Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults in short-term studies of major depressive disorder
(MDD) and other psychiatric disorders. Anyone considering the use of PAXIL CR or
any other antidepressant in a child, adolescent, or young adult must balance
this risk with the clinical need. Short-term studies did not show an increase in
the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction in risk with antidepressants compared to
placebo in adults aged 65 and older. Depression and certain other psychiatric
disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior. Families and caregivers should be
advised of the need for close observation and communication with the prescriber.
PAXIL CR is not approved for use in pediatric patients. (See WARNINGS: Clinical
Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and
PRECAUTIONS: Pediatric Use.)
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults in short-term studies of major depressive disorder
(MDD) and other psychiatric disorders. Anyone considering the use of PAXIL CR or
any other antidepressant in a child, adolescent, or young adult must balance
this risk with the clinical need. Short-term studies did not show an increase in
the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction in risk with antidepressants compared to
placebo in adults aged 65 and older. Depression and certain other psychiatric
disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior. Families and caregivers should be
advised of the need for close observation and communication with the prescriber.
PAXIL CR is not approved for use in pediatric patients. (See WARNINGS: Clinical
Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and
PRECAUTIONS: Pediatric Use.)
Description Section
DESCRIPTION PAXIL CR (paroxetine hydrochloride) is an orally administered
psychotropic drug with a chemical structure unrelated to other selective
serotonin reuptake inhibitors or to tricyclic, tetracyclic, or other available
antidepressant or antipanic agents. It is the hydrochloride salt of a
phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine
hydrochloride hemihydrate and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is
374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride
is:
Clinical Pharmacology Section
CLINICAL PHARMACOLOGYPharmacodynamics The efficacy of paroxetine in the treatment of major depressive
disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric
disorder (PMDD) is presumed to be linked to potentiation of serotonergic
activity in the central nervous system resulting from inhibition of neuronal
reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically
relevant doses in humans have demonstrated that paroxetine blocks the uptake of
serotonin into human platelets. In vitro studies in animals also suggest that
paroxetine is a potent and highly selective inhibitor of neuronal serotonin
reuptake and has only very weak effects on norepinephrine and dopamine neuronal
reuptake. In vitro radioligand binding studies indicate that paroxetine has
little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-,
5-HT1-, 5-HT2-, and histamine
(H1)-receptors; antagonism of muscarinic, histaminergic,
and alpha1-adrenergic receptors has been associated with
various anticholinergic, sedative, and cardiovascular effects for other
psychotropic drugs.
Because the relative potencies of paroxetine’s major metabolites are at most
1/50 of the parent compound, they are essentially inactive. Pharmacokinetics Paroxetine hydrochloride is completely absorbed after oral dosing
of a solution of the hydrochloride salt. The elimination half-life is
approximately 15 to 20 hours after a single dose of PAXIL CR. Paroxetine is
extensively metabolized and the metabolites are considered to be inactive.
Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine
metabolism is mediated in part by CYP2D6, and the metabolites are primarily
excreted in the urine and to some extent in the feces. Pharmacokinetic behavior
of paroxetine has not been evaluated in subjects who are deficient in CYP2D6
(poor metabolizers). Absorption and
Distribution Tablets of PAXIL CR contain a degradable polymeric matrix
(GEOMATRIX™) designed to control the dissolution rate of paroxetine over a
period of approximately 4 to 5 hours. In addition to controlling the rate of
drug release in vivo, an enteric coat delays the start of drug release until
tablets of PAXIL CR have left the stomach.
Paroxetine hydrochloride is completely absorbed after oral dosing of a
solution of the hydrochloride salt. In a study in which normal male and female
subjects (n = 23) received single oral doses of PAXIL CR at 4 dosage strengths
(12.5 mg, 25 mg, 37.5 mg, and 50 mg), paroxetine Cmax and
AUC0-inf increased disproportionately with dose (as seen
also with immediate-release formulations). Mean Cmax and
AUC0-inf values at these doses were 2.0, 5.5, 9.0, and
12.5 ng/mL, and 121, 261, 338, and 540 ng•hr./mL, respectively. Tmax was observed typically between 6 and 10 hours post-dose,
reflecting a reduction in absorption rate compared with immediate-release
formulations. The bioavailability of 25 mg PAXIL CR is not affected by food.
Paroxetine distributes throughout the body, including the CNS, with only 1%
remaining in the plasma.
Approximately 95% and 93% of paroxetine is bound to plasma protein at
100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine
concentrations would normally be less than 400 ng/mL. Paroxetine does not alter
the in vitro protein binding of phenytoin or warfarin. Metabolism and
Excretion The mean elimination half-life of paroxetine was 15 to 20 hours
throughout a range of single doses of PAXIL CR (12.5 mg, 25 mg, 37.5 mg, and
50 mg). During repeated administration of PAXIL CR (25 mg once daily), steady
state was reached within 2 weeks (i.e., comparable to immediate-release
formulations). In a repeat-dose study in which normal male and female subjects
(n = 23) received PAXIL CR (25 mg daily), mean steady state Cmax, Cmin, and AUC0-24 values were 30 ng/mL, 20 ng/mL, and 550 ng•hr./mL,
respectively.
Based on studies using immediate-release formulations, steady-state drug
exposure based on AUC0-24 was several-fold greater than
would have been predicted from single-dose data. The excess accumulation is a
consequence of the fact that 1 of the enzymes that metabolizes paroxetine is
readily saturable.
In steady-state dose proportionality studies involving elderly and nonelderly
patients, at doses of the immediate-release formulation of 20 mg to 40 mg daily
for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity
was observed in both populations, again reflecting a saturable metabolic
pathway. In comparison to Cmin values after 20 mg daily,
values after 40 mg daily were only about 2 to 3 times greater than doubled.
Paroxetine is extensively metabolized after oral administration. The
principal metabolites are polar and conjugated products of oxidation and
methylation, which are readily cleared. Conjugates with glucuronic acid and
sulfate predominate, and major metabolites have been isolated and identified.
Data indicate that the metabolites have no more than 1/50 the potency of the
parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses
appears to account for the nonlinearity of paroxetine kinetics with increasing
dose and increasing duration of treatment. The role of this enzyme in paroxetine
metabolism also suggests potential drug-drug interactions (see PRECAUTIONS).
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in
the urine with 2% as the parent compound and 62% as metabolites over a 10-day
post-dosing period. About 36% was excreted in the feces (probably via the bile),
mostly as metabolites and less than 1% as the parent compound over the 10-day
post-dosing period. Other Clinical Pharmacology InformationSpecific
PopulationsRenal and Liver
Disease Increased plasma concentrations of paroxetine occur in subjects
with renal and hepatic impairment. The mean plasma concentrations in patients
with creatinine clearance below 30 mL/min. were approximately 4 times greater
than seen in normal volunteers. Patients with creatinine clearance of 30 to
60 mL/min. and patients with hepatic functional impairment had about a 2-fold
increase in plasma concentrations (AUC, Cmax).
The initial dosage should therefore be reduced in patients with severe renal
or hepatic impairment, and upward titration, if necessary, should be at
increased intervals (see DOSAGE AND ADMINISTRATION). Elderly
Patients In a multiple-dose study in the elderly at daily doses of 20, 30,
and 40 mg of the immediate-release formulation, Cmin
concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. Therefore the
initial dosage in the elderly should be reduced (see DOSAGE AND
ADMINISTRATION). Drug-Drug
Interactions In vitro drug interaction studies reveal that paroxetine inhibits
CYP2D6. Clinical drug interaction studies have been performed with substrates of
CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized
by CYP2D6 including desipramine, risperidone, and atomoxetine (see
PRECAUTIONS—Drug Interactions). Clinical TrialsMajor Depressive Disorder The efficacy of PAXIL CR controlled-release tablets as a
treatment for major depressive disorder has been established in two 12-week,
flexible-dose, placebo-controlled studies of patients with DSM-IV Major
Depressive Disorder. One study included patients in the age range 18 to
65 years, and a second study included elderly patients, ranging in age from 60
to 88. In both studies, PAXIL CR was shown to be significantly more effective
than placebo in treating major depressive disorder as measured by the following:
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood li, and
the Clinical Global Impression (CGI)–Severity of Illness score.
A study of outpatients with major depressive disorder who had responded to
immediate-release paroxetine tablets (HDRS total score less than 8) during an initial
8-week open-treatment phase and were then randomized to continuation on
immediate-release paroxetine tablets or placebo for 1 year demonstrated a
significantly lower relapse rate for patients taking immediate-release
paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness was
similar for male and female patients. Panic Disorder The effectiveness of PAXIL CR in the treatment of panic disorder
was evaluated in three 10-week, multicenter, flexible-dose studies (Studies 1,
2, and 3) comparing paroxetine controlled-release (12.5 to 75 mg daily) to
placebo in adult outpatients who had panic disorder (DSM-IV), with or without
agoraphobia. These trials were assessed on the basis of their outcomes on 3
variables: (1) the proportions of patients free of full panic attacks at
endpoint; (2) change from baseline to endpoint in the median number of full
panic attacks; and (3) change from baseline to endpoint in the median Clinical
Global Impression Severity score. For Studies 1 and 2, PAXIL CR was consistently
superior to placebo on 2 of these 3 variables. Study 3 failed to consistently
demonstrate a significant difference between PAXIL CR and placebo on any of
these variables.
For all 3 studies, the mean dose of PAXIL CR for completers at endpoint was
approximately 50 mg/day. Subgroup analyses did not indicate that there were any
differences in treatment outcomes as a function of age or gender.
Long-term maintenance effects of the immediate-release formulation of
paroxetine in panic disorder were demonstrated in an extension study. Patients
who were responders during a 10-week double-blind phase with immediate-release
paroxetine and during a 3-month double-blind extension phase were randomized to
either immediate-release paroxetine or placebo in a 3-month double-blind relapse
prevention phase. Patients randomized to paroxetine were significantly less
likely to relapse than comparably treated patients who were randomized to
placebo. Social Anxiety Disorder The efficacy of PAXIL CR as a treatment for social anxiety
disorder has been established, in part, on the basis of extrapolation from the
established effectiveness of the immediate-release formulation of paroxetine. In
addition, the effectiveness of PAXIL CR in the treatment of social anxiety
disorder was demonstrated in a 12-week, multicenter, double-blind,
flexible-dose, placebo-controlled study of adult outpatients with a primary
diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness
of PAXIL CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the
basis of (1) change from baseline in the Liebowitz Social Anxiety Scale (LSAS)
total score and (2) the proportion of responders who scored 1 or 2 (very much
improved or much improved) on the Clinical Global Impression (CGI) Global
Improvement score.
PAXIL CR demonstrated statistically significant superiority over placebo on
both the LSAS total score and the CGI Improvement responder criterion. For
patients who completed the trial, 64% of patients treated with PAXIL CR compared
to 34.7% of patients treated with placebo were CGI Improvement responders.
Subgroup analyses did not indicate that there were any differences in
treatment outcomes as a function of gender. Subgroup analyses of studies
utilizing the immediate-release formulation of paroxetine generally did not
indicate differences in treatment outcomes as a function of age, race, or
gender. Premenstrual Dysphoric Disorder The effectiveness of PAXIL CR for the treatment of PMDD utilizing
a continuous dosing regimen has been established in 2 placebo-controlled trials.
Patients in these trials met DSM-IV criteria for PMDD. In a pool of 1,030
patients, treated with daily doses of PAXIL CR 12.5 or 25 mg/day, or placebo the
mean duration of the PMDD symptoms was approximately 11 ± 7 years. Patients on
systemic hormonal contraceptives were excluded from these trials. Therefore, the
efficacy of PAXIL CR in combination with systemic (including oral) hormonal
contraceptives for the continuous daily treatment of PMDD is unknown. In both
positive studies, patients (N = 672) were treated with 12.5 mg/day or 25 mg/day
of PAXIL CR or placebo continuously throughout the menstrual cycle for a period
of 3 menstrual cycles. The VAS-Total score is a patient-rated instrument that
mirrors the diagnostic criteria of PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms.
12.5 mg/day and 25 mg/day of PAXIL CR were significantly more effective than
placebo as measured by change from baseline to the endpoint on the luteal phase
VAS-Total score.
In a third study employing intermittent dosing, patients (N = 366) were
treated for the 2 weeks prior to the onset of menses (luteal phase dosing, also
known as intermittent dosing) with 12.5 mg/day or 25 mg/day of PAXIL CR or
placebo for a period of 3 months. 12.5 mg/day and 25 mg/day of PAXIL CR, as
luteal phase dosing, was significantly more effective than placebo as measured
by change from baseline luteal phase VAS total score.
There is insufficient information to determine the effect of race or age on
outcome in these studies.
Indications & Usage Section
INDICATIONS AND USAGEMajor Depressive Disorder PAXIL CR is indicated for the treatment of major depressive
disorder.
The efficacy of PAXIL CR in the treatment of a major depressive episode was
established in two 12-week controlled trials of outpatients whose diagnoses
corresponded to the DSM-IV category of major depressive disorder (see CLINICAL
PHARMACOLOGY—Clinical Trials).
A major depressive episode (DSM-IV) implies a prominent and relatively
persistent (nearly every day for at least 2 weeks) depressed mood or loss of
interest or pleasure in nearly all activities, representing a change from
previous functioning, and includes the presence of at least 5 of the following 9
symptoms during the same 2-week period: Depressed mood, markedly diminished
interest or pleasure in usual activities, significant change in weight and/or
appetite, insomnia or hypersomnia, psychomotor agitation or retardation,
increased fatigue, feelings of guilt or worthlessness, slowed thinking or
impaired concentration, a suicide attempt, or suicidal ideation.
The antidepressant action of paroxetine in hospitalized depressed patients
has not been adequately studied.
PAXIL CR has not been systematically evaluated beyond 12 weeks in controlled
clinical trials; however, the effectiveness of immediate-release paroxetine
hydrochloride in maintaining a response in major depressive disorder for up to
1 year has been demonstrated in a placebo-controlled trial (see CLINICAL
PHARMACOLOGY—Clinical Trials). The physician who elects to use PAXIL CR for
extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient. Panic Disorder PAXIL CR is indicated for the treatment of panic disorder, with
or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by
the occurrence of unexpected panic attacks and associated concern about having
additional attacks, worry about the implications or consequences of the attacks,
and/or a significant change in behavior related to the attacks.
The efficacy of PAXIL CR controlled-release tablets was established in two
10-week trials in panic disorder patients whose diagnoses corresponded to the
DSM-IV category of panic disorder (see CLINICAL PHARMACOLOGY—Clinical
Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic
attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or
more) of the following symptoms develop abruptly and reach a peak within
10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2)
sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9)
derealization (feelings of unreality) or depersonalization (being detached from
oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias
(numbness or tingling sensations); (13) chills or hot flushes.
Long-term maintenance of efficacy with the immediate-release formulation of
paroxetine was demonstrated in a 3-month relapse prevention trial. In this
trial, patients with panic disorder assigned to immediate-release paroxetine
demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL
PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who prescribes PAXIL
CR for extended periods should periodically re-evaluate the long-term usefulness
of the drug for the individual patient. Social Anxiety Disorder PAXIL CR is indicated for the treatment of social anxiety
disorder, also known as social phobia, as defined in DSM-IV (300.23). Social
anxiety disorder is characterized by a marked and persistent fear of 1 or more
social or performance situations in which the person is exposed to unfamiliar
people or to possible scrutiny by others. Exposure to the feared situation
almost invariably provokes anxiety, which may approach the intensity of a panic
attack. The feared situations are avoided or endured with intense anxiety or
distress. The avoidance, anxious anticipation, or distress in the feared
situation(s) interferes significantly with the person's normal routine,
occupational or academic functioning, or social activities or relationships, or
there is marked distress about having the phobias. Lesser degrees of performance
anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of PAXIL CR as a treatment for social anxiety disorder has been
established, in part, on the basis of extrapolation from the established
effectiveness of the immediate-release formulation of paroxetine. In addition,
the efficacy of PAXIL CR was established in a 12-week trial, in adult
outpatients with social anxiety disorder (DSM-IV). PAXIL CR has not been studied
in children or adolescents with social phobia (see CLINICAL
PHARMACOLOGY—Clinical Trials).
The effectiveness of PAXIL CR in long-term treatment of social anxiety
disorder, i.e., for more than 12 weeks, has not been systematically evaluated in
adequate and well-controlled trials. Therefore, the physician who elects to
prescribe PAXIL CR for extended periods should periodically re-evaluate the
long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION). Premenstrual Dysphoric Disorder PAXIL CR is indicated for the treatment of PMDD.
The efficacy of PAXIL CR in the treatment of PMDD has been established in 3
placebo-controlled trials (see CLINICAL PHARMACOLOGY—Clinical Trials).
The essential features of PMDD, according to DSM-IV, include markedly
depressed mood, anxiety or tension, affective lability, and persistent anger or
irritability. Other features include decreased interest in usual activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and
feeling out of control. Physical symptoms associated with PMDD include breast
tenderness, headache, joint and muscle pain, bloating, and weight gain. These
symptoms occur regularly during the luteal phase and remit within a few days
following the onset of menses; the disturbance markedly interferes with work or
school or with usual social activities and relationships with others. In making
the diagnosis, care should be taken to rule out other cyclical mood disorders
that may be exacerbated by treatment with an antidepressant.
The effectiveness of PAXIL CR in long-term use, that is, for more than 3
menstrual cycles, has not been systematically evaluated in controlled trials.
Therefore, the physician who elects to use PAXIL CR for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual
patient.
Contraindications Section
CONTRAINDICATIONS Concomitant use in patients taking either monoamine oxidase
inhibitors (MAOIs), including linezolid, an antibiotic which is a reversible
non-selective MAOI, or thioridazine is contraindicated (see WARNINGS and
PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
PAXIL CR is contraindicated in patients with a hypersensitivity to paroxetine
or to any of the inactive ingredients in PAXIL CR.
Warnings Section
WARNINGSClinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and
pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior,
whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of
depression and certain other psychiatric disorders, and these disorders
themselves are the strongest predictors of suicide. There has been a
long-standing concern, however, that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients
during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that
these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults (ages 18-24) with major depressive
disorder (MDD) and other psychiatric disorders. Short-term studies did not show
an increase in the risk of suicidality with antidepressants compared to placebo
in adults beyond age 24; there was a reduction with antidepressants compared to
placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents
with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders
included a total of 24 short-term trials of 9 antidepressant drugs in over
4,400 patients. The pooled analyses of placebo-controlled trials in adults with
MDD or other psychiatric disorders included a total of 295 short-term trials
(median duration of 2 months) of 11 antidepressant drugs in over 77,000
patients. There was considerable variation in risk of suicidality among drugs,
but a tendency toward an increase in the younger patients for almost all drugs
studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences
(drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of
cases of suicidality per 1,000 patients treated) are provided in Table 1.
Table 1
Age
Range
Drug-Placebo
Difference in Number of Cases of Suicidality per 1,000 Patients
Treated
Increases Compared
to Placebo
less than 18
14 additional cases
18-24
5 additional cases
Decreases Compared
to Placebo
25-64
1 fewer case
≥65
6 fewer
cases
No suicides occurred in any of the pediatric trials. There were suicides in
the adult trials, but the number was not sufficient to reach any conclusion
about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e.,
beyond several months. However, there is substantial evidence from
placebo-controlled maintenance trials in adults with depression that the use of
antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any
indication should be monitored appropriately and observed closely for clinical
worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, and mania, have been reported in adult and pediatric
patients being treated with antidepressants for major depressive disorder as
well as for other indications, both psychiatric and nonpsychiatric. Although a
causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established,
there is concern that such symptoms may represent precursors to emerging
suicidality.
Consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients whose depression is
persistently worse, or who are experiencing emergent suicidality or symptoms
that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s
presenting symptoms.
If the decision has been made to discontinue treatment, medication should be
tapered, as rapidly as is feasible, but with recognition that abrupt
discontinuation can be associated with certain symptoms (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION—Discontinuation of Treatment With PAXIL CR, for a
description of the risks of discontinuation of PAXIL CR).
Families and caregivers of patients being treated with
antidepressants for major depressive disorder or other indications, both
psychiatric and nonpsychiatric, should be alerted about the need to monitor
patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of
suicidality, and to report such symptoms immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for PAXIL CR should be written for the smallest quantity of
tablets consistent with good patient management, in order to reduce the risk of
overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of
bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase
the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened
to determine if they are at risk for bipolar disorder; such screening should
include a detailed psychiatric history, including a family history of suicide,
bipolar disorder, and depression. It should be noted that PAXIL CR is not
approved for use in treating bipolar depression. Potential for Interaction With Monoamine Oxidase
Inhibitors In patients receiving another serotonin reuptake
inhibitor drug in combination with an MAOI, there have been reports of serious,
sometimes fatal, reactions including hyperthermia, rigidity, myoclonus,
autonomic instability with possible rapid fluctuations of vital signs, and
mental status changes that include extreme agitation progressing to delirium and
coma. These reactions have also been reported in patients who have recently
discontinued that drug and have been started on an MAOI. Some cases presented
with features resembling neuroleptic malignant syndrome. While there are no
human data showing such an interaction with paroxetine hydrochloride, limited
animal data on the effects of combined use of paroxetine and MAOIs suggest that
these drugs may act synergistically to elevate blood pressure and evoke
behavioral excitation. Therefore, it is recommended that PAXIL CR not be used in
combination with an MAOI (including linezolid, an antibiotic which is a
reversible non-selective MAOI), or within 14 days of discontinuing treatment
with an MAOI (see CONTRAINDICATIONS). At least 2 weeks should be allowed after
stopping PAXIL CR before starting an MAOI. Serotonin Syndrome or Neuroleptic Malignant Syndrome
(NMS)-like Reactions The development of a potentially
life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like
reactions have been reported with SNRIs and SSRIs alone, including treatment
with PAXIL CR, but particularly with concomitant use of serotonergic drugs
(including triptans) with drugs which impair metabolism of serotonin (including
MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome
symptoms may include mental status changes (e.g., agitation, hallucinations,
coma), autonomic instability (e.g., tachycardia, labile blood pressure,
hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination)
and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin
syndrome, in its most severe form can resemble neuroleptic malignant syndrome,
which includes hyperthermia, muscle rigidity, autonomic instability with
possible rapid fluctuation of vital signs, and mental status changes. Patients
should be monitored for the emergence of serotonin syndrome or NMS-like signs
and symptoms.
The concomitant use of PAXIL CR with MAOIs intended to treat
depression is contraindicated.
If concomitant treatment of PAXIL CR with a
5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful
observation of the patient is advised, particularly during treatment initiation
and dose increases.
The concomitant use of PAXIL CR with serotonin precursors
(such as tryptophan) is not recommended.
Treatment with PAXIL CR and any concomitant serotonergic or
antidopaminergic agents, including antipsychotics, should be discontinued
immediately if the above events occur and supportive symptomatic treatment
should be initiated. Potential Interaction With Thioridazine Thioridazine administration alone produces
prolongation of the QTc interval, which is associated with serious ventricular
arrhythmias, such as torsade de pointes–type arrhythmias, and sudden death. This
effect appears to be dose related.
An in vivo study suggests that drugs which inhibit CYP2D6,
such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is
recommended that paroxetine not be used in combination with thioridazine (see
CONTRAINDICATIONS and PRECAUTIONS). Usage in PregnancyTeratogenic
Effects Epidemiological studies have shown that infants exposed to
paroxetine in the first trimester of pregnancy have an increased risk of
congenital malformations, particularly cardiovascular malformations. The
findings from these studies are summarized below:
A study based on Swedish national registry data demonstrated that infants
exposed to paroxetine during pregnancy (n = 815) had an increased risk of
cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to
the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95%
confidence interval 1.1 to 2.8). No increase in the risk of overall congenital
malformations was seen in the paroxetine-exposed infants. The cardiac
malformations in the paroxetine-exposed infants were primarily ventricular
septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in
severity from those that resolve spontaneously to those which require surgery.
A separate retrospective cohort study from the United States (United
Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants
during the first trimester (n = 815 for paroxetine). This study showed a trend
towards an increased risk for cardiovascular malformations for paroxetine (risk
of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95%
confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with
cardiovascular malformations, 9 had VSDs. This study also suggested an increased
risk of overall major congenital malformations including cardiovascular defects
for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8;
95% confidence interval 1.2 to 2.8).
Two large case-control studies using separate databases, each with >9,000
birth defect cases and >4,000 controls, found that maternal use of paroxetine
during the first trimester of pregnancy was associated with a 2- to 3-fold
increased risk of right ventricular outflow tract obstructions. In one study the
OR was 2.5 (95% confidence interval, 1.0 to 6.0, 7 exposed infants) and in the
other study the OR was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed
infants).
Other studies have found varying results as to whether there was an increased
risk of overall, cardiovascular, or specific congenital malformations. A
meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on
first trimester paroxetine use in pregnancy and congenital malformations
included the above-noted studies in addition to others (n = 17 studies that
included overall malformations and n = 14 studies that included cardiovascular
malformations; n = 20 distinct studies). While subject to limitations, this
meta-analysis suggested an increased occurrence of cardiovascular malformations
(prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and
overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with
paroxetine use during the first trimester. It was not possible in this
meta-analysis to determine the extent to which the observed prevalence of
cardiovascular malformations might have contributed to that of overall
malformations, nor was it possible to determine whether any specific types of
cardiovascular malformations might have contributed to the observed prevalence
of all cardiovascular malformations.
If a patient becomes pregnant while taking paroxetine, she should be advised
of the potential harm to the fetus. Unless the benefits of paroxetine to the
mother justify continuing treatment, consideration should be given to either
discontinuing paroxetine therapy or switching to another antidepressant (see
PRECAUTIONS—Discontinuation of Treatment With PAXIL CR).
For women who intend to become pregnant or are in their first trimester of
pregnancy, paroxetine should only be initiated after consideration of the other
available treatment options. Animal
Findings Reproduction studies were performed at doses up to 50 mg/kg/day
in rats and 6 mg/kg/day in rabbits administered during organogenesis. These
doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended
human dose (MRHD) on an mg/m2 basis. These studies have
revealed no evidence of teratogenic effects. However, in rats, there was an
increase in pup deaths during the first 4 days of lactation when dosing occurred
during the last trimester of gestation and continued throughout lactation. This
effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD
on an mg/m2 basis. The no-effect dose for rat pup
mortality was not determined. The cause of these deaths is not known. Nonteratogenic
Effects Neonates exposed to PAXIL CR and other SSRIs or serotonin and
norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory
support, and tube feeding. Such complications can arise immediately upon
delivery. Reported clinical findings have included respiratory distress,
cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor,
jitteriness, irritability, and constant crying. These features are consistent
with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug
discontinuation syndrome. It should be noted that, in some cases, the clinical
picture is consistent with serotonin syndrome (see WARNINGS—Potential for
Interaction With Monoamine Oxidase Inhibitors).
Infants exposed to SSRIs in late pregnancy may have an increased risk for
persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2
per 1,000 live births in the general population and is associated with
substantial neonatal morbidity and mortality. In a retrospective case-control
study of 377 women whose infants were born with PPHN and 836 women whose infants
were born healthy, the risk for developing PPHN was approximately six-fold
higher for infants exposed to SSRIs after the 20th week
of gestation compared to infants who had not been exposed to antidepressants
during pregnancy. There is currently no corroborative evidence regarding the
risk for PPHN following exposure to SSRIs in pregnancy; this is the first study
that has investigated the potential risk. The study did not include enough cases
with exposure to individual SSRIs to determine if all SSRIs posed similar levels
of PPHN risk.
There have also been postmarketing reports of premature births in pregnant
women exposed to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester,
the physician should carefully consider both the potential risks and benefits of
treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a
prospective longitudinal study of 201 women with a history of major depression
who were euthymic at the beginning of pregnancy, women who discontinued
antidepressant medication during pregnancy were more likely to experience a
relapse of major depression than women who continued antidepressant medication.
Precautions Section
PRECAUTIONSGeneralActivation of
Mania/Hypomania During premarketing testing of immediate-release paroxetine
hydrochloride, hypomania or mania occurred in approximately 1.0% of
paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3%
of placebo-treated unipolar patients. In a subset of patients classified as
bipolar, the rate of manic episodes was 2.2% for immediate-release paroxetine
and 11.6% for the combined active-control groups. Among 1,627 patients with
major depressive disorder, panic disorder, social anxiety disorder, or PMDD
treated with PAXIL CR in controlled clinical studies, there were no reports of
mania or hypomania. As with all drugs effective in the treatment of major
depressive disorder, PAXIL CR should be used cautiously in patients with a
history of mania. Seizures During premarketing testing of immediate-release paroxetine
hydrochloride, seizures occurred in 0.1% of paroxetine-treated patients, a rate
similar to that associated with other drugs effective in the treatment of major
depressive disorder. Among 1,627 patients who received PAXIL CR in controlled
clinical trials in major depressive disorder, panic disorder, social anxiety
disorder, or PMDD, 1 patient (0.1%) experienced a seizure. PAXIL CR should be
used cautiously in patients with a history of seizures. It should be
discontinued in any patient who develops seizures. Discontinuation
of Treatment With PAXIL CR Adverse events while discontinuing therapy with PAXIL CR were not
systematically evaluated in most clinical trials; however, in recent
placebo-controlled clinical trials utilizing daily doses of PAXIL CR up to
37.5 mg/day, spontaneously reported adverse events while discontinuing therapy
with PAXIL CR were evaluated. Patients receiving 37.5 mg/day underwent an
incremental decrease in the daily dose by 12.5 mg/day to a dose of 25 mg/day for
1 week before treatment was stopped. For patients receiving 25 mg/day or
12.5 mg/day, treatment was stopped without an incremental decrease in dose. With
this regimen in those studies, the following adverse events were reported for
PAXIL CR, at an incidence of 2% or greater for PAXIL CR and were at least twice
that reported for placebo: Dizziness, nausea, nervousness, and additional
symptoms described by the investigator as associated with tapering or
discontinuing PAXIL CR (e.g., emotional lability, headache, agitation, electric
shock sensations, fatigue, and sleep disturbances). These events were reported
as serious in 0.3% of patients who discontinued therapy with PAXIL CR.
During marketing of PAXIL CR and other SSRIs and SNRIs, there have been
spontaneous reports of adverse events occurring upon discontinuation of these
drugs, (particularly when abrupt), including the following: Dysphoric mood,
irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias
such as electric shock sensations and tinnitus), anxiety, confusion, headache,
lethargy, emotional lability, insomnia, and hypomania. While these events are
generally self-limiting, there have been reports of serious discontinuation
symptoms.
Patients should be monitored for these symptoms when discontinuing treatment
with PAXIL CR. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a
decrease in the dose or upon discontinuation of treatment, then resuming the
previously prescribed dose may be considered. Subsequently, the physician may
continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
See also PRECAUTIONS—Pediatric Use, for adverse events reported upon
discontinuation of treatment with paroxetine in pediatric patients. Akathisia The use of paroxetine or other SSRIs has been associated with the
development of akathisia, which is characterized by an inner sense of
restlessness and psychomotor agitation such as an inability to sit or stand
still usually associated with subjective distress. This is most likely to occur
within the first few weeks of treatment. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and
SNRIs, including PAXIL CR. In many cases, this hyponatremia appears to be the
result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Cases with serum sodium lower than 110 mmol/L have been reported. Elderly
patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.
Also, patients taking diuretics or who are otherwise volume depleted may be at
greater risk (see Geriatric Use). Discontinuation of PAXIL CR should be
considered in patients with symptomatic hyponatremia and appropriate medical
intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty
concentrating, memory impairment, confusion, weakness, and unsteadiness, which
may lead to falls. Signs and symptoms associated with more severe and/or acute
cases have included hallucination, syncope, seizure, coma, respiratory arrest,
and death. Abnormal
Bleeding SSRIs and SNRIs, including paroxetine, may increase the risk of
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory
drugs, warfarin, and other anticoagulants may add to this risk. Case reports and
epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the
occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and
SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages. Patients should be cautioned about the risk of
bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin,
or other drugs that affect coagulation. Use in Patients
With Concomitant Illness Clinical experience with immediate-release paroxetine
hydrochloride in patients with certain concomitant systemic illness is limited.
Caution is advisable in using PAXIL CR in patients with diseases or conditions
that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing
studies with paroxetine hydrochloride. A few cases of acute angle closure
glaucoma associated with therapy with immediate-release paroxetine have been
reported in the literature. As mydriasis can cause acute angle closure in
patients with narrow angle glaucoma, caution should be used when PAXIL CR is
prescribed for patients with narrow angle glaucoma.
PAXIL CR or the immediate-release formulation has not been evaluated or used
to any appreciable extent in patients with a recent history of myocardial
infarction or unstable heart disease. Patients with these diagnoses were
excluded from clinical studies during premarket testing. Evaluation of
electrocardiograms of 682 patients who received immediate-release paroxetine
hydrochloride in double-blind, placebo-controlled trials, however, did not
indicate that paroxetine is associated with the development of significant ECG
abnormalities. Similarly, paroxetine hydrochloride does not cause any clinically
important changes in heart rate or blood pressure.
Increased plasma concentrations of paroxetine occur in patients with severe
renal impairment (creatinine clearance less than 30 mL/min.) or severe hepatic
impairment. A lower starting dose should be used in such patients (see DOSAGE
AND ADMINISTRATION).
Information For Patients Section
Information for Patients PAXIL CR should not be chewed or crushed, and should be swallowed
whole.
Patients should be cautioned about the risk of serotonin syndrome with the
concomitant use of PAXIL CR and triptans, tramadol, or other serotonergic
agents.
Prescribers or other health professionals should inform patients, their
families, and their caregivers about the benefits and risks associated with
treatment with PAXIL CR and should counsel them in its appropriate use. A
patient Medication Guide about “Antidepressant Medicines, Depression and Other
Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for
PAXIL CR. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist
them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any
questions they may have. The complete text of the Medication Guide is reprinted
at the end of this document.
Patients should be advised of the following issues and asked to alert their
prescriber if these occur while taking PAXIL CR. Clinical
Worsening and Suicide Risk Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in behavior,
worsening of depression, and suicidal ideation, especially early during
antidepressant treatment and when the dose is adjusted up or down. Families and
caregivers of patients should be advised to look for the emergence of such
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms
should be reported to the patient’s prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very
close monitoring and possibly changes in the medication. Drugs That
Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Patients should be cautioned about the concomitant use of
paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation
since combined use of psychotropic drugs that interfere with serotonin reuptake
and these agents has been associated with an increased risk of bleeding. Interference
With Cognitive and Motor Performance Any psychoactive drug may impair judgment, thinking, or motor
skills. Although in controlled studies immediate-release paroxetine
hydrochloride has not been shown to impair psychomotor performance, patients
should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that therapy with PAXIL CR does not affect
their ability to engage in such activities. Completing
Course of Therapy While patients may notice improvement with use of PAXIL CR in 1
to 4 weeks, they should be advised to continue therapy as directed. Concomitant
Medications Patients should be advised to inform their physician if they are
taking, or plan to take, any prescription or over-the-counter drugs, since there
is a potential for interactions. Alcohol Although immediate-release paroxetine hydrochloride has not been
shown to increase the impairment of mental and motor skills caused by alcohol,
patients should be advised to avoid alcohol while taking PAXIL CR. Pregnancy Patients should be advised to notify their physician if they
become pregnant or intend to become pregnant during therapy (see WARNINGS—Usage
in Pregnancy: Teratogenic and Nonteratogenic
Effects). Nursing Patients should be advised to notify their physician if they are
breastfeeding an infant (see PRECAUTIONS—Nursing Mothers). Laboratory Tests There are no specific laboratory tests recommended. Drug InteractionsTryptophan 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). 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, linezolid (an
antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.
John's Wort (see WARNINGS—Serotonin Syndrome). The concomitant use of PAXIL CR
with MAOIs (including linezolid) is contraindicated (see CONTRAINDICATIONS). The
concomitant use of PAXIL CR with other SSRIs, SNRIs or tryptophan is not
recommended (see PRECAUTIONS—Drug Interactions, Tryptophan). 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 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) 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 (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 P450 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, tamoxifen, 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 and hence reduced efficacy of tamoxifen.
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). 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 Ki 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 ECT and
PAXIL CR. Carcinogenesis, Mutagenesis, Impairment of
FertilityCarcinogenesis Two-year carcinogenicity studies were conducted in rodents given
paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and
20 mg/kg/day (rats). These doses are up to approximately 2 (mouse) and 3 (rat)
times the MRHD on a mg/m2 basis. There was a
significantly greater number of male rats in the high-dose group with reticulum
cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and
high-dose groups, respectively) and a significantly increased linear trend
across dose groups for the occurrence of lymphoreticular tumors in male rats.
Female rats were not affected. Although there was a dose-related increase in the
number of tumors in mice, there was no drug-related increase in the number of
mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis Paroxetine produced no genotoxic effects in a battery of 5 in
vitro and 2 in vivo assays that included the following: Bacterial mutation
assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests
for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human
lymphocytes and in a dominant lethal test in rats. Impairment of
Fertility A reduced pregnancy rate was found in reproduction studies in
rats at a dose of paroxetine of 15 mg/kg/day, which is approximately twice the
MRHD on a mg/m2 basis. Irreversible lesions occurred in
the reproductive tract of male rats after dosing in toxicity studies for 2 to
52 weeks. These lesions consisted of vacuolation of epididymal tubular
epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of
the testes with arrested spermatogenesis at 25 mg/kg/day (approximately 8 and
4 times the MRHD on a mg/m2 basis) Pregnancy Pregnancy Category D. See WARNINGS—Usage in Pregnancy: Teratogenic and Nonteratogenic Effects. Labor and Delivery The effect of paroxetine on labor and delivery in humans is
unknown. Nursing Mothers Like many other drugs, paroxetine is secreted in human milk, and
caution should be exercised when PAXIL CR is administered to a nursing
woman. Pediatric Use Safety and effectiveness in the pediatric population have not
been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide
Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have
been conducted with PAXIL, and the data were not sufficient to support a claim
for use in pediatric patients. Anyone considering the use of PAXIL CR in a child
or adolescent must balance the potential risks with the clinical need.
In placebo-controlled clinical trials conducted with pediatric patients, the
following adverse events were reported in at least 2% of pediatric patients
treated with immediate-release paroxetine hydrochloride and occurred at a rate
at least twice that for pediatric patients receiving placebo: emotional lability
(including self-harm, suicidal thoughts, attempted suicide, crying, and mood
fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia,
and agitation.
Events reported upon discontinuation of treatment with immediate-release
paroxetine hydrochloride in the pediatric clinical trials that included a taper
phase regimen, which occurred in at least 2% of patients who received
immediate-release paroxetine hydrochloride and which occurred at a rate at least
twice that of placebo, were: emotional lability (including suicidal ideation,
suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea,
and abdominal pain (see Discontinuation of Treatment With PAXIL CR). Geriatric Use SSRIs and SNRIs, including PAXIL CR, have been associated with
cases of clinically significant hyponatremia in elderly patients, who may be at
greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
In worldwide premarketing clinical trials with immediate-release paroxetine
hydrochloride, 17% of paroxetine-treated patients (approximately 700) were
65 years or older. Pharmacokinetic studies revealed a decreased clearance in the
elderly, and a lower starting dose is recommended; there were, however, no
overall differences in the adverse event profile between elderly and younger
patients, and effectiveness was similar in younger and older patients (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
In a controlled study focusing specifically on elderly patients with major
depressive disorder, PAXIL CR was demonstrated to be safe and effective in the
treatment of elderly patients (>60 years) with major depressive disorder.
(See CLINICAL PHARMACOLOGY—Clinical Trials and ADVERSE REACTIONS—Table 2.)
Adverse Reactions Section
ADVERSE REACTIONS 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). Adverse Findings Observed in Short-Term,
Placebo-Controlled Trials With PAXIL CR:Adverse Events Associated With Discontinuation of
TreatmentMajor 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:
PAXIL CR (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:
PAXIL CR (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).
PAXIL CR
25 mg (n = 348)
PAXIL CR
12.5 mg (n = 333)
Placebo (n = 349)
TOTAL
15%
9.9%
6.3%
Nausea*
6.0%
2.4%
0.9%
Asthenia
4.9%
3.0%
1.4%
Somnolence*
4.3%
1.8%
0.3%
Insomnia
2.3%
1.5%
0.0%
Concentration Impaired*
2.0%
0.6%
0.3%
Dry mouth*
2.0%
0.6%
0.3%
Dizziness*
1.7%
0.6%
0.6%
Decreased Appetite*
1.4%
0.6%
0.0%
Sweating*
1.4%
0.0%
0.3%
Tremor*
1.4%
0.3%
0.0%
Yawn*
1.1%
0.0%
0.0%
Diarrhea
0.9%
1.2%
0.0%
* 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 EventsMajor 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 Disorder1,2
Body System/Adverse Event
%
Reporting Event
PAXIL CR (n=212)
Placebo (n= 211)
Body as a
Whole
Headache
27%
20%
Asthenia
14%
9%
Infection3
8%
5%
Abdominal Pain
7%
4%
Back Pain
5%
3%
Trauma4
5%
1%
Pain5
3%
1%
Allergic Reaction6
2%
1%
Cardiovascular
System
Tachycardia
1%
0%
Vasodilatation7
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 Vision8
5%
1%
Taste Perversion
2%
0%
Urogenital
System
Abnormal Ejaculation9,10
26%
1%
Female Genital Disorder9,11
10%
less than 1%
Impotence9
5%
3%
Urinary Tract Infection
3%
1%
Menstrual Disorder9
2%
less than 1%
Vaginitis9
2%
0%
1 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.
2 less than 1% means greater than zero and less than 1%.
3 Mostly flu.
4 A wide variety of injuries with no obvious
pattern.
5 Pain in a variety of locations with no obvious
pattern.
6 Most frequently seasonal allergic symptoms.
7 Usually flushing.
8 Mostly blurred vision.
9 Based on the number of males or females.
10 Mostly anorgasmia or delayed ejaculation.
11 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
Disorder1,2
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%
less than 1%
Tremor
7%
0%
Skin and
Appendages
Sweating
10%
less than 1%
Urogenital
System
Abnormal Ejaculation3,4
17%
3%
Impotence3
9%
3%
1 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.
2 less than 1% means greater than zero and less than 1%.
3 Based on the number of males.
4 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 Studies1,2
Body System/Adverse Event
%
Reporting Event
PAXIL CR (n = 444)
Placebo (n = 445)
Body as a
Whole
Asthenia
15%
10%
Abdominal Pain
6%
4%
Trauma3
5%
4%
Cardiovascular
System
Vasodilation4
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%
Hypertonia5
2%
less than 1%
Myoclonus
2%
less than 1%
Respiratory
System
Sinusitis
8%
5%
Yawn
3%
0%
Skin and
Appendages
Sweating
7%
2%
Special
Senses
Abnormal Vision6
3%
less than 1%
Urogenital
System
Abnormal Ejaculation7,8
27%
3%
Impotence7
10%
1%
Female Genital Disorders9,10
7%
1%
Urinary Frequency
2%
less than 1%
Urination Impaired
2%
less than 1%
Vaginitis9
1%
less than 1%
1 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.
2 less than 1% means greater than zero and less than 1%.
3 Various physical injuries.
4 Mostly flushing.
5 Mostly muscle tightness or stiffness.
6 Mostly blurred vision.
7 Based on the number of male patients.
8 Mostly anorgasmia or delayed ejaculation.
9 Based on the number of female patients.
10 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 Study1,2
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%
Trauma3
3%
less than 1%
Allergic Reaction4
2%
less than 1%
Chest Pain
1%
less than 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%
less than 1%
Decreased Appetite
1%
less than 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%
less than 1%
Paresthesia
1%
less than 1%
Respiratory
System
Yawn
2%
0%
Skin and
Appendages
Sweating
14%
3%
Eczema
1%
0%
Special
Senses
Abnormal Vision5
2%
0%
Abnormality of
Accommodation
2%
0%
Urogenital
System
Abnormal Ejaculation6,7
15%
1%
Impotence6
9%
0%
Female Genital Disorders8,9
3%
0%
1 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.
2 less than 1% means greater than zero and less than 1%.
3 Various physical injuries.
4 Most frequently seasonal allergic symptoms.
5 Mostly blurred vision.
6 Based on the number of male patients.
7 Mostly anorgasmia or delayed ejaculation.
8 Based on the number of female patients.
9 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 Dosing1,2,3
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%
less than 1%
-
-
Digestive
System
Nausea
17%
7%
18%
2%
Diarrhea
6%
2%
6%
0%
Constipation
5%
1%
2%
less than 1%
Dry Mouth
4%
2%
2%
less than 1%
Increased Appetite
3%
less than 1%
-
-
Decreased Appetite
2%
less than 1%
2%
0%
Dyspepsia
2%
1%
2%
2%
Gingivitis
-
-
1%
0%
Metabolic and
Nutritional Disorders
Generalized Edema
-
-
1%
less than 1%
Weight Gain
-
-
1%
less than 1%
Musculoskeletal
System
Arthralgia
2%
1%
-
-
Nervous
System
Libido Decreased
12%
5%
9%
6%
Somnolence
9%
2%
3%
less than 1%
Insomnia
8%
2%
7%
3%
Dizziness
7%
3%
6%
3%
Tremor
4%
less than 1%
5%
0%
Concentration Impaired
3%
less than 1%
1%
0%
Nervousness
2%
less than 1%
3%
2%
Anxiety
2%
1%
-
-
Lack of Emotion
2%
less than 1%
-
-
Depression
-
-
2%
less than 1%
Vertigo
-
-
2%
less than 1%
Abnormal Dreams
1%
less than 1%
-
-
Amnesia
-
-
1%
0%
Respiratory
System
Sinusitis
-
-
4%
2%
Yawn
2%
less than 1%
-
-
Bronchitis
-
-
2%
0%
Cough Increased
1%
less than 1%
-
-
Skin and
Appendages
Sweating
7%
less than 1%
6%
less than 1%
Special
Senses
Abnormal Vision
-
-
1%
0%
Urogenital
System
Female Genital Disorders4
8%
1%
2%
0%
Menorrhagia
1%
less than 1%
-
-
Vaginal Moniliasis
1%
less than 1%
-
-
Menstrual Disorder
-
-
1%
0%
1 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.
2 less than 1% means greater than zero and less than 1%.
3 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 5 should be avoided.
4 Mostly anorgasmia or difficulty achieving
orgasm. Dose Dependency
of Adverse Events The following table 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.
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
PAXIL CR
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%
less than 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 uled in Tables 2 through 6 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 uled 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 uled in the tabulated results from placebo-controlled
trials appear in this uling); 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 uled for controlled-release paroxetine are included. The extent to
which these events may be associated with PAXIL CR is unknown.
Events are uled 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 uled above that may have no causal relationship with the
drug include acute pancreatitis, elevated liver function tests (the most severe
cases were deaths due to liver necrosis, and grossly elevated transaminases
associated with severe liver dysfunction), Guillain-Barré syndrome, toxic
epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion,
symptoms suggestive of prolactinemia and galactorrhea; 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, ventricular fibrillation, ventricular tachycardia
(including torsade de pointes), thrombocytopenia, hemolytic anemia, events
related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone
marrow aplasia, and agranulocytosis), and vasculitic syndromes (such as
Henoch-Schönlein purpura). There has been a case report of an elevated phenytoin
level after 4 weeks of immediate-release paroxetine and phenytoin
coadministration. There has been a case report of severe hypotension when
immediate-release paroxetine was added to chronic metoprolol treatment.
Drug Abuse And Dependence Section
DRUG ABUSE AND DEPENDENCEControlled 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).
Overdosage Section
OVERDOSAGEHuman Experience Since the introduction of immediate-release paroxetine
hydrochloride in the United States, 342 spontaneous cases of deliberate or
accidental overdosage during paroxetine treatment have been reported worldwide
(circa 1999). These include overdoses with paroxetine alone and in combination
with other substances. Of these, 48 cases were fatal and of the fatalities,
17 appeared to involve paroxetine alone. Eight fatal cases that documented the
amount of paroxetine ingested were generally confounded by the ingestion of
other drugs or alcohol or the presence of significant comorbid conditions. Of
145 non-fatal cases with known outcome, most recovered without sequelae. The
largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum
recommended daily dose) in a patient who recovered.
Commonly reported adverse events associated with paroxetine overdosage
include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and
dizziness. Other notable signs and symptoms observed with overdoses involving
paroxetine (alone or with other substances) include mydriasis, convulsions
(including status epilepticus), ventricular dysrhythmias (including torsade de
pointes), hypertension, aggressive reactions, syncope, hypotension, stupor,
bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic
steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure,
and urinary retention. Overdosage Management Treatment should consist of those general measures employed in
the management of overdosage with any drugs effective in the treatment of major
depressive disorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac
rhythm and vital signs. General supportive and symptomatic measures are also
recommended. Induction of emesis is not recommended. Gastric lavage with a
large-bore orogastric tube with appropriate airway protection, if needed, may be
indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to the large volume of
distribution of this drug, forced diuresis, dialysis, hemoperfusion, and
exchange transfusion are unlikely to be of benefit. No specific antidotes for
paroxetine are known.
A specific caution involves patients taking or recently having taken
paroxetine who might ingest excessive quantities of a tricyclic antidepressant.
In such a case, accumulation of the parent tricyclic and an active metabolite
may increase the possibility of clinically significant sequelae and extend the
time needed for close medical observation (see PRECAUTIONS—Drugs Metabolized by Cytochrome CYP2D6).
In managing overdosage, consider the possibility of multiple-drug
involvement. The physician should consider contacting a poison control center
for additional information on the treatment of any overdose. Telephone numbers
for certified poison control centers are uled in the Physicians' Desk Reference (PDR).
Dosage & Administration Section
DOSAGE AND ADMINISTRATIONMajor Depressive DisorderUsual Initial
Dosage PAXIL CR should be administered as a single daily dose, usually
in the morning, with or without food. The recommended initial dose is 25 mg/day.
Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials
demonstrating the effectiveness of PAXIL CR in the treatment of major depressive
disorder. As with all drugs effective in the treatment of major depressive
disorder, the full effect may be delayed. Some patients not responding to a
25-mg dose may benefit from dose increases, in 12.5-mg/day increments, up to a
maximum of 62.5 mg/day. Dose changes should occur at intervals of at least
1 week.
Patients should be cautioned that PAXIL CR should not be chewed or crushed,
and should be swallowed whole. Maintenance
Therapy There is no body of evidence available to answer the question of
how long the patient treated with PAXIL CR should remain on it. It is generally
agreed that acute episodes of major depressive disorder require several months
or longer of sustained pharmacologic therapy. Whether the dose of an
antidepressant needed to induce remission is identical to the dose needed to
maintain and/or sustain euthymia is unknown.
Systematic evaluation of the efficacy of immediate-release paroxetine
hydrochloride has shown that efficacy is maintained for periods of up to 1 year
with doses that averaged about 30 mg, which corresponds to a 37.5-mg dose of
PAXIL CR, based on relative bioavailability considerations (see CLINICAL
PHARMACOLOGY—Pharmacokinetics). Panic DisorderUsual Initial
Dosage PAXIL CR should be administered as a single daily dose, usually
in the morning. Patients should be started on 12.5 mg/day. Dose changes should
occur in 12.5-mg/day increments and at intervals of at least 1 week. Patients
were dosed in a range of 12.5 to 75 mg/day in the clinical trials demonstrating
the effectiveness of PAXIL CR. The maximum dosage should not exceed
75 mg/day.
Patients should be cautioned that PAXIL CR should not be chewed or crushed,
and should be swallowed whole. Maintenance
Therapy Long-term maintenance of efficacy with the immediate-release
formulation of paroxetine was demonstrated in a 3-month relapse prevention
trial. In this trial, patients with panic disorder assigned to immediate-release
paroxetine demonstrated a lower relapse rate compared to patients on placebo.
Panic disorder is a chronic condition, and it is reasonable to consider
continuation for a responding patient. Dosage adjustments should be made to
maintain the patient on the lowest effective dosage, and patients should be
periodically reassessed to determine the need for continued treatment. Social Anxiety DisorderUsual Initial
Dosage PAXIL CR should be administered as a single daily dose, usually
in the morning, with or without food. The recommended initial dose is
12.5 mg/day. Patients were dosed in a range of 12.5 mg to 37.5 mg/day in the
clinical trial demonstrating the effectiveness of PAXIL CR in the treatment of
social anxiety disorder. If the dose is increased, this should occur at
intervals of at least 1 week, in increments of 12.5 mg/day, up to a maximum of
37.5 mg/day.
Patients should be cautioned that PAXIL CR should not be chewed or crushed,
and should be swallowed whole. Maintenance
Therapy There is no body of evidence available to answer the question of
how long the patient treated with PAXIL CR should remain on it. Although the
efficacy of PAXIL CR beyond 12 weeks of dosing has not been demonstrated in
controlled clinical trials, social anxiety disorder is recognized as a chronic
condition, and it is reasonable to consider continuation of treatment for a
responding patient. Dosage adjustments should be made to maintain the patient on
the lowest effective dosage, and patients should be periodically reassessed to
determine the need for continued treatment. Premenstrual Dysphoric DisorderUsual Initial
Dosage PAXIL CR should be administered as a single daily dose, usually
in the morning, with or without food. PAXIL CR may be administered either daily
throughout the menstrual cycle or limited to the luteal phase of the menstrual
cycle, depending on physician assessment. The recommended initial dose is
12.5 mg/day. In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be
effective. Dose changes should occur at intervals of at least 1 week.
Patients should be cautioned that PAXIL CR should not be chewed or crushed,
and should be swallowed whole. Maintenance/Continuation Therapy The effectiveness of PAXIL CR for a period exceeding 3 menstrual
cycles has not been systematically evaluated in controlled trials. However,
women commonly report that symptoms worsen with age until relieved by the onset
of menopause. Therefore, it is reasonable to consider continuation of a
responding patient. Patients should be periodically reassessed to determine the
need for continued treatment. Special PopulationsTreatment of
Pregnant Women During the Third Trimester Neonates exposed to PAXIL CR and other SSRIs or SNRIs, late in
the third trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding (see WARNINGS). When
treating pregnant women with paroxetine during the third trimester, the
physician should carefully consider the potential risks and benefits of
treatment. The physician may consider tapering paroxetine in the third
trimester. Dosage for
Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic
Impairment The recommended initial dose of PAXIL CR is 12.5 mg/day for
elderly patients, debilitated patients, and/or patients with severe renal or
hepatic impairment. Increases may be made if indicated. Dosage should not exceed
50 mg/day. Switching Patients to or From a Monoamine Oxidase
Inhibitor At least 14 days should elapse between discontinuation of an MAOI
and initiation of therapy with PAXIL CR. Similarly, at least 14 days should be
allowed after stopping PAXIL CR before starting an MAOI. Discontinuation of Treatment With PAXIL CR Symptoms associated with discontinuation of immediate-release
paroxetine hydrochloride or PAXIL CR have been reported (see PRECAUTIONS).
Patients should be monitored for these symptoms when discontinuing treatment,
regardless of the indication for which PAXIL CR is being prescribed. A gradual
reduction in the dose rather than abrupt cessation is recommended whenever
possible. If intolerable symptoms occur following a decrease in the dose or upon
discontinuation of treatment, then resuming the previously prescribed dose may
be considered. Subsequently, the physician may continue decreasing the dose but
at a more gradual rate.
How Supplied Section
HOW SUPPLIED PAXIL CR is supplied as an enteric film-coated,
controlled-release, round tablet, as follows:
12.5-mg yellow tablets, engraved with PAXIL CR and 12.5
NDC 0029-3206-13 Bottles of 30
25-mg pink tablets, engraved with PAXIL CR and 25
NDC 0029-3207-13 Bottles of 30
37.5 mg blue tablets, engraved with PAXIL CR and 37.5
NDC 0029-3208-13 Bottles of 30
Store at or below 25°C (77°F) [see USP].
PAXIL CR is a registered trademark of GlaxoSmithKline.
GEOMATRIX is a trademark of Jago Pharma, Muttenz, Switzerland.
Spl Medguide Section
Medication Guide Antidepressant Medicines, Depression and Other
Serious Mental Illnesses, and Suicidal Thoughts or Actions
Read the Medication Guide that comes with your or your family member’s
antidepressant medicine. This Medication Guide is only about the risk of
suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider
about:
All risks and benefits of treatment with antidepressant medicines
All treatment choices for depression or other serious mental illness
What is the most important information I should know about
antidepressant medicines, depression and other serious mental illnesses, and
suicidal thoughts or action?
1. Antidepressant medicines may increase suicidal thoughts
or actions in some children, teenagers, and young adults within the first few
months of treatment.
2. Depression and other serious mental illnesses are the
most important causes of suicidal thoughts and actions. Some people may have a
particularly high risk of having suicidal thoughts or actions. These
include people who have (or have a family history of) bipolar illness (also
called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts
and actions in myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call
the healthcare provider between visits as needed, especially if you have
concerns about symptoms.
Call a healthcare provider right away if you or your
family member has any of the following symptoms, especially if they are new,
worse, or worry you:
Thoughts about suicide or dying
Attempts to commit suicide
New or worse depression
New or worse anxiety
Feeling very agitated or restless
Panic attacks
Trouble sleeping (insomnia)
New or worse irritability
Acting aggressive, being angry, or violent
Acting on dangerous impulses
An extreme increase in activity and talking (mania)
Other unusual changes in behavior or mood
What else do I need to know about antidepressant
medicines?
Never stop an antidepressant medicine without first talking
to a healthcare provider. Stopping an antidepressant medicine suddenly
can cause other symptoms.
Antidepressants are medicines used to treat depression and
other illnesses. It is important to discuss all the risks of treating
depression and also the risks of not treating it. Patients and their families or
other caregivers should discuss all treatment choices with the healthcare
provider, not just the use of antidepressants.
Antidepressant medicines have other side effects.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1–800–FDA-1088.
Antidepressant medicines can interact with other
medicines. Know all of the medicines that you or your family member
takes. Keep a ul of all medicines to show the healthcare provider. Do not
start new medicines without first checking with your healthcare provider.
Not all antidepressant medicines prescribed for children
are FDA approved for use in children. Talk to your child’s healthcare
provider for more information.
This Medication Guide has been approved by the U.S. Food and Drug
Administration for all antidepressants.
August 2009 PCR:32PI principal display panel NDC 0029-3206-13
PAXIL CR®
PAROXETINE HCl
CONTROLLED-RELEASE TABLETS
30 Tablets
Rx only
Federal Law requires dispensing of Paxil CR® with the
Medication Guide under this label. Store at or below 25oC
(77oF) [see USP].
Each controlled-release tablet contains paroxetine hydrochloride equivalent
to 12.5 mg paroxetine.
Dosage: See accompanying prescribing information.
Important: Use safety closures when dispensing this product unless otherwise
directed by physician or requested by purchaser.
GlaxoSmithKline
RTP, NC 27709
Made in Ireland
A053835 Rev. 4/08
Package Label.principal Display Panel
PAXIL CR 12.5 MG Package Label
DISCLAIMER:
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
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