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 MRHD for major depressive disorder, social anxiety disorder, GAD and PTSD on a mg/m 2 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.
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.
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, GAD and PTSD or 2.4 times the MRHD for OCD on a mg/m 2 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/m 2 basis).
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 paroxetine tablets, 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. Decreased appetite and weight loss have been observed in association with the use of SSRIs.
Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as paroxetine. 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 tablets 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 paroxetine tablets in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine tablets 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 DOSAGE AND ADMINISTRATION: Discontinuation of Treatment with Paroxetine Tablets).
SSRIs and SNRIs, including paroxetine, 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 paroxetine tablets, 17% of patients treated with paroxetine tablets (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).
Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735) and 11.7% (79/676) of patients treated with paroxetine tablets in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD and PTSD, respectively, discontinued treatment due to an adverse event. 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 paroxetine tablets compared to placebo) included the following:
Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine tablets were not >1% or were not greater than or equal to 2 times the incidence of placebo.
|Major Depressive Disorder||OCD||Panic Disorder||Social Anxiety Disorder||Generalized Anxiety Disorder||PTSD|
|Paroxetine Tablets||Placebo||Paroxetine Tablets||Placebo||Paroxetine Tablets||Placebo||Paroxetine Tablets||Placebo||Paroxetine Tablets||Placebo||Paroxetine Tablets||Placebo|
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