PEXEVA - paroxetine mesylate tablet, film coated 
Noven Therapeutics, LLC

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PEXEVA®
Brand of
(paroxetine mesylate) tablets

DESCRIPTION

PEXEVA® (paroxetine mesylate) is an orally administered psychotropic drug with a chemical structure related to paroxetine hydrochloride (Paxil®). It is the mesylate salt of a phenylpiperidine compound identified chemically as (-)-trans -4R- (4'-fluorophenyl) - 3S - [(3', 4'-methylenedioxyphenoxy) methyl] piperidine mesylate and has the empirical formula of C19H20FNO3•CH3SO3H. The molecular weight is 425.5 (329.4 as free base). The structural formula is:

Paroxetine mesylate is an odorless, off-white powder, having a melting point range of 147° to 150°C and a solubility of more than 1 g/ml in water.

Tablets

Each oval, film-coated tablet contains paroxetine mesylate equivalent to paroxetine as follows: 10 mg (white); 20 mg (scored, dark orange); 30 mg (yellow); 40 mg (rose). Inactive ingredients consist of dibasic calcium phosphate, hydroxypropyl methylcellulose, hydroxypropylcellulose, magnesium stearate, sodium starch glycolate, titanium dioxide, ferric oxide red (C.I. 77491) (20 mg and 40 mg only) and ferric oxide yellow (C.I. 77492) (20 mg, 30 mg, and 40 mg only).

CLINICAL PHARMACOLOGY

Pharmacodynamics

The efficacy of paroxetine in the treatment of MDD, 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 mesylate is completely absorbed after oral dosing of the mesylate salt. In a study in which normal male subjects (n=25) received paroxetine 30 mg tablets daily for 24 days, steady-state paroxetine concentrations were achieved by approximately 13 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T1/2 were 81.3 ng/ml (CV 41%), 8.1 hr. (CV 56%), 43.2 ng/ml (CV 52%), and 33.2 hr. (CV 52%), respectively. The steady-state Cmax and Cmin values were about 7 and 10 times what would be predicted from single dose studies. Steady-state drug exposure based on AUC0-24 was about 10 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable.

In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 to 40 mg daily for the elderly and 20 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 were only about 2 to 3 times greater than doubled.

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 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 cytochrome 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.

Distribution: Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.

Protein Binding: 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.

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 MDD has been established in 6 placebo-controlled studies of patients with MDD (ages 18 to 73). In these studies paroxetine was shown to be significantly more effective than placebo in treating MDD 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 MDD 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 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 the placebo-treated patients.

The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impressions (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 PD was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had PD (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown to be significantly more effective than placebo in treating PD 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 PD 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.

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 GAD (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 GAD, 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

Major Depressive Disorder

PEXEVA® (paroxetine mesylate) is indicated for the treatment of MDD.

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 MDD (see CLINICAL PHARMACOLOGY). 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 MDD for up to 1 year was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use PEXEVA® (paroxetine mesylate) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Obsessive Compulsive Disorder

PEXEVA® (paroxetine mesylate) is indicated for the treatment of obsessions and compulsions in patients with 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 OCD (see CLINICAL PHARMACOLOGY—Clinical Trials).

OCD 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 PEXEVA® (paroxetine mesylate) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Panic Disorder

PEXEVA® (paroxetine mesylate) is indicated for the treatment of PD, with or without agoraphobia, as defined in DSM-IV. PD 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 PD patients whose diagnoses corresponded to the DSM-IIIR category of PD (see CLINICAL PHARMACOLOGY—Clinical Trials).

PD (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, 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 PD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who prescribes PEXEVA® (paroxetine mesylate) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

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 reevaluate 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).

PEXEVA® (paroxetine mesylate) tablets are contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in PEXEVA® (paroxetine mesylate) tablets.

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. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behaviour (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

TABLE 1

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
	Increases Compared to Placebo
<18	14 additional cases
18-24	5 additional cases
	Decreases Compared to Placebo
25-64	1 fewer case
≥65	6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and 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.

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 PEXEVA® (paroxetine mesylate), for a description of the risks of discontinuation of PEXEVA® (paroxetine mesylate)).

Families and caregivers of 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for PEXEVA® (paroxetine mesylate) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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 PEXEVA® (paroxetine mesylate) 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 a 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 a MAOI, or within 14 days of discontinuing treatment with a MAOI. At least 2 weeks should be allowed after stopping PEXEVA® (paroxetine mesylate) before starting a MAOI.

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including PEXEVA® (paroxetine mesylate) treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. 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). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

The concomitant use of PEXEVA® (paroxetine mesylate) with MAOIs intended to treat depression is contraindicated.

If concomitant treatment of PEXEVA® (paroxetine mesylate) with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The concomitant use of PEXEVA® (paroxetine mesylate) with serotonin precursors (such as tryptophan) is not recommended.

Treatment with PEXEVA® (paroxetine mesylate) and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

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.

Anin vivostudy 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. 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 PEXEVA® (paroxetine mesylate)). 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.

In two studies, the cardiovascular defects observed were 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. 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 5956 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.

In two large multi-center case-control studies using separate databases, infants born to women who had first trimester paroxetine exposure had a two- to three-fold increased risk of right ventricular outflow tract obstructions. In a study of 9622 infants with birth defects ascertained through birth defects surveillance systems in eight U.S. states and 4092 control infants, the odds ratio for right ventricular outflow tract obstruction was 2.5 (95% confidence interval 1.0-6.0) for infants exposed to paroxetine in the first trimester of pregnancy compared to infants with no SSRI exposure. In a study of 9849 infants with birth defects and 5860 control infants without birth defects participating in the Slone Epidemiology Center Birth Defects Study, the odds ratio for right ventricular outflow tract obstruction was 3.3 (95% confidence interval 1.3-8.8) for infants exposed to paroxetine in the first trimester of pregnancy compared to infants with no antidepressant exposure.

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 PEXEVA® (paroxetine mesylate) and other SSRIs or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS—Potential for Interaction With Monoamine Oxidase Inhibitors).

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 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 6-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 of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

PRECAUTIONS

General

Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 1.0% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of MDD, paroxetine should be used cautiously in patients with a history of mania.

Seizures: During premarketing testing, seizures occurred in 0.1% of paroxetine-treated patients, a rate similar to that associated with other drugs effective in the treatment of MDD. 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 PEXEVA® (paroxetine mesylate): 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 and PTSD 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 for paroxetine at an incidence 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 (serotonin and norepinephrine reuptake inhibitors), 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 (eg, 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: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PEXEVA® (paroxetine mesylate). 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 Geriatric Use). Discontinuation of PEXEVA® (paroxetine mesylate) 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 PEXEVA® (paroxetine mesylate), may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants 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 PEXEVA® (paroxetine mesylate) and 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 the 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

Patients should be cautioned about the concomitant use of PEXEVA® (paroxetine mesylate) 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.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PEXEVA® (paroxetine mesylate) and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for PEXEVA® (paroxetine mesylate). 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 PEXEVA® (paroxetine mesylate).

PEXEVA® (paroxetine mesylate) 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.

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 (NSAIDs, Aspirin, Warfarin, etc.): Patients should be cautioned about concomitant use of paroxetine with 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 paroxetine therapy does not affect their ability to engage in such activities.

Completing Course of Therapy: While patients may notice improvement with paroxetine therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Concomitant Medication: Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Patients should be made aware that paroxetine, the active ingredient in PEXEVA® (paroxetine mesylate), is also the active ingredient of Paxil® and that these two medications should not be taken concomitantly.

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 PEXEVA® (paroxetine mesylate).

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.

Paxil® (paroxetine hydrochloride)

Paroxetine, the active ingredient in PEXEVA® (paroxetine mesylate), is also the active ingredient of Paxil®. Thus, these two agents should not be coadministered.

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.

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.

Pimozide: In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, coadministration 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 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.

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 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 qd) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg tid) 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 qd for 14 days), paroxetine AUC and T1/2 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 paroxetine dosage adjustment 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 qd for 14 days), paroxetine AUC and T1/2 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 qd 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 Cytochrome CYP2D6: Many drugs, including most drugs effective in the treatment of MDD (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 one study, daily dosing of paroxetine (20 mg qd) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T1/2 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 one 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 it is given with paroxetine.

Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug.

Therefore, coadministration of PEXEVA® (paroxetine mesylate) with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of MDD (eg, nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (eg, propafenone, flecainide, and encainide), or that inhibit this enzyme (eg, 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).

At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes, which, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS—Tricyclic Antidepressants).

Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome 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 3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic Antidepressants (TCA): Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with PEXEVA® (paroxetine mesylate), 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 PEXEVA® (paroxetine mesylate). (See PRECAUTIONS—Drugs Metabolized by Cytochrome CYP2D6).

Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of PEXEVA® (paroxetine mesylate) 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 PEXEVA® (paroxetine mesylate) 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 PEXEVA® (paroxetine mesylate).

Lithium—A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, since there is little clinical experience, the concurrent administration of paroxetine and lithium should be undertaken with caution.

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 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 paroxetine (30 mg qd) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral qd) 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 bid) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine (30 mg qd) 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 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—Coadministration 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.

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 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for MDD and GAD on a mg/m2 basis. Because the MRHD for MDD is slightly less than that for OCD (50 mg vs 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. 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 groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.

Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.

Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for MDD and GAD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for MDD and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2 basis).

Pregnancy

Pregnancy Category D (see WARNINGS—Usage in Pregnancy: Teratogenic 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 PEXEVA® (paroxetine mesylate) is 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 paroxetine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine mesylate in a child or adolescent must balance the potential risks with the clinical need.

In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.

Events reported upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine 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 Discontinuation of Treatment with Paroxetine).

Geriatric Use

In worldwide premarketing paroxetine clinical trials, 17% of paroxetine-treated patients (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

SSRIs and SNRIs, including PEXEVA® (paroxetine mesylate), 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).

ADVERSE REACTIONS

Associated with Discontinuation of Treatment

Twenty percent (1199/6145) of patients treated with paroxetine in worldwide clinical trials in MDD and 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine in worldwide trials in OCD, PD, and GAD, respectively, discontinued treatment due to an adverse event. The most common events (≥1%) associated with discontinuation and considered to be drug related (ie, those events associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) included the following:

Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not >1% or was not greater than or equal to two times the incidence of placebo.
1 Incidence corrected for gender.
	MDD		OCD		PD		GAD
	Paroxetine	Placebo	Paroxetine	Placebo	Paroxetine	Placebo	Paroxetine	Placebo
CNS
Somnolence	2.3%	0.7%	-	-	1.9%	0.3%	2.0%	0.2%
Insomnia	-	-	1.7%	0%	1.3%	0.3%	-	-
Agitation	1.1%	0.5%	-	-	-	-	-	-
Tremor	1.1%	0.3%	-
Dizziness	-	-	1.5%	0%	-	-	1.0%	0.2%
Gastrointestinal
Constipation	-	-	1.1%	0%	-	-	-	-
Nausea	3.2%	1.1%	1.9%	0%	3.2%	1.2%	2.0%	0.2%
Diarrhea	1.0%	0.3%	-	-	-	-	-	-
Dry mouth	1.0%	0.3%	-	-	-	-	-	-
Vomiting	1.0%	0.3%	-	-	-	-	-	-
Other
Asthenia	1.6%	0.4%	1.9%	0.4%	-	-	1.8%	0.2%
Abnormal       Ejaculation 1	1.6%	0%	2.1%	0%	-	-	2.5%	0.5%
Sweating	1.0%	0.3%	-	-	-	-	1.1%	0.2%
Impotence1	-	-	1.5%	0%	-	-	-	-

Commonly Observed Adverse Events

Major Depressive Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 2 below) were: asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders.

Obsessive Compulsive Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that of placebo, derived from Table 3 below) were: nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.

Panic Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 3 below) were: asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.

Generalized Anxiety Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 4) were: asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.

Incidence in Controlled Clinical Trials

The prescriber should be aware that the figures in the tables following 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 populations studied.

Major Depressive Disorder

Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

TABLE 2

1 Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”), trauma, and vomiting.
2 Includes mostly “lump in throat” and “tightness in throat.”
3 Percentage corrected for gender.
4 Mostly “ejaculatory delay.”
5 Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction” and “impotence.”
6 Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7 Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for MDD1
Body System	Preferred Term	Paroxetine (n=421)	Placebo (n=421)
Body as a Whole	Headache	18%	17%
	Asthenia	15%	6%
Cardiovascular	Palpitation	3%	1%
	Vasodilation	3%	1%
Dermatologic	Sweating	11%	2%
	Rash	2%	1%
Gastrointestinal	Nausea	26%	9%
	Dry Mouth	18%	12%
	Constipation	14%	9%
	Diarrhea	12%	8%
	Decreased Appetite	6%	2%
	Flatulence	4%	2%
	Oropharynx Disorder2	2%	0%
	Dyspepsia	2%	1%
Musculoskeletal	Myopathy	2%	1%
	Myalgia	2%	1%
	Myasthenia	1%	0%
Nervous System	Somnolence	23%	9%
	Dizziness	13%	6%
	Insomnia	13%	6%
	Tremor	8%	2%
	Nervousness	5%	3%
	Anxiety	5%	3%
	Paresthesia	4%	2%
	Libido Decreased	3%	0%
	Drugged Feeling	2%	1%
	Confusion	1%	0%
Respiration	Yawn	4%	0%
Special Senses	Blurred Vision	4%	1%
	Taste Perversion	2%	0%
Urogenital System	Ejaculatory Disturbance3,4	13%	0%
	Other Male Genital Disorders 3,5	10%	0%
	Urinary Frequency	3%	1%
	Urination Disorder 6	3%	0%
	Female Genital Disorders 3,7	2%	0%

Obsessive Compulsive Disorder and Panic Disorder

Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 to 60 mg/day or among patients with PD on paroxetine who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 to 60 mg/day.

TABLE 3

1 Events reported by at least 2% of OCD or PD paroxetine-treated patients are included, except the following events which had an incidence on placebo ≥ paroxetine [OCD]: abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [PD]: abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation.
2 Percentage corrected for gender.
Treatment-Emergent Adverse Experience Incidence in Clinical Trials for Obsessive Compulsive Disorder and Panic Disorder 1
		Obsessive Compulsive Disorder		Panic Disorder
Body System	Preferred Term	Paroxetine (n=542)	Placebo (n=265)	Paroxetine (n=469)	Placebo (n=324)
Body as a Whole	Asthenia	22%	14%	14%	5%
	Abdominal Pain	-	-	4%	3%
	Chest Pain	3%	2%	-	-
	Back Pain	-	-	3%	2%
	Chills	2%	1%	2%	1%
Cardiovascular	Vasodilation	4%	1%	-	-
	Palpitation	2%	0%	-	-
Dermatologic	Sweating	9%	3%	14%	6%
	Rash	3%	2%	-	-
Gastrointestinal	Nausea	23%	10%	23%	17%
	Dry Mouth	18%	9%	18%	11%
	Constipation	16%	6%	8%	5%
	Diarrhea	10%	10%	12%	7%
	Decreased Appetite	9%	3%	7%	3%
	Increased Appetite	4%	3%	2%	1%
Nervous System	Insomnia	24%	13%	18%	10%
	Somnolence	24%	7%	19%	11%
	Dizziness	12%	6%	14%	10%
	Tremor	11%	1%	9%	1%
	Nervousness	9%	8%	-	-
	Libido Decreased	7%	4%	9%	1%
	Agitation	-	-	5%	4%
	Anxiety	-	-	5%	4%
	Abnormal Dreams	4%	1%	-	-
	Concentration Impaired	3%	2%	-	-
	Depersonalization	3%	0%	-	-
	Myoclonus	3%	0%	3%	2%
	Amnesia	2%	1%	-	-
Respiratory System	Rhinitis	-	-	3%	0%
Special Senses	Abnormal Vision	4%	2%	-	-
	Taste Perversion	2%	0%	-	-
Urogenital System	Abnormal Ejaculation2	23%	1%	21%	1%
	Female Genital Disorder2	3%	0%	9%	1%
	Impotence2	8%	1%	5%	0%
	Urinary Frequency	3%	1%	2%	0%
	Urination Impaired	3%	0%	-	-
	Urinary Tract Infection	2%	1%	2%	1%

Generalized Anxiety Disorder

Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day.

TABLE 4

1 Events reported by at least 2% of GAD patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis.
2 Percentage corrected for gender.
Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized Anxiety Disorder1
Body System	Preferred Term	Paroxetine (n=735)	Placebo (n=529)
Body as a Whole	Asthenia	14%	6%
	Headache	17%	14%
	Infection	6%	3%
Cardiovascular	Vasodilation	3%	1%
Dermatologic	Sweating	6%	2%
Gastrointestinal	Nausea	20%	5%
	Dry Mouth	11%	5%
	Constipation	10%	2%
	Diarrhea	9%	7%
	Decreased Appetite	5%	1%
	Vomiting	3%	2%
Nervous System	Insomnia	11%	8%
	Somnolence	15%	5%
	Dizziness	6%	5%
	Tremor	5%	1%
	Nervousness	4%	3%
	Libido Decreased	9%	2%
Respiratory System	Respiratory Disorder	7%	5%
	Sinusitis	4%	3%
	Yawn	4%	-
Special Senses	Abnormal Vision	2%	1%
Urogenital System	Abnormal Ejaculation2	25%	2%
	Female Genital Disorder2	4%	1%
	Impotence2	4%	3%

Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose study comparing paroxetine 10, 20, 30, and 40 mg/day with placebo in the treatment of MDD revealed a clear dose dependency for some of the more common adverse events associated with paroxetine use, as shown in the following table:

TABLE 5

*Rule for including adverse events in table: incidence at least 5% for one of paroxetine groups and ≥ twice the placebo incidence for at least one paroxetine group.
Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of MDD*
Body System/    Preferred Term	Placebo	Paroxetine
	n=51	10 mg n=102	20 mg n=104	30 mg n=101	40 mg n=102
Body as a Whole
Asthenia	0.0%	2.9%	10.6%	13.9%	12.7%
Dermatology
Sweating	2.0%	1.0%	6.7%	8.9%	11.8%
Gastrointestinal
Constipation	5.9%	4.9%	7.7%	9.9%	12.7%
Decreased Appetite	2.0%	2.0%	5.8%	4.0%	4.9%
Diarrhea	7.8%	9.8%	19.2%	7.9%	14.7%
Dry Mouth	2.0%	10.8%	18.3%	15.8%	20.6%
Nausea	13.7%	14.7%	26.9%	34.7%	36.3%
Nervous System
Anxiety	0.0%	2.0%	5.8%	5.9%	5.9%
Dizziness	3.9%	6.9%	6.7%	8.9%	12.7%
Nervousness	0.0%	5.9%	5.8%	4.0%	2.9%
Paresthesia	0.0%	2.9%	1.0%	5.0%	5.9%
Somnolence	7.8%	12.7%	18.3%	20.8%	21.6%
Tremor	0.0%	0.0%	7.7%	7.9%	14.7%
Special Senses
Blurred Vision	2.0%	2.9%	2.9%	2.0%	7.8%
Urogenital System
Abnormal Ejaculation	0.0%	5.8%	6.5%	10.6%	13.0%
Impotence	0.0%	1.9%	4.3%	6.4%	1.9%
Male Genital Disorders	0.0%	3.8	8.7%	6.4%	3.7%

In a fixed-dose study comparing placebo and paroxetine 20, 40, and 60 mg in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned. No new adverse events were observed in the paroxetine 60 mg dose group compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and paroxetine 10, 20, and 40 mg in the treatment of PD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation.

In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of GAD, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for the following adverse events: asthenia, constipation, and abnormal ejaculation.

In flexible dose studies, no new adverse events were observed in patients receiving paroxetine 60 mg compared to any of the other treatment groups.

Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, nausea and dizziness), but less to other effects (eg, dry mouth, somnolence, and asthenia).

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.

In placebo-controlled clinical trials involving more than 3200 patients the ranges for the reported incidence of sexual side effects in males and females with MDD, OCD, PD, social anxiety disorder, GAD, and post traumatic stress disorder (PTSD) are displayed in Table 6.

TABLE 6

Incidence of Sexual Adverse Events in Controlled Clinical Trials
	Paroxetine	Placebo
n (males)	1146	1042
Decreased Libido	6% - 15%	0% - 5%
Ejaculatory Disturbance	13% - 28%	0% - 2%
Impotence	2% - 9%	0% - 3%
n (females)	1822	1340
Decreased Libido	0% - 9%	0% - 2%
Orgasmic Disturbance	2% - 9%	0% - 1%

There are no adequate and well-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 had minimal (about 1 pound) weight loss vs smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature) were observed in patients treated with paroxetine in controlled clinical trials.

ECG Changes: In an analysis of ECGs obtained in 682 patients treated with 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 placebo-controlled clinical trials, patients treated with paroxetine exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine vs placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities.

Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo.

Other Events Observed During the Premarketing Evaluation of Paroxetine

During its premarketing assessment in MDD, multiple doses of paroxetine were administered to 6145 patients in phase 2 and 3 studies. The conditions and duration of exposure to 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. During premarketing clinical trials in OCD, PD, and GAD, 542, 469, and 735 patients, respectively, received multiple doses of paroxetine. 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 standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9089 patients exposed to multiple doses of paroxetine who experienced an event of the type cited on at least one occasion while receiving paroxetine. All reported events are included except those already listed in Tables 2 to 4, those reported in terms so general as to be uninformative, and those events where a drug cause was remote.

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 one 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 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section.

Body as a Whole:infrequent: allergic reaction, chills, face edema, malaise, neck pain; rare: adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System: frequent: hypertension, tachycardia; infrequent: bradycardia, hematoma, hypotension, migraine, syncope; rare: angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarction, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles. Digestive System:infrequent: bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; rare: aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, chlolelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System:rare: diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems:infrequent: anemia, leukopenia, lymphadenopathy, purpura; rare: abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional:frequent: weight gain; infrequent: edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased. Musculoskeletal System:frequent: arthralgia; infrequent: arthritis, arthrosis; rare: bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System:frequent: emotional lability, vertigo; infrequent: abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome. Respiratory System:infrequent: asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages:frequent: pruritus; infrequent: acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis, herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses:frequent: tinnitus; infrequent: abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia ptosis, retinal hemorrhage, taste loss, visual field defect. Urogenital System:infrequent: amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, pyuria, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis.

Postmarketing Reports

Voluntary reports of adverse events in patients taking paroxetine 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, 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, 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), and vasculitic syndromes (such as Henoch-Schönlein purpura).

There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class: Paroxetine is not a controlled substance.

Physical and Psychologic Dependence: Paroxetine has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of PEXEVA® (paroxetine mesylate) misuse or abuse (eg, development of tolerance, incrementations of dose, drug-seeking behavior).

OVERDOSAGE

Human Experience: Since the introduction of paroxetine in the US, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and, of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases which documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.

Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.

Overdosage Management: Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of MDD.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for paroxetine are known.

A specific caution involves patients who are taking or have recently taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Drugs Metabolized by Cytochrome CYP2D6 under PRECAUTIONS).

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

DOSAGE AND ADMINISTRATION

Major Depressive Disorder

Usual Initial Dosage: PEXEVA® (paroxetine mesylate) should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine in the treatment of MDD. As with all drugs effective in the treatment of MDD, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.

Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with paroxetine should remain on it. It is generally agreed that acute episodes of MDD require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Systematic evaluation of the efficacy of paroxetine has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.

Obsessive Compulsive Disorder

Usual Initial Dosage: PEXEVA® (paroxetine mesylate) should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine in the treatment of OCD. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY). OCD is a chronic condition, and it is reasonable to consider continuation 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.

Panic Disorder

Usual Initial Dosage: PEXEVA® (paroxetine mesylate) should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine in the treatment of PD is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with PD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY). PD is a chronic condition, and it is reasonable to consider continuation 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.

Generalized Anxiety Disorder

Usual Initial Dosage: PEXEVA® (paroxetine mesylate) should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week.

Maintenance Therapy: Systematic evaluation of continuing paroxetine for periods of up to 24 weeks in patients with GAD who had responded while taking paroxetine during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Special Populations

Treatment of Pregnant Women During the Third Trimester: Neonates exposed to paroxetine and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering paroxetine in the third trimester.

Dosage for Elderly or Debilitated, and Patients with Severe Renal or Hepatic Impairment: The recommended initial dose is 10 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 40 mg/day.

Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of a MAOI and initiation of paroxetine therapy. Similarly, at least 14 days should be allowed after stopping paroxetine before starting a MAOI.

Discontinuation of Treatment with PEXEVA® (paroxetine mesylate): Symptoms associated with discontinuation of paroxetine have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine is 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.

HOW SUPPLIED

Tablets:

Film-coated, modified-oval tablets as follows:

10 mg white tablets with the inscription POT 10 on one side.

 

NDC 68968-2010-1 Bottles of 30

20 mg dark orange tablets with the inscription POT 20 on one side.

The tablets are scored on both sides.

 

NDC 68968-2020-1 Bottles of 30

30 mg yellow tablets with the inscription POT 30 on one side.

 

NDC 68968-2030-1 Bottles of 30

40 mg rose tablets with the inscription POT 40 on one side.

 

NDC 68968-2040-1 Bottles of 30

Protect from Humidity. Store at 25°C (77°F); excursions permitted to 15°-30°C

(59° and 86°F) (see USP Controlled Room Temperature)

PI-2000-12

DATE OF ISSUANCE: 02/2009

Noven Therapeutics, LLC
Miami, FL 33186
©2009 Noven Therapeutics, LLC All rights reserved.

Rx only

Medication Guide

Antidepressant Medicines, Depression and other Serious Mental Illnesses,
and Suicidal Thoughts or Actions

Read the Medication Guide that comes with your, or your family member's, antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:

• All risks and benefits of treatment with antidepressant medicines
• All treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions?

1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?

• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Trouble sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking (mania)
• Other unusual changes in behavior or mood

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. To report SUSPECTED ADVERSE REACTIONS, contact Noven Therapeutics, LLC at 1-800-455-8070.

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

PEXEVA  paroxetine mesylate   tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68968-2010 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength paroxetine mesylate (paroxetine) Active 10 MILLIGRAM  In 1 TABLET dibasic calcium phosphate Inactive   hydroxypropyl methylcellulose Inactive   hydroxypropylcellulose Inactive   magnesium stearate Inactive   sodium starch glycolate Inactive   titanium dioxide Inactive

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Packaging # NDC Package Description Multilevel Packaging 1 68968-2010-1 30 TABLET In 1 BOTTLE None

PEXEVA  paroxetine mesylate   tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68968-2020 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength paroxetine mesylate (paroxetine) Active 20 MILLIGRAM  In 1 TABLET dibasic calcium phosphate Inactive   hydroxypropyl methylcellulose Inactive   hydroxypropylcellulose Inactive   magnesium stearate Inactive   sodium starch glycolate Inactive   titanium dioxide Inactive   ferric oxide red Inactive   ferric oxide yellow Inactive

Product Characteristics Color orange (ORANGE) Score 2 pieces Shape OVAL (OVAL) Size 4mm Flavor Imprint Code 20;mg;POT;20 Contains      Coating true Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 68968-2020-1 30 TABLET In 1 BOTTLE None

PEXEVA  paroxetine mesylate   tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68968-2030 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength paroxetine mesylate (paroxetine) Active 30 MILLIGRAM  In 1 TABLET dibasic calcium phosphate Inactive   hydroxypropyl methylcellulose Inactive   hydroxypropylcellulose Inactive   magnesium stearate Inactive   sodium starch glycolate Inactive   titanium dioxide Inactive   ferric oxide yellow Inactive

Product Characteristics Color yellow (YELLOW) Score no score Shape OVAL (OVAL) Size 4mm Flavor Imprint Code 30;mg;POT;30 Contains      Coating true Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 68968-2030-1 30 TABLET In 1 BOTTLE None

PEXEVA  paroxetine mesylate   tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68968-2040 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength paroxetine mesylate (paroxetine) Active 40 MILLIGRAM  In 1 TABLET dibasic calcium phosphate Inactive   hydroxypropyl methylcellulose Inactive   hydroxypropylcellulose Inactive   magnesium stearate Inactive   sodium starch glycolate Inactive   titanium dioxide Inactive   ferric oxide red Inactive   ferric oxide yellow Inactive

Product Characteristics Color red (RED) Score no score Shape OVAL (OVAL) Size 5mm Flavor Imprint Code 40;mg;POT;40 Contains      Coating true Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 68968-2040-1 30 TABLET In 1 BOTTLE None

Revised: 02/2009Noven Therapeutics, LLC