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.
Based on studies using immediate-release formulations, steady-state drug exposure based on AUC0 to 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: Drugs Metabolized by CYP2D6).
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.
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).
A study of outpatients with major depressive disorder who had responded to immediate-release paroxetine tablets (HDRS total score <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.
For all 3 studies, the mean dose of paroxetine extended-release tablets 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.
Paroxetine extended-release tablets 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 paroxetine extended-release tablets 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.
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 paroxetine extended-release tablets or placebo for a period of 3 months. 12.5 mg/day and 25 mg/day of paroxetine extended-release tablets, 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.
The efficacy of paroxetine extended-release tablets 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 paroxetine extended-release tablets was established in a 12-week trial, in adult outpatients with social anxiety disorder (DSM-IV). Paroxetine extended-release tablets have not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY: Clinical Trials).
The effectiveness of paroxetine extended-release tablets 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 paroxetine extended-release tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
The efficacy of paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of paroxetine extended-release tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Paroxetine extended-release tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine extended-release tablets. Paroxetine extended-release tablets should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of paroxetine extended-release tablets with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with paroxetine extended-release tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- 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 Paroxetine Extended-Release 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.
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 paroxetine extended-release tablets 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: Serotonin Syndrome).
Infants exposed to SSRIs in 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. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including paroxetine extended-release tablets) in pregnancy and PPHN. Other studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with paroxetine extended-release tablets, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS, Postmarketing Reports).
Discontinuation of Treatment With Paroxetine Extended-Release Tablets: Adverse events while discontinuing therapy with paroxetine extended-release tablets were not systematically evaluated in most clinical trials; however, in recent placebo-controlled clinical trials utilizing daily doses of paroxetine extended-release tablets up to 37.5 mg/day, spontaneously reported adverse events while discontinuing therapy with paroxetine extended-release tablets 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 paroxetine extended-release tablets, at an incidence of 2% or greater for paroxetine extended-release tablets 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 paroxetine extended-release tablets (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 paroxetine extended-release tablets.
During marketing of paroxetine extended-release tablets 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 paroxetine extended-release 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 (see DOSAGE AND ADMINISTRATION).
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients.
Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine's irreversible inhibition of CYP2D6 (see Drug Interactions). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
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 paroxetine extended-release tablets. 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 PRECAUTIONS: Geriatric Use). Discontinuation of paroxetine extended-release tablets 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.
Bone Fracture: Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising.
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 paroxetine extended-release 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 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 paroxetine extended-release tablets are prescribed for patients with narrow angle glaucoma.
Paroxetine extended-release tablets 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 <30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients: Paroxetine extended-release tablets 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 paroxetine extended-release tablets and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking paroxetine tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine extended-release tablets and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine extended-release tablets. 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 paroxetine extended-release tablets.
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 paroxetine extended-release tablets do not affect their ability to engage in such activities.
Completing Course of Therapy: While patients may notice improvement with use of paroxetine extended-release tablets 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 paroxetine extended-release tablets.
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 Effects 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 Interactions: Tryptophan: 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets are coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John's Wort (see WARNINGS: Serotonin Syndrome).
The concomitant use of paroxetine extended-release tablets with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS). The concomitant use of paroxetine extended-release tablets 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 paroxetine extended-release tablets and warfarin should be undertaken with caution (see PRECAUTIONS: 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets are 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 paroxetine extended-release tablets with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine extended-release tablets or the other drug.
Therefore, coadministration of paroxetine extended-release tablets 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, 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 (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS).
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 [TCAs]).
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 paroxetine extended-release tablets, 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 paroxetine extended-release tablets (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6).
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of paroxetine extended-release tablets 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 paroxetine extended-release tablets.
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 paroxetine extended-release tablets 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 to 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 paroxetine extended-release tablets.
Carcinogenesis, Mutagenesis, 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 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: Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men.
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 Effects 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 paroxetine extended-release tablets are 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 immediate release paroxetine tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine extended-release 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 extended-release tablets.
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 DOSAGE AND ADMINISTRATION: Discontinuation of Treatment With Paroxetine Extended-Release Tablets).
Geriatric Use: SSRIs and SNRIs, including paroxetine extended-release tablets, 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, paroxetine extended-release tablets were 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 3).
Paroxetine extended-release tablets, 12.5 mg contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Incidence in Controlled Clinical Trials: Table 2 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with paroxetine extended-release tablets, 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 Paroxetine Extended-Release Tablets in a Pool of 2 Studies in Major Depressive DisorderAdverse events for which the paroxetine extended-release tablets 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.
,<1% means greater than zero and less than 1%.
Body System/Adverse Event
| % Reporting Event
|
| Paroxetine Extended-Release Tablets
(n = 212)
| Placebo
(n = 211)
|
Body as a Whole
|
|
|
Headache
| 27%
| 20%
|
Asthenia
| 14%
| 9%
|
| Infection Mostly flu.
| 8%
| 5%
|
Abdominal Pain
| 7%
| 4%
|
Back Pain
| 5%
| 3%
|
| Trauma A wide variety of injuries with no obvious pattern.
| 5%
| 1%
|
| Pain Pain in a variety of locations with no obvious pattern.
| 3%
| 1%
|
| Allergic Reaction Most frequently seasonal allergic symptoms.
| 2%
| 1%
|
Cardiovascular System
|
|
|
Tachycardia
| 1%
| 0%
|
| Vasodilatation Usually flushing.
| 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 Vision Mostly blurred vision.
| 5%
| 1%
|
Taste Perversion
| 2%
| 0%
|
Urogenital System
|
|
|
| Abnormal Ejaculation Based on the number of males or females. ,Mostly anorgasmia or delayed ejaculation.
| 26%
| 1%
|
| Female Genital Disorder, Mostly anorgasmia or delayed orgasm.
| 10%
| <1%
|
Impotence
| 5%
| 3%
|
Urinary Tract Infection
| 3%
| 1%
|
Menstrual Disorder
| 2%
| <1%
|
Vaginitis
| 2%
| 0%
|
Table 3. Treatment-Emergent Adverse Events Occurring in ≥5% of Patients Treated With Paroxetine Extended-Release Tablets in a Study of Elderly Patients With Major Depressive DisorderAdverse events for which the paroxetine extended-release tablets reporting incidence was less than or equal to the placebo incidence are not included. These events are nausea and respiratory disorder.
,<1% means greater than zero and less than 1%.
Body System/Adverse Event
| % Reporting Event
|
| Paroxetine Extended-Release Tablets
(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%
| <1%
|
Tremor
| 7%
| 0%
|
Skin and Appendages
|
|
|
Sweating
| 10%
| <1%
|
Urogenital System
|
|
|
| Abnormal Ejaculation Based on the number of males. ,Mostly anorgasmia or delayed ejaculation.
| 17%
| 3%
|
Impotence
| 9%
| 3%
|
Table 4. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine Extended-Release Tablets in a Pool of 3 Panic Disorder StudiesAdverse events for which the reporting rate for paroxetine extended-release tablets 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.
,<1% means greater than zero and less than 1%.
Body System/Adverse Event
| % Reporting Event
|
| Paroxetine Extended-Release Tablets
(n = 444)
| Placebo
(n = 445)
|
Body as a Whole
|
|
|
Asthenia
| 15%
| 10%
|
Abdominal Pain
| 6%
| 4%
|
| Trauma Various physical injuries.
| 5%
| 4%
|
Cardiovascular System
|
|
|
| Vasodilation Mostly flushing.
| 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%
|
| Hypertonia Mostly muscle tightness or stiffness.
| 2%
| <1%
|
Myoclonus
| 2%
| <1%
|
Respiratory System
|
|
|
Sinusitis
| 8%
| 5%
|
Yawn
| 3%
| 0%
|
Skin and Appendages
|
|
|
Sweating
| 7%
| 2%
|
Special Senses
|
|
|
| Abnormal Vision Mostly blurred vision.
| 3%
| <1%
|
Urogenital System
|
|
|
| Abnormal Ejaculation Based on the number of male patients. ,Mostly anorgasmia or delayed ejaculation.
| 27%
| 3%
|
Impotence
| 10%
| 1%
|
| Female Genital Disorders Based on the number of female patients. ,Mostly anorgasmia or difficulty achieving orgasm.
| 7%
| 1%
|
Urinary Frequency
| 2%
| <1%
|
Urination Impaired
| 2%
| <1%
|
Vaginitis
| 1%
| <1%
|
Table 5. Treatment-Emergent Adverse Effects Occurring in ≥1% of Patients Treated With Paroxetine Extended-Release Tablets in a Social Anxiety Disorder StudyAdverse events for which the reporting rate for paroxetine extended-release tablets 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.
,<1% means greater than zero and less than 1%.
Body System/Adverse Event
| % Reporting Event
|
| Paroxetine Extended-Release Tablets
(n = 186)
| Placebo
(n = 184)
|
Body as a Whole
|
|
|
Headache
| 23%
| 17%
|
Asthenia
| 18%
| 7%
|
Abdominal Pain
| 5%
| 4%
|
Back Pain
| 4%
| 1%
|
| Trauma Various physical injuries.
| 3%
| <1%
|
| Allergic Reaction Most frequently seasonal allergic symptoms.
| 2%
| <1%
|
Chest Pain
| 1%
| <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%
| <1%
|
Decreased Appetite
| 1%
| <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%
| <1%
|
Paresthesia
| 1%
| <1%
|
Respiratory System
|
|
|
Yawn
| 2%
| 0%
|
Skin and Appendages
|
|
|
Sweating
| 14%
| 3%
|
Eczema
| 1%
| 0%
|
Special Senses
|
|
|
| Abnormal Vision Mostly blurred vision.
| 2%
| 0%
|
Abnormality of Accommodation
| 2%
| 0%
|
Urogenital System
|
|
|
| Abnormal Ejaculation Based on the number of male patients. ,Mostly anorgasmia or delayed ejaculation.
| 15%
| 1%
|
Impotence
| 9%
| 0%
|
| Female Genital Disorders Based on the number of female patients. ,Mostly anorgasmia or difficulty achieving orgasm.
| 3%
| 0%
|
Table 6. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine Extended-Release Tablets in a Pool of 3 Premenstrual Dysphoric Disorder Studies With Continuous Dosing or in 1 Premenstrual Dysphoric Disorder Study With Luteal Phase DosingAdverse events for which the reporting rate of paroxetine extended-release tablets 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.
,<1% means greater than zero and less than 1%.
,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 6 should be avoided.
Body System/Adverse Event
| % Reporting Event
|
| Continuous Dosing
| Luteal Phase Dosing
|
| Paroxetine Extended-
Release Tablets
(n = 681)
| Placebo
(n = 349)
| Paroxetine Extended-
Release Tablets
(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%
| <1%
| -
| -
|
Digestive System
|
|
|
|
|
Nausea
| 17%
| 7%
| 18%
| 2%
|
Diarrhea
| 6%
| 2%
| 6%
| 0%
|
Constipation
| 5%
| 1%
| 2%
| <1%
|
Dry Mouth
| 4%
| 2%
| 2%
| <1%
|
Increased Appetite
| 3%
| <1%
| -
| -
|
Decreased Appetite
| 2%
| <1%
| 2%
| 0%
|
Dyspepsia
| 2%
| 1%
| 2%
| 2%
|
Gingivitis
| -
| -
| 1%
| 0%
|
Metabolic and Nutritional Disorders
|
|
|
|
|
Generalized Edema
| -
| -
| 1%
| <1%
|
Weight Gain
| -
| -
| 1%
| <1%
|
Musculoskeletal System
|
|
|
|
|
Arthralgia
| 2%
| 1%
| -
| -
|
Nervous System
|
|
|
|
|
Libido Decreased
| 12%
| 5%
| 9%
| 6%
|
Somnolence
| 9%
| 2%
| 3%
| <1%
|
Insomnia
| 8%
| 2%
| 7%
| 3%
|
Dizziness
| 7%
| 3%
| 6%
| 3%
|
Tremor
| 4%
| <1%
| 5%
| 0%
|
Concentration Impaired
| 3%
| <1%
| 1%
| 0%
|
Nervousness
| 2%
| <1%
| 3%
| 2%
|
Anxiety
| 2%
| 1%
| -
| -
|
Lack of Emotion
| 2%
| <1%
| -
| -
|
Depression
| -
| -
| 2%
| <1%
|
Vertigo
| -
| -
| 2%
| <1%
|
Abnormal Dreams
| 1%
| <1%
| -
| -
|
Amnesia
| -
| -
| 1%
| 0%
|
Respiratory System
|
|
|
|
|
Sinusitis
| -
| -
| 4%
| 2%
|
Yawn
| 2%
| <1%
| -
| -
|
Bronchitis
| -
| -
| 2%
| 0%
|
Cough Increased
| 1%
| <1%
| -
| -
|
Skin and Appendages
|
|
|
|
|
Sweating
| 7%
| <1%
| 6%
| <1%
|
Special Senses
|
|
|
|
|
Abnormal Vision
| -
| -
| 1%
| 0%
|
Urogenital System
|
|
|
|
|
| Female Genital Disorders Mostly anorgasmia or difficulty achieving orgasm.
| 8%
| 1%
| 2%
| 0%
|
Menorrhagia
| 1%
| <1%
| -
| -
|
Vaginal Moniliasis
| 1%
| <1%
| -
| -
|
Menstrual Disorder
| -
| -
| 1%
| 0%
|
Dose Dependency of Adverse Events: Table 7 shows results in PMDD trials of common adverse events, defined as events with an incidence of ≥1% with 25 mg of paroxetine extended-release tablets that was at least twice that with 12.5 mg of paroxetine extended-release tablets and with placebo.
Table 7. Incidence of Common Adverse Events in Placebo, 12.5 mg, and 25 mg of Paroxetine Extended-Release Tablets in a Pool of 3 Fixed-Dose PMDD Trials
| Paroxetine Extended-Release Tablets
25 mg
(n = 348)
| Paroxetine Extended-Release Tablets
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
|
| Paroxetine Extended-
Release Tablets
| Placebo
| Paroxetine Extended-
Release Tablets
| Placebo
| Paroxetine Extended-
Release Tablets
| Placebo
| Paroxetine Extended-
Release Tablets
| Placebo
| Paroxetine Extended-
Release Tablets
| 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%
| <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 paroxetine extended-release tablets 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 paroxetine extended-release tablets, 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets and none of 109 placebo patients experienced liver transaminase elevations of potential clinical concern.
Two of the patients treated with paroxetine extended-release tablets 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 paroxetine extended-release tablets and none of 445 placebo patients experienced liver transaminase elevations of potential clinical concern. Elevations in all 4 patients decreased substantially after discontinuation of paroxetine extended-release tablets. 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets who experienced an event of the type cited on at least 1 occasion while receiving paroxetine extended-release tablets. All reported events are included except those already listed in Tables 2 through 7 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 listed 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 listed in the tabulated results from placebo-controlled trials appear in this listing); 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 listed for controlled-release paroxetine are included. The extent to which these events may be associated with paroxetine extended-release tablets is unknown.
Events are listed 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 listed 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, Stevens-Johnson 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, restless legs syndrome (RLS), 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), vasculitic syndromes (such as Henoch-SchÖnlein purpura) and premature births in pregnant women. 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.
Social Anxiety Disorder: Usual Initial Dosage: Paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets 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 paroxetine extended-release tablets should remain on it. Although the efficacy of paroxetine extended-release tablets 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 Disorder: Usual Initial Dosage: Paroxetine extended-release tablets should be administered as a single daily dose, usually in the morning, with or without food. Paroxetine extended-release tablets 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 paroxetine extended-release tablets should not be chewed or crushed, and should be swallowed whole.
Maintenance/Continuation Therapy: The effectiveness of paroxetine extended-release tablets 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 Populations: Treatment of Pregnant Women During the Third Trimester: Neonates exposed to paroxetine extended-release tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic Impairment: The recommended initial dose of paroxetine extended-release tablets 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 a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with paroxetine extended-release tablets. Conversely, at least 14 days should be allowed after stopping paroxetine extended-release tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
Use of Paroxetine Extended-Release Tablets With Other MAOIs, Such as Linezolid or Methylene Blue: Do not start paroxetine extended-release tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving therapy with paroxetine extended-release tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, paroxetine extended-release tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with paroxetine extended-release tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with paroxetine hydrochloride is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Discontinuation of Treatment With Paroxetine Extended-Release Tablets: Symptoms associated with discontinuation of immediate-release paroxetine hydrochloride or paroxetine extended-release tablets have been reported (see PRECAUTIONS: Discontinuation of Treatment with Paroxetine Extended-Release Tablets). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine extended-release tablets are 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.
Manufactured for:
Lupin Pharmaceuticals, Inc.
Baltimore, Maryland 21202
United States
Manufactured by:
Lupin Limited
Pithampur (M.P.) - 454 775
India
January 2017 ID#: 250647
Medication Guide
PAROXETINE (pa rox' e teen) EXTENDED-RELEASE TABLETS, USP
Rx Only
Paroxetine extended-release tablets, 12.5 mg contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Read the Medication Guide that comes with paroxetine extended-release tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.
What is the most important information I should know about paroxetine extended-release tablets?
Paroxetine extended-release tablets and other antidepressant medicines may cause serious side effects, including:
1. Suicidal thoughts or actions:
- Paroxetine extended-release tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment or when the dose is changed.
- Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions.
- Watch for these changes, and call your healthcare provider right away if you notice:
• New or sudden changes, in mood, behavior, actions, thoughts, or feelings, especially if severe.
• Pay particular attention to such changes when paroxetine extended-release tablets is started or when the dose is changed.
Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:
- attempts to commit suicide
- acting on dangerous impulses
- acting aggressive or violent
- thoughts about suicide or dying
- new or worse depression
- new or worse anxiety or panic attacks
- feeling agitated, restless, angry, or irritable
- trouble sleeping
- an increase in activity and talking more than what is normal for you
- other unusual changes in behavior or mood
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Paroxetine extended-release tablets may be associated with these serious side effects:
2. Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This condition can be life-threatening and may include:
