Paroxetine

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Paroxetine


Generic Name: Paroxetine hydrochloride
Dosage Form: Tablets

Suicidality in Children and Adolescents

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Paroxetine tablets USP or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Paroxetine tablets USP are not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS—Pediatric Use.)

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4,400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

Paroxetine Description

Paroxetine hydrochloride is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4"-fluorophenyl)-3S-[(3",4"-methylenedioxyphenoxy) methyl] piperidine hydrochloride anhydrous and has the empirical formula of C19H20FNO3•HCl. The molecular weight is 365.8 (anhydrous) (329.4 as free base). The structural formula of Paroxetine hydrochloride is:

Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 116° to 120°C and a solubility of 5.4 mg/mL in water.

Each film-coated tablet, for oral administration, contains Paroxetine hydrochloride equivalent to Paroxetine as follows: 10 mg; 20 mg; 30 mg; 40 mg. Inactive ingredients consist of anhydrous lactose, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, sodium starch glycolate and titanium dioxide.

Paroxetine tablets USP comply with USP Related Impurities Test 1.

Paroxetine - Clinical Pharmacology

Pharmacodynamics

The efficacy of Paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that Paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that Paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that Paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs.

Because the relative potencies of Paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive.

Pharmacokinetics

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of Paroxetine daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of Paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

Absorption and Distribution

Paroxetine is equally bioavailable from the oral suspension and tablet.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state Paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax,Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes Paroxetine is readily saturable.

The effects of food on the bioavailability of Paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.

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.

Metabolism and Excretion

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of Paroxetine hydrochloride. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses 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).

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.

Other Clinical Pharmacology Information

Specific Populations

Renal and Liver Disease

Increased plasma concentrations of Paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. was approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, Cmax).

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).

Elderly Patients

In a multiple-dose study in the elderly at daily Paroxetine doses of 20, 30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

In vitro drug interaction studies reveal that Paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that Paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see PRECAUTIONS—Drug Interactions).

Clinical Trials

Major Depressive Disorder

The efficacy of Paroxetine as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, Paroxetine was shown to be significantly more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor.

A study of outpatients with major depressive disorder who had responded to Paroxetine (HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on Paroxetine or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking Paroxetine (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.

Obsessive Compulsive Disorder

The effectiveness of Paroxetine in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of Paroxetine/day demonstrated that daily doses of Paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60 mg Paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing Paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving Paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients.

The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1.

Outcome Classification (%) on CGI-Global Improvement Item

for Completers in Study 1

Outcome Classification

Placebo (n = 74)

Paroxetine 20 mg (n = 75)

Paroxetine 40 mg (n = 66)

Paroxetine 60 mg (n = 66)

Worse

14%

7%

7%

3%

No Change

44%

35%

22%

19%

Minimally Improved

24%

33%

29%

34%

Much Improved

11%

18%

22%

24%

Very Much Improved

7%

7%

20%

20%

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

The long-term maintenance effects of Paroxetine in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on Paroxetine during the 3-month double-blind phase and a 6-month extension on open-label Paroxetine (20 to 60 mg/day) were randomized to either Paroxetine or placebo in a 6-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.

Panic Disorder

The effectiveness of Paroxetine in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, Paroxetine was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score.

Study 1 was a 10-week dose-range finding study; patients were treated with fixed Paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving Paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients.

Study 2 was a 12-week flexible-dose study comparing Paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of Paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients.

Study 3 was a 12-week flexible-dose study comparing Paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the Paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients.

In both Studies 2 and 3, the mean Paroxetine dose for completers at endpoint was approximately 40 mg/day of Paroxetine.

Long-term maintenance effects of Paroxetine in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either Paroxetine (10, 20, or 40 mg/day) 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.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

Social Anxiety Disorder

The effectiveness of Paroxetine in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of Paroxetine compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS).

Studies 1 and 2 were flexible-dose studies comparing Paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of Paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the Paroxetine- and placebo-treated patients, respectively.

Study 3 was a 12-week study comparing fixed Paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day.

Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.

Generalized Anxiety Disorder

The effectiveness of Paroxetine in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).

Study 1 was an 8-week study comparing fixed Paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of Paroxetine were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose.

Study 2 was a flexible-dose study comparing Paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing Paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of Paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.

Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.

In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of Paroxetine, were randomized to continuation of Paroxetine at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or withdrawal due to lack of efficacy. Patients receiving continued Paroxetine experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.

Indications and Usage for Paroxetine

Major Depressive Disorder

Paroxetine is indicated for the treatment of major depressive disorder.

The efficacy of Paroxetine in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The effects of Paroxetine in hospitalized depressed patients have not been adequately studied.

The efficacy of Paroxetine in maintaining a response in major depressive disorder for up to 1 year was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who elects to use Paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Obsessive Compulsive Disorder

Paroxetine is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of Paroxetine was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).

Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to Paroxetine showed a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who elects to use Paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Panic Disorder

Paroxetine is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of Paroxetine was established in three 10- to 12-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to Paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who prescribes Paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Social Anxiety Disorder

Paroxetine is indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person"s normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.

The efficacy of Paroxetine was established in three 12-week trials in adult patients with social anxiety disorder (DSM-IV). Paroxetine has not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY—Clinical Trials).

The effectiveness of Paroxetine 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 for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Generalized Anxiety Disorder

Paroxetine is indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

The efficacy of Paroxetine in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. Paroxetine has not been studied in children or adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance.

The efficacy of Paroxetine in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking Paroxetine and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who elects to use Paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Contraindications

Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).

Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

Paroxetine is contraindicated in patients with a hypersensitivity to Paroxetine or any of the inactive ingredients in Paroxetine.

Warnings

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4,400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months.  It is unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment With Paroxetine, for a description of the risks of discontinuation of Paroxetine).

Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.Such monitoring should include daily observation by families and caregivers. Prescriptions for Paroxetine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Paroxetine is not approved for use in treating bipolar depression.

Potential for Interaction With Monoamine Oxidase Inhibitors

In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with Paroxetine, limited animal data on the effects of combined use of Paroxetine and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that Paroxetine not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. At least 2 weeks should be allowed after stopping Paroxetine before starting an MAOI.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with use of Paroxetine, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of Paroxetine with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS—Potential for Interaction with Monoamine Oxidase Inhibitors).

If concomitant use of Paroxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS—Drug Interactions).

The concomitant use of Paroxetine with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS—Drug Interactions).

Potential Interaction With Thioridazine

Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes−type arrhythmias, and sudden death. This effect appears to be dose related.

An in vivo study suggests that drugs which inhibit CYP2D6, such as Paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that Paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).

Usage in Pregnancy

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). 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 1.1-2.8). 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 US 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 0.8-2.9). 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 1.2-2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for Paroxetine vs. 2% for other antidepressants.

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 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 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 of persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 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 AND ADMINISTRATION).

Physicians should note that in a prospective longitudinal study of 201 women with a history 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.

Precautions

General

Activation of Mania/Hypomania

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

Seizures

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

Discontinuation of Treatment With Paroxetine

Recent clinical trials supporting the various approved indications for Paroxetine employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD 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 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 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. 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.

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

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

Abnormal Bleeding

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 nonsteroidal 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.

Use in Patients With Concomitant Illness

Clinical experience with Paroxetine in patients with certain concomitant systemic illness is limited. Caution is advisable in using Paroxetine 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. 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 is prescribed for patients with narrow angle glaucoma.

Paroxetine 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 in double-blind, placebo-controlled trials, however, did not indicate that Paroxetine is associated with the development of significant ECG abnormalities. Similarly, Paroxetine 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 tablets USP 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 and triptans, tramadol, or other serotonergic agents.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Paroxetine and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Paroxetine. 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.

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 observe 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 (NSAIDs, Aspirin, Warfarin, etc.)

Patients should be cautioned about the concomitant use of Paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation since the 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 Paroxetine 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 does not affect their ability to engage in such activities.

Completing Course of Therapy

While patients may notice improvement with treatment with Paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed.

Concomitant Medication

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.

Alcohol

Although Paroxetine 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.

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 and Nonteratogenic Effects).

Nursing

Patients should be advised to notify their physician if they are breast-feeding 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 Paroxetine. Consequently, concomitant use of Paroxetine 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 Paroxetine 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. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and Paroxetine is contraindicated (see CONTRAINDICATIONS).

Serotonergic Drugs

Based on the mechanism of action of Paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when Paroxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John"s Wort (see WARNINGS—Serotonin Syndrome). The concomitant use of Paroxetine 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 and warfarin should be undertaken with caution (see 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 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 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 after the 20-mg 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 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 of Paroxetine 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 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 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 these drugs are coadministered; 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 si




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