Paroxetine precautions

List of precautions
General Lab tests Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Labor & delivery Nursing mothers Pediatric use Geriatric use
 * Activation of mania/hypomania
 * Seizures
 * Discontinuation of treatment
 * Akathisia
 * Hyponatremia
 * Abnormal bleeding
 * Use in patients with concomitant illness
 * Teratogenic effects
 * Nonteratogenic effects

Activation of mania/hypomania
During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with Paroxetine hydrochloride 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 Paroxetine hydrochloride and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, Paroxetine hydrochloride should be used cautiously in patients with a history of mania. Return to top

Seizures
During premarketing testing, seizures occurred in 0.1% of patients treated with Paroxetine hydrochloride, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine hydrochloride should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Return to top

Discontinuation of treatment
Recent clinical trials supporting the various approved indications for Paroxetine hydrochloride employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and other clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for Paroxetine hydrochloride and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention. During marketing of Paroxetine hydrochloride and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring, upon the 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 Paroxetine tablets. 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. Return to top

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. Return to top

Hyponatremia
Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when Paroxetine hydrochloride was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted. Return to top

Abnormal bleeding
Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In 2 studies, concurrent use of a non-steroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of Paroxetine with NSAIDs, aspirin, or other drugs that affect coagulation. Return to top

Use in patients with concomitant illness
Clinical experience with Paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using Paroxetine tablets 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 Paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when Paroxetine tablets are prescribed for patients with narrow angle glaucoma. Paroxetine hydrochloride 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 Paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate that Paroxetine hydrochloride 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 < 30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients. Return to top

Lab tests
There are no specific laboratory tests recommended. Return to top

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 up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, and GAD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. 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. Return to top

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 cytogenic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Return to top

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 major depressive disorder, social anxiety disorder, and GAD or 2.4 times the MRHD for OCD 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 (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2 basis). Return to top

Pregnancy

 * Pregnancy category D. Return to top

Teratogenic effects
Epidemiological studies have shown that infants born to women who had first trimester Paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. 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 Paroxetine Tablets). 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. A study based on Swedish national registry data evaluated infants of 6,896 women exposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for Paroxetine). Infants exposed to Paroxetine in early pregnancy had an increased risk of cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry population (OR 1.8; 95% confidence interval 1.1 to 2.8). The rate of cardiovascular malformations following early pregnancy Paroxetine exposure was 2% vs. 1% in the entire registry population. Among the same Paroxetine exposed infants, an examination of the data showed no increase in the overall risk for congenital malformations. A separate retrospective cohort study using U.S. United Healthcare data evaluated 5,956 infants of mothers dispensed Paroxetine or other antidepressants during the first trimester (n = 815 for Paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for Paroxetine compared to other antidepressants (OR 1.5; 95% confidence interval 0.8 to 2.9). The prevalence of cardiovascular malformations following first trimester dispensing was 1.5% for Paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with cardiovascular malformations whose mothers were dispensed Paroxetine in the first trimester had VSDs. This study also suggested an increased risk of overall major congenital malformations (inclusive of the cardiovascular defects) for Paroxetine compared to other antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for Paroxetine vs. 2% for other antidepressants. Return to top

Nonteratogenic effects
Neonates exposed to Paroxetine hydrochloride 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 to 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 ANDADMINISTRATION). 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. Return to top

Labor & delivery
The effect of Paroxetine on labor and delivery in humans is unknown. Return to top

Nursing mothers
Like many other drugs, Paroxetine is secreted in human milk, and caution should be exercised when Paroxetine tablets are administered to a nursing woman. Return to top

Pediatric use
Safety and effectiveness in the pediatric population have not been established. Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with Paroxetine hydrochloride, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Paroxetine tablets 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 Paroxetine 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, hyperkinesias, and agitation. Events reported upon discontinuation of treatment with Paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received 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 Return to top

Geriatric use
In worldwide premarketing clinical trials with Paroxetine hydrochloride, 17% of patients treated with Paroxetine hydrochloride (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. Return to top