WARNINGS
Potential for Interaction with Monoamine Oxidase
Inhibitors
In patients receiving another serotonin reuptake inhibitor
drug in combination with a monoamine oxidase inhibitor
(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 a MAOI. Some cases presented with features resembling
neuroleptic malignant syndrome. While there are no human
data showing such an interaction with paroxetine HCl,
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 paroxetine
HCl not be used in combination with a MAOI, or within
14 days of discontinuing treatment with a MAOI. At least
2 weeks should be allowed after stopping paroxetine HCl
before starting a MAOI.
PRECAUTIONS
General
Activation of Mania/Hypomania: During
premarketing testing of immediate-release paroxetine HCl,
hypomania or mania occurred in approximately 1.0% of paroxetine
HCl-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 HCl and 11.6%
for the combined active-control groups. As with all antidepressants,
paroxetine HCl should be used cautiously in patients with
a history of mania.
Seizures: During premarketing
testing of immediate-release paroxetine HCl, seizures
occurred in 0.1% of paroxetine HCl-treated patients, a
rate similar to that associated with other antidepressants.
Paroxetine HCl should be used cautiously in patients with
a history of seizures. It should be discontinued in any
patient who develops seizures.
Suicide: The possibility of
a suicide attempt is inherent in depression and may persist
until significant remission occurs. Close supervision
of high-risk patients should accompany initial drug therapy.
Prescriptions for paroxetine HCl should be written for
the smallest quantity of tablets consistent with good
patient management, in order to reduce the risk of overdose.
Hyponatremia: Several cases
of hyponatremia have been reported with immediate-release
paroxetine HCl. The hyponatremia appeared to be reversible
when paroxetine HCl was discontinued. The majority of
these occurrences have been in elderly individuals, some
in patients taking diuretics or who were otherwise volume
depleted.
Abnormal Bleeding: There have
been several reports of abnormal bleeding (mostly ecchymosis
and purpura) associated with immediate-release paroxetine
treatment, including a report of impaired platelet aggregation.
While a causal relationship to paroxetine is unclear,
impaired platelet aggregation may result from platelet
serotonin depletion and contribute to such occurrences.
Use in Patients with Concomitant Illness:
Clinical experience with immediate-release paroxetine
HCl in patients with certain concomitant systemic illness
is limited. Caution is advisable in using paroxetine HCl
in patients with diseases or conditions that could affect
metabolism or hemodynamic responses.
Paroxetine HCl 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 the product's premarket testing. Evaluation of
electrocardiograms of 682 patients who received immediate-release
paroxetine HCl in double-blind, placebo-controlled trials,
however, did not indicate that paroxetine HCl is associated
with the development of significant ECG abnormalities.
Similarly, paroxetine HCl 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
<30 ml/min) or severe hepatic impairment. A lower starting
dose should be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for the Patient
Physicians are advised to discuss the following issues
with patients for whom they prescribe paroxetine HCl.
Interference with Cognitive and Motor Performance:
Any psychoactive drug may impair judgment,
thinking or motor skills. Although in controlled studies
immediate-release paroxetine HCl has not been shown to
impair psychomotor performance, patients should be cautioned
about operating hazardous machinery, including automobiles,
until they are reasonably certain that paroxetine HCl
therapy does not affect their ability to engage in such
activities.
Completing Course of Therapy:
While patients may notice improvement with paroxetine
HCl therapy in 1 to 4 weeks, they should be advised to
continue therapy as directed.
Concomitant Medication: 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 HCl 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 paroxetine
HCl.
Pregnancy: Patients should
be advised to notify their physician if they become pregnant
or intend to become pregnant during therapy.
Nursing: Patients should be
advised to notify their physician if they are breast-feeding
an infant (see Nursing Mothers).
Additional Information for Controlled-Release
Tablets: Paroxetine HCl controlled-release
tablets should not be chewed or crushed, and should be
swallowed whole.
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Carcinogenesis: 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 [for the immediate-release
tablets and oral suspension: up to 2.4 (mouse) and 3.9
(rat) times and for the controlled-release tablets: 2
(mouse) and 3 (rat)] times the maximum recommended human
dose (MRHD) for depression (and social anxiety disorder
for immediate-release formulations only) on a mg/m2 basis.
Because the MRHD for depression is slightly less than
that for OCD (50 mg vs. 60 mg), the doses used in these
carcinogenicity studies were only 2.0 (mouse) and 3.2
(rat) times the MRHD for OCD for the immediate-release
tablets and oral suspension. 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 2.9 times the MRHD for depression (and social anxiety
disorder for immediate-release formulations only) or approximately
twice the MRHD for OCD on a mg/m2 basis for the immediate-release
tablets and oral suspension, and approximately twice the
MRHD on a mg/m2 basis for the controlled-release tablets.
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 (9.8 and 4.9 times the
MRHD for depression [and social anxiety disorder for immediate-release
formulations only]; 8.2 and 4.1 times the MRHD for OCD
and PD on a mg/m2 basis for the immediate-release tablets
and oral suspension, and approximately 8 and 4 times the
MRHD on a mg/m2 basis for the controlled-release tablets).
Pregnancy, Teratogenic Effects, Pregnancy Category
C
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 equivalent to 9.7
(rat) and 2.2 (rabbit) times the maximum recommended human
dose (MRHD) for depression [and social anxiety disorder
for immediate-release formulations only] (50 mg) and 8.1
(rat) and 1.9 (rabbit) times the MRHD for OCD, on a mg/m2
basis for the immediate-release tablets and oral suspension
and approximately 8 (rat) and 2 (rabbit) times the maximum
recommended human dose (MRHD) on a mg/m2 basis for the
controlled-release tablets. 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 0.19
times (mg/m2) the MRHD for depression (and social anxiety
disorder for immediate-release formulations only) and
at 0.16 times (mg/m2) the MRHD for OCD for the immediate-release
tablets and oral suspension, and approximately one-sixth
of the MRHD on a mg/m2 basis for the controlled-release
tablets. The no-effect dose for rat pup mortality was
not determined. The cause of these deaths is not known.
There are no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always
predictive of human response, this drug should be used
during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
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 paroxetine
HCl is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population
have not been established.
Geriatric Use
In worldwide premarketing immediate-release paroxetine
HCl clinical trials, 17% of paroxetine HCl-treated patients
(approximately 700) were 65 years of age 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).
Additional Information for Controlled-Release Tablets:
In a controlled study focusing specifically on elderly
patients, paroxetine HCl controlled-release tablets was
demonstrated to be safe and effective in the treatment
of elderly patients (>60 years of age) with depression
(see CLINICAL STUDIES and ADVERSE REACTIONS: TABLE 9).
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