
2% |
1% |
| Cardiovascular
System |
| Tachycardia |
1% |
0% |
| Vasodilatation** |
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†† |
5% |
1% |
| Taste
Perversion |
2% |
0% |
| Urogenital
System |
| Abnormal
Ejaculation§§‡‡ |
26% |
1% |
| Female
Genital Disorder‡‡¤¤ |
10% |
<1% |
| Impotence‡‡ |
5% |
3% |
| Urinary
Tract Infection |
3% |
1% |
| Menstrual
Disorder‡‡ |
2% |
<1% |
| Vaginitis‡‡ |
2% |
0% |
| * Adverse
events for which the paroxetine 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. |
| † <1%
means greater than zero and less than 1%. |
| ‡ Mostly
flu. |
| § A
wide variety of injuries with no obvious pattern. |
| ¤
Pain in a variety of locations with no obvious pattern. |
| ¶ Most
frequently seasonal allergic symptoms. |
| ** Usually
flushing. |
| †† Mostly
blurred vision. |
| ‡‡ Based
on the number of males or females. |
| §§
Mostly anorgasmia or delayed ejaculation. |
| ¤¤
Mostly anorgasmia or delayed orgasm. |
| TABLE 9 Treatment
Emergent Adverse Events Occurring in ³5%
of Paroxetine Controlled-Release Tablets Patients
in a Study of Elderly Patients*† |
| Body System/Adverse Event |
% Reporting Event |
| |
Paroxetine 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
Ejaculationठ|
17% |
3% |
| Impotence‡ |
9% |
3% |
| * Adverse
events for which the paroxetine controlled-release
tablets reporting incidence was less than or equal
to the placebo incidence are not included. These events
are nausea and respiratory disorder. |
| † <1%
means greater than zero and less than 1%. |
| ‡ Based
on the number of males. |
| § Mostly
anorgasmia or delayed ejaculation. |
Dose Dependency of Adverse Events
A comparison of adverse event rates in a fixed-dose study
comparing immediate-release paroxetine with placebo in
the treatment of depression 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 selective serotonin reuptake inhibitors
(SSRI's) 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 party 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 the pool of two placebo-controlled clinical trials
in depressed patients in the age range 18-65, the reported
incidence of decreased libido, abnormal ejaculation (mostly
delayed ejaculation), and impotence in male patients receiving
paroxetine HCl controlled-release tablets (n=78) was 10%,
26%, and 5%, respectively. In female patients receiving
paroxetine HCl controlled-release tablets (n=134), the
reported incidence of decreased libido and either anorgasmia
or delayed orgasm was 4% and 10%, respectively. The reported
incidence of each of these adverse events was £5%
among male and female patients receiving placebo.
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 SSRI's, physicians
should routinely inquire about such possible side effects.
Liver Function Tests
In a pool of two placebo-controlled clinical trials,
patients treated with paroxetine HCl controlled-release
tablets or placebo exhibited abnormal values on liver
function tests at comparable rates. In particular, the
controlled-release paroxetine-vs.-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 depressed patients, three of 104
paroxetine HCl controlled-release tablets patients and
none of 109 placebo patients experienced liver transaminase
elevations of potential clinical concern. Two of the paroxetine
HCl controlled-release tablets patients dropped out of
the study due to abnormal liver function tests; the third
patient experienced normalization of transaminase levels
with continued treatment. The clinical significance of
these findings is unknown.
In placebo-controlled clincial 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.
Other Events Observed During the Clinical Development
of Paroxetine
The following adverse events were reported during the
clinical development of paroxetine HCl 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 depression, multiple doses of paroxetine HCl controlled-release
tablets were administered to 316 inpatients in Phase 3
double-blind, controlled, inpatient 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 316 inpatients exposed to paroxetine HCl controlled-release
tablets who experienced an event of the type cited on
at least one occasion while receiving paroxetine HCl controlled-release
tablets. All reported events are included except those
already listed in TABLE 8 and TABLE 9, those reported
in terms so general as to be uninformative and those events
where a drug cause was remote. It is important to emphasize
that although the events reported occurred during treatment
with paroxetine, they were not necessarily caused by it.
Events are further categorized by body system and listed
in order of decreasing frequency according to the following
definitions: frequent adverse events are those occurring
on one or more occasions in at least 1/100 patients (only
those not already listed in the tabulated results from
placebo-controlled trials appear in this listing); infrequent
adverse events are those occurring in 1/100 to 1/1000
patients.
Adverse events for which frequencies are not provided
occurred during the premarketing assessment of immediate-release
paroxetine in Phase 2 and 3 studies of depression, obsessive
compulsive disorder and panic 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 HCl controlled-release tablets is unknown.
Events are listed alphabetically within the respective
body system. Events of major clinical importance are also
described in PRECAUTIONS.
Body as a Whole: Infrequent:
Cellulitis, chest pain, chills, fever, malaise, neoplasm,
rheumatoid arthritis; also observed were abscess, adrenergic
syndrome, carcinoma, face edema, flu syndrome, moniliasis,
neck pain, neck rigidity, pelvic pain, peritonitis, ulcer.
Cardiovascular System: Frequent:
Hypertension, hypotension; Infrequent: Angina pectoris,
arrhythmia, bradycardia, bundle branch block, palpitation,
postural hypotension, syncope, vascular disorder; also
observed were atrial fibrillation, cerebral ischemia,
cerebrovascular accident, conduction abnormalities, congestive
heart failure, electrocardiogram abnormal, heart block,
hematoma, low cardiac output, migraine, myocardial infarct,
myocardial ischemia, pallor, peripheral vascular disorder,
phlebitis, pulmonary embolus, supraventricular extrasystoles,
thrombophlebitis, thrombosis, varicose vein, vascular
headache, ventricular extrasystoles.
Digestive System: Frequent:
Liver function tests abnormal, tooth disorder; Infrequent:
Bruxism, dysphagia, eructation, gastroenteritis, gastrointestinal
disorder, gingivitis, glossitis, hepatosplenomegaly, intestional
obstruction, melena, pancreatitis, peptic ulcer, rectal
disorder, rectal hemorrhage, stomach ulcer, tooth caries,
ulcerative stomatitis; also observed were aphthous stomatitis,
bloody diarrhea, bulimia, cholelithiasis, colitis, duodenitis,
enteritis, esophagitis, fecal impactions, fecal incontinence,
gastritis, gum hemorrhage, hematemesis, hepatitis, ileus,
increased salivation, jaundice, mouth ulceration, oropharynx
disorder, salivary gland enlargement, stomatitis, tongue
discoloration, tongue edema, tooth malformation.
Endocrine System: Infrequent:
Hyperthyroidism, ovary disorder, testes disorder; also
observed were diabetes mellitus, hypothyroidism, thyroiditis.
Hemic and Lymphatic System:
Infrequent: Anemia, chronic lymphocytic leukemia, eosinophilia,
leukocytosis, leukopenia; also observed were abnormal
erythrocytes, abnormal lymphocytes, basophilia, hypochromic
anemia, iron deficiency anemia, lymphadenopathy, lymphedema,
lymphocytosis, microcytic anemia, monocytosis, normocytic
anemia, thrombocythemia.
Metabolic and Nutritional Disorders: Infrequent:
Generalized edema, hyperglycemia, hyperkalemia, hypokalemia,
peripheral edema, thirst; also observed were alkaline
phosphatase increased, bilirubinemia, BUN increased, creatinine
phosphokinase increased, dehydration, edema, gamma globulins
increased, gout, hypercalcemia, hypercholesteremia, hyperphosphatemia,
hypocalcemia, hypoglycemia, hyponatremia, ketosis, lactic
dehydrogenase increased, SGOT increased, SGPT increased,
weight loss.
Musculoskeletal System: Infrequent:
Arthrosis, bursitis, myasthenia; also observed were arthritis,
generalized spasm, myopathy, myositis, osteoporosis, tenosynovitis,
tetany.
Nervous System: Frequent: Depression,
lack of emotion, myoclonus; Infrequent: Amnesia, concentration
impaired, diplopia, drug dependence, dystonia, emotional
lability, hallucinations, hypokinesia, incoordination,
neuralgia, neuropathy, paralysis, thinking abnormal, vertigo;
also observed were abnormal electroencephalogram, abnormal
gait, abnormal thinking, akinesia, alcohol abuse, antisocial
reaction, aphasia, ataxia, choreoathetosis, circumoral
paresthesia, CNS stimulation, convulsion, delirium, delusions,
drugged feeling, dysarthria, dyskinesia, euphoria, extrapyramidal
syndrome, fasciculations, grand mal convulsion, hostility,
hyperalgesia, hypesthesia, hysteria, libido increased,
manic reaction, manic-depressive reaction, meningitis,
myelitis, neurosis, nystagmus, paranoid reaction, peripheral
neuritis, psychosis, psychotic depression, reflexes decreased,
reflexes increased, stupor, trismus, vertigo, withdrawal
syndrome.
Respiratory System: Infrequent:
Asthma, dyspnea, epistaxis, larynx disorder, pneumonia,
stridor; also observed were emphysema, hemoptysis, hiccups,
hyperventilation, lung fibrosis, pulmonary edema, respiratory
flu, sputum increased, voice alteration.
Skin and Appendages: Infrequent:
Acne, alopecia, dry skin, exfoliative dermatitis, furunculosis,
herpes simplex, herpes zoster, pruritus, seborrhea, urticaria;
also observed were angioedema, contact dermatitis, ecchymosis,
eczema, erythema multiforme, erythema nodosum, fungal
dermatitis, hirsutism, maculopapular rash, skin discoloration,
skin hypertrophy, skin melanoma, skin ulcer, vesiculobullous
rash.
Special Senses: Frequent: Conjunctivitis;
Infrequent: Abnormality of accommodation, ear disorder,
ear pain, eye appendage disorder, eye disorder, eye hemorrhage,
keratoconjunctivitis, mydriasis, otitis media, tinnitus;
also observed were amblyopia, anisocoria, blepharitis,
blurred vision, cataract, conjunctival edema, conjunctivitis,
corneal ulcer, deafness, exophthalmos, eye pain, glaucoma,
hyperacusis, night blindness, otitis externa, parosmia,
photophobia, ptosis, retinal hemorrhage, taste loss, visual
field defect.
Urogenital System: Infrequent:
Albuminuria, hematuria, kidney calculus, kidney function
abnormal, menorrhagia,* prostate disorder,* urinary incontinence,
urinary retention, urine abnormality; also observed were
abortion, amenorrhea, breast atrophy, breast carcinoma,
breast enlargement, breast neoplasm, breast pain, cystitis,
dysuria, ejaculatory disturbance, epididymitis, female
lactation, fibrocystic breast, kidney pain, leukorrhea,
male genital disorder, mastitis, metrorrhagia, nephritis,
nocturia, oliguria, other male genital disorders, polyuria,
prostatic carcinoma, pyuria, urethritis, urinary urgency,
urination disorder, urination impaired, urolith, uterine
spasm, vaginal hemorrhage, vaginal moniliasis.
*Based on the number of men and women as appropriate.
Immediate-Release Tablets, Oral Suspension, and
Controlled Release Tablets
Weight and Vital Sign Changes:
Significant weight loss may be an undesirable result of
treatment with paroxetine HCl for some patients but, on
average, patients in controlled trials with paroxetine
HCl had minimal weight loss (about 1 pound) [vs. smaller
changes on placebo and active control for the immediate-release
formulations]. No significant changes in vital signs (systolic
and diastolic blood pressure, pulse and temperature) were
observed in patients treated with paroxetine HCl 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.
Postmarketing Reports: Voluntary
reports of adverse events in patients taking immediate-release
paroxetine HCl that have been received since market introduction
and not listed above that may have no causal relationship
with the drug include acute pancreatitis, elevated liver
function tests (the most severe cases were deaths due
to liver necrosis, and grossly elevated transaminases
associated with severe liver dysfunction), Guillain-Barré
syndrome, toxic epidermal necrolysis, priapism, thrombocytopenia,
syndrome of inappropriate ADH secretion, symptoms suggestive
of prolactinemia and galactorrhea, neuroleptic malignant
syndrome-like events; extrapyramidal symptoms which have
included akathisia, bradykinesia, cogwheel rigidity, dystonia,
hypertonia, oculogyric crisis which has been associated
with concomitant use of pimozide, tremor and trismus;
and serotonin syndrome, associated in some cases with
concomitant use of serotonergic drugs and with drugs which
may have impaired paroxetine HCl metabolism (symptoms
have included agitation, confusion, diaphoresis, hallucinations,
hyperreflexia, myoclonus, shivering, tachycardia and tremor).
There have been spontaneous reports that abrupt discontinuation
may lead to symptoms such as dizziness, sensory disturbances,
agitation or anxiety, nausea and sweating; these events
are generally self-limiting. There has been a case report
of an elevated phenytoin level after 4 weeks of immediate-release
paroxetine HCl and phenytoin co-administration. There
has been a case report of severe hypotension when immediate-release
paroxetine HCl was added to chronic metoprolol treatment.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Paroxetine
HCl is not a controlled substance.
Physical and Psychologic Dependence:
Paroxetine HCl 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
paroxetine HCl misuse or abuse (e.g., development of tolerance,
incrementations of dose, drug-seeking behavior).
DRUG INTERACTIONS
Tryptophan: As with other serotonin
reuptake inhibitors, an interaction between paroxetine
and tryptophan may occur when they are co-administered.
Adverse experiences, consisting primarily of headache,
nausea, sweating, and dizziness, have been reported when
tryptophan was administered to patients taking immediate-release
paroxetine HCl. Consequently, concomitant use of paroxetine
HCl with tryptophan is not recommended.
Monoamine Oxidase Inhibitors:
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 paroxetine HCl and warfarin
should be undertaken with caution.
Sumatriptan: There have been
rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of
a selective serotonin reuptake inhibitor (SSRI) and sumatriptan.
If concomitant treatment with sumatriptan and an SSRI
(e.g., fluoxetine, fluvoxamine, paroxetine, sertraline)
is clinically warranted, appropriate observation of the
patient is advised.
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 P450 (oxidative)
enzymes. In a study where immediate-release paroxetine
HCl (30 mg qd) was dosed orally for 4 weeks, steady-state
plasma concentrations of paroxetine were increased by
approximately 50% during co-administration with oral cimetidine
(300 mg tid) for the final week. Therefore, when these
drugs are administered concurrently, dosage adjustment
of paroxetine HCl after the 20 mg (for immediate-release
tablets and oral suspension) and 25 mg (for controlled-release
tablets) 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 HCl was
administered at phenobarbital steady state (100 mg qd
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 HCl exhibits nonlinear pharmacokinetics, the
results of this study may not address the case where the
two drugs are both being chronically dosed. No initial
paroxetine HCl dosage adjustment is considered necessary
when co-administered with phenobarbital; any subsequent
adjustment should be guided by clinical effect. Phenytoin:
When a single oral 30 mg dose of immediate-release paroxetine
HCl was administered at phenytoin steady state (300 mg
qd for 14 days), paroxetine AUC and T½ were reduced
(by an average of 50% and 35%, respectively) compared
to immediate-release paroxetine HCl administered alone.
In a separate study, when a single oral 300 mg dose of
phenytoin was administered at paroxetine steady state
(30 mg qd 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 two drugs
are both being chronically dosed. No initial dosage adjustments
are considered necessary when these drugs are co-administered;
any subsequent adjustments should be guided by clinical
effect (see ADVERSE REACTIONS, Postmarketing Reports).
Drug Metabolized by Cytochrome P450IID6:
Many drugs, including most antidepressants (paroxetine,
other SSRIs and many tricyclics), are metabolized by the
cytochrome P450 isozyme P450IID6. Like other agents that
are metabolized by P450IID6, paroxetine may significantly
inhibit the activity of this isozyme. In most patients
(>90%), this P450IID6 isozyme is saturated early during
paroxetine HCl dosing. In one study, daily dosing of immediate-release
paroxetine HCl (20 mg qd) under steady-state conditions
increased single-dose desipramine (100 mg ) Cmax, AUC,
and T½ by an average of approximately two-, five-,
and three-fold, respectively. Concomitant use of paroxetine
HCl with other drugs metabolized by cytochrome P450IID6
has not been formally studied but may require lower doses
than usually prescribed for either paroxetine HCl or the
other drug.
Therefore, co-administration of paroxetine HCl with other
drugs that are metabolized by this isozyme, including
certain antidepressants (e.g., nortriptyline, amitriptyline,
imipramine, desipramine, and fluoxetine), phenothiazines
(e.g., thioridazine) and Type 1C antiarrhythmics (e.g.,
propafenone, flecainide, and encainide), or that inhibit
this enzyme (e.g., quinidine), should be approached with
caution.
At steady state, when the P450IID6 pathway is essentially
saturated, paroxetine clearance is governed by alternative
P450 isozymes which, unlike P450IID6, show no evidence
of saturation (see Tricyclic Antidepressants - below).
Drugs Metabolized by Cytochrome P450IIIA4:
An in vivo interaction study involving the
co-administration under steady-state conditions of paroxetine
and terfenadine, a substrate for cytochrome P450IIIA4,
revealed no effect of paroxetine on terfenadine pharmacokinetics.
In addition, in vitro studies have shown ketoconazole,
a potent inhibitor of P450IIIA4 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 cyclosporin. Based on the assumption that the relationship
between paroxetine's in vitro Ki and its lack of effect
on terfenadine's in vivo clearance predicts its effect
on other IIIA4 substrates, paroxetine's extent of inhibition
of IIIA4 activity is not likely to be of clinical significance.
Tricyclic Antidepressants (TCA):
Caution is indicated in the co-administration of tricyclic
antidepressants (TCAs) with paroxetine HCl, 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 co-administered with paroxetine
HCl (see Drugs Metabolized by Cytochrome P450IID6 - above).
Drugs Highly Bound to Plasma Protein: Because
paroxetine is highly bound to plasma protein, administration
of paroxetine HCl 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.
Alcohol: Although paroxetine
HCl does not increase the impairment of mental and motor
skills caused by alcohol, patients should be advised to
avoid alcohol while taking paroxetine HCl.
Lithium: A multiple-dose study
with immediate-release paroxetine HCl has shown that there
is no pharmacokinetic interaction between paroxetine HCl
and lithium carbonate. However, since there is little
clinical experience, the concurrent administration of
paroxetine HCl and lithium should be undertaken with caution.
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
paroxetine 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 HCl (30 mg qd) increased
steady-state AUC0-24, Cmax and Cmin values of procyclidine
(5 mg oral qd) 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 bid) was dosed orally for 18 days,
the established steady-state plasma concentrations of
propranolol were unaltered during co-administration with
immediate-release paroxetine HCl (30 mg qd) for the final
10 days. The effects of propranolol on paroxetine have
not been evaluated (see
SIDE EFFECTS
, Postmarketing Reports).
Theophylline: Reports of elevated
theophylline levels associated with immediate-release
paroxetine HCl 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.
Electroconvulsive Therapy (ECT):
There are no clinical studies of the combined use of ECT
and paroxetine HCl.
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