CONTRAINDICATIONS
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see
WARNINGS and PRECAUTIONS).
Paroxetine HCl is contraindicated in patients with a hypersensitivity to paroxetine or to any of the
inactive ingredients in paroxetine HCl formulations.
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 TABLE 9).