PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of C₁₉H₂₀FNO_3• HCl• 1/2H₂O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is:

Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120° to 138° C and a solubility of 5.4 mg/mL in water.

Tablets

Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.

Suspension for Oral Administration

Each 5 mL of orange-colored, orange-flavored liquid contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methylparaben, propylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, flavorings, FD&C Yellow No. 6 aluminum lake, and simethicone emulsion, USP.

Last updated on RxList: 3/20/2009

Major Depressive Disorder

PAXIL is indicated for the treatment of major depressive disorder.

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

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

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

Obsessive Compulsive Disorder

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

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

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

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

Panic Disorder

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

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

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

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

Social Anxiety Disorder

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

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

The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Generalized Anxiety Disorder

PAXIL 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 PAXIL in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. PAXIL 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 PAXIL in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking PAXIL 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 PAXIL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Posttraumatic Stress Disorder

PAXIL is indicated for the treatment of Posttraumatic Stress Disorder (PTSD).

The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebo-controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY - Clinical Trials).

PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Major Depressive Disorder

Usual Initial Dosage

PAXIL 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 PAXILin the treatment of major depressi ve disorder. As with all drugs effective in the treatment of major depressive disorder, 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 PAXIL should remain on it. It is generally agreed that acute episodes of major depressive disorder 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 PAXIL 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

PAXIL should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of PAXIL 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 PAXIL 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 - Clinical Trials). 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

PAXIL should be administered as a single daily dose with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic disorder 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 PAXIL. 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 panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY - Clinical Trials). Panic disorder 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.

Social Anxiety Disorder

Usual Initial Dosage

PAXIL should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY - Clinical Trials).

Maintenance Therapy

There is no body of evidence availa ble to answer the question of how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Generalized Anxiety Disorder

Usual Initial Dosage

PAXIL should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of PAXIL 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 PAXIL for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL 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.

Posttraumatic Stress Disorder

Usual Initial Dosage

PAXIL should be administered as a single daily dose with or without food, usually in the morning. The recommended starting dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and 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 PAXIL should remain on it. Although the efficacy of PAXIL beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Special Populations

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to PAXIL and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS). 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 Patients, 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 an MAOI and initiation of therapy with PAXIL. Similarly, at least 14 days should be allowed after stopping PAXILbefore starting an MAOI.

Discontinuation of Treatment With PAXIL

Symptoms associated with discontinuation of PAXIL have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which PAXIL 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.

NOTE: SHAKE SUSPENSION WELL BEFORE USING.

Tablets: Film-coated, modified-oval as follows:

10-mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.

NDC 0029-3210-13 Bottles of 30

20-mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.

NDC 0029-3211-13 Bottles of 30
NDC 0029-3211-59 Bottles of 90
NDC 0029-3211-21 SUP 100s (intended for institutional use only)

30-mg blue tablets engraved on the front with PAXIL and on the back with 30.

NDC 0029-3212-13 Bottles of 30

40-mg green tablets engraved on the front with PAXIL and on the back with 40.

NDC 0029-3213-13 Bottles of 30

Store tablets between 15° and 30° C (59° and 86° F).

Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.

NDC 0029-3215-48

Store suspension at or below 25° C (77° F).

January 2009. GlaxoSmithKline, Research Triangle Park, NC 27709.

Last updated on RxList: 3/20/2009

Associated With Discontinuation of Treatment

Twenty percent (1,199/6,145) of patients treated with PAXIL in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with PAXIL in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD, and PTSD, respectively, discontinued treatment due to an adverse event. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo) included the following:

	Major Depressive Disorder		OCD		Panic Disorder		Social Anxiety Disorder		Generalized Anxiety Disorder		PTSD
	PAXIL	Placebo	PAXIL	Placebo	PAXIL	Placebo	PAXIL	Placebo	PAXIL	Placebo	PAXIL	Placebo
CNS
Somnolence	2.3%	0.7%	—		1.9%	0.3%	3.4%	0.3%	2.0%	0.2%	2.8%	0.6%
Insomnia	—	—	1.7%	0%	1.3%	0.3%	3.1%	0%			—	—
Agitation	1.1%	0.5%	—								—	—
Tremor	1.1%	0.3%	—				1.7%	0%			1.0%	0.2%
Anxiety	—	—	—				1.1%	0%			—	—
Dizziness	—	—	1.5%	0%			1.9%	0%	1.0%	0.2%	—	—
Gastrointestinal
Constipation	—		1.1%	0%							—	—
Nausea	3.2%	1.1%	1.9%	0%	3.2%	1.2%	4.0%	0.3%	2.0%	0.2%	2.2%	0.6%
Diarrhea	1.0%	0.3%	—
Dry mouth	1.0%	0.3%	—								—	—
Vomiting	1.0%	0.3%	—				1.0%	0%			—	—
Flatulence							1.0%	0.3%			—	—
Other
Asthenia	1.6%	0.4%	1.9%	0.4%			2.5%	0.6%	1.8%	0.2%	1.6%	0.2%
Abnormal ejaculation1	1.6%	0%	2.1%	0%			4.9%	0.6%	2.5%	0.5%	—	—
Sweating	1.0%	0.3%	—				1.1%	0%	1.1%	0.2%	—	—
Impotence1	—		1.5%	0%							—	—
Libido Decreased							1.0%	0%			—	—
Where numbers are not provided the incidence of the adverse events in patients treated with PAXIL was not > 1% or was not greater than or equal to 2 times the incidence of placebo. 1. Incidence corrected for gender.

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 PAXIL at least twice that for placebo, derived from Table 2) 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 PAXIL at least twice that of placebo, derived from Table 3) 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 PAXIL at least twice that for placebo, derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.

Social Anxiety Disorder

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

Posttraumatic Stress Disorder

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

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 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder¹

Body System	Preferred Term	PAXIL (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 Disorders3,5	10%	0%
	Urinary Frequency	3%	1%
	Urination Disorder6	3%	0%
	Female Genital Disorders3,7	2%	0%
1. Events reported by at least 1% of patients treated with PAXIL are included, except the following events which had an incidence on placebo PAXIL: 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.”

Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder

Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on PAXIL who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day.

Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder¹

Body System	Preferred Term	Obsessive Compulsive Disorder		Panic Disorder		Social Anxiety Disorder
		PAXIL (n = 542)	Placebo (n = 265)	PAXIL (n = 469)	Placebo (n = 324)	PAXIL (n = 425)	Placebo (n = 339)
Body as a Whole	Asthenia	22%	14%	14%	5%	22%	14%
	Abdominal Pain	—	—	4%	3%	—	—
	Chest Pain	3%	2%	—	—	—	—
	Back Pain	—	—	3%	2%	—	—
	Chills	2%	1%	2%	1%	—	—
	Trauma	—	—	—	—	3%	1%
Cardiovascular	Vasodilation	4%	1%	—	—	—	—
	Palpitation	2%	0%	—	—	—	—
Dermatologic	Sweating	9%	3%	14%	6%	9%	2%
	Rash	3%	2%	—	—	—	—
Gastrointestinal	Nausea	23%	10%	23%	17%	25%	7%
	Dry Mouth	18%	9%	18%	11%	9%	3%
	Constipation	16%	6%	8%	5%	5%	2%
	Diarrhea	10%	10%	12%	7%	9%	6%
	Decreased Appetite	9%	3%	7%	3%	8%	2%
	Dyspepsia	—	—	—	—	4%	2%
	Flatulence	—	—	—	—	4%	2%
	Increased
	Appetite	4%	3%	2%	1%	—	—
	Vomiting	—	—	—	—	2%	1%
Musculoskeletal	Myalgia	—	—	—	—	4%	3%
Nervous System	Insomnia	24%	13%	18%	10%	21%	16%
	Somnolence	24%	7%	19%	11%	22%	5%
	Dizziness	12%	6%	14%	10%	11%	7%
	Tremor	11%	1%	9%	1%	9%	1%
	Nervousness	9%	8%	—	—	8%	7%
	Libido Decreased	7%	4%	9%	1%	12%	1%
	Agitation	—	—	5%	4%	3%	1%
	Anxiety	—	—	5%	4%	5%	4%
	Abnormal Dreams	4%	1%	—	—	—	—
	Concentration Impaired	3%	2%	—	—	4%	1%
	Depersonalization	3%	0%	—	—	—	—
	Myoclonus	3%	0%	3%	2%	2%	1%
	Amnesia	2%	1%	—	—	—	—
Respiratory System	Rhinitis	—	—	3%	0%	—	—
	Pharyngitis	—	—	—	—	4%	2%
	Yawn	—	—	—	—	5%	1%
Special Senses	Abnormal Vision	4%	2%	—	—	4%	1%
	Taste Perversion	2%	0%	—	—	—	—
Urogenital System	Abnormal Ejaculation2	23%	1%	21%	1%	28%	1%
	Dysmenorrhea	—	—	—	—	5%	4%
	Female Genital Disorder2	3%	0%	9%	1%	9%	1%
	Impotence2	8%	1%	5%	0%	5%	1%
	Urinary Frequency	3%	1%	2%	0%	—	—
	Urination Impaired	3%	0%	—	—	—	—
	Urinary Tract Infection	2%	1%	2%	1%	—	—
1. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with PAXIL are included, except the following events which had an incidence on placebo ≥ PAXIL: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [panic disorder]: 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. [social anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and sinusitis. 2. Percentage corrected for gender.

Generalized Anxiety Disorder and Posttraumatic Stress Disorder

Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on PAXIL 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 or among PTSD patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg/day to 50 mg/day.

Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disorder¹

Body System	Preferred Term	Generalized Anxiety Disorder		Posttraumatic Stress Disorder
		PAXIL (n = 735)	Placebo (n = 529)	PAXIL (n = 676)	Placebo (n = 504)
Body as a Whole	Asthenia	14%	6%	12%	4%
	Headache	17%	14%	—	—
	Infection	6%	3%	5%	4%
	Abdominal Pain			4%	3%
	Trauma			6%	5%
Cardiovascular	Vasodilation	3%	1%	2%	1%
Dermatologic	Sweating	6%	2%	5%	1%
Gastrointestinal	Nausea	20%	5%	19%	8%
	Dry Mouth	11%	5%	10%	5%
	Constipation	10%	2%	5%	3%
	Diarrhea	9%	7%	11%	5%
	Decreased Appetite	5%	1%	6%	3%
	Vomiting	3%	2%	3%	2%
	Dyspepsia	—	—	5%	3%
Nervous System	Insomnia	11%	8%	12%	11%
	Somnolence	15%	5%	16%	5%
	Dizziness	6%	5%	6%	5%
	Tremor	5%	1%	4%	1%
	Nervousness	4%	3%	—	—
	Libido Decreased	9%	2%	5%	2%
	Abnormal Dreams			3%	2%
Respiratory System	Respiratory Disorder	7%	5%	—	—
	Sinusitis	4%	3%	—	—
	Yawn	4%	—	2%	< 1%
Special Senses	Abnormal Vision	2%	1%	3%	1%
Urogenital System	Abnormal	25%	2%	13%	2%
	Ejaculation2
	Female Genital	4%	1%	5%	1%
	Disorder2
	Impotence2	4%	3%	9%	1%
1. Events reported by at least 2% of GAD and PTSD in patients treated with PAXIL are included, except the following events which had an incidence on placebo ≥ PAXIL [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain, headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis. 2. Percentage corrected for gender.

Dose Dependency of Adverse Events

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

Table 5 . Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder*

Body System/ Preferred Term	Placebo n= 51	PAXIL
		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%
* Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups and ≥ twice the placebo incidence for at least 1 paroxetine group.

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

In a fixed-dose study comparing placebo and 10, 20, and 40 mg of PAXIL in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of PAXIL to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of PAXIL compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of PAXIL to which patients were assigned.

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

In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of posttraumatic stress disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of PAXIL to which patients were assigned, except for impotence and abnormal ejaculation.

Adaptation to Certain Adverse Events

Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., 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 selective serotonin reuptake inhibitors (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 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.

Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials

	PAXIL	Placebo
n (males)	1446	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 PAXIL for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus 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 PAXIL in controlled clinical trials.

ECG Changes

In an analysis of ECGs obtained in 682 patients treated with PAXIL 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 PAXIL exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the PAXIL-versus-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 PAXIL

During its premarketing assessment in major depressive disorder, multiple doses of PAXIL were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to PAXIL 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, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676 patients, respectively, received multiple doses of PAXIL. 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 9,089 patients exposed to multiple doses of PAXIL who experienced an event of the type cited on at least 1 occasion while receiving PAXIL. 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 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. 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, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, 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, cholelithiasis, 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, polyuria, pyuria, 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 PAXIL 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 PAXIL and phenytoin coadministration. There has been a case report of severe hypotension when PAXIL was added to chronic metoprolol treatment.

Drug Abuse And Dependence

Controlled Substance Class

PAXIL is not a controlled substance.

Physical and Psychologic Dependence

PAXIL 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 misuse or abuse of PAXIL (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

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 PAXIL. Consequently, concomitant use of PAXIL with tryptophan is not recommended (see WARNINGS - Serotonin Syndrome).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS and WARNINGS.

Pimozide

In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and PAXIL is contraindicated (see CONTRAINDICATIONS).

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when PAXIL is coadministered with other drugs 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 PAXIL with MAOIs (including linezolid) is contraindicated (see CONTRAINDICATIONS). The concomitant use of PAXIL 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 PAXIL and warfarin should be undertaken with caution (see Drugs That Interfere With Hemostasis).

Triptans

There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of PAXIL with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS - Serotonin Syndrome).

Drugs Affecting Hepatic Metabolism

The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.

Cimetidine

Cimetidine inhibits many cytochrome P₄₅₀ (oxidative) enzymes. In a study where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of PAXIL 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 PAXIL was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of PAXIL 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 PAXIL was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS - Postmarketing Reports).

Drugs Metabolized by CYP2D6

Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients ( > 90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine.

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

Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, tamoxifen, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.

However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS).

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite and hence reduced efficacy of tamoxifen.

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

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 K_i and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic Antidepressants (TCAs)

Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with PAXIL, 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 PAXIL (see PRECAUTIONS - Drugs Metabolized by Cytochrome CYP2D6).

Drugs Highly Bound to Plasma Protein

Because paroxetine is highly bound to plasma protein, administration of PAXIL to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.

Alcohol

Although PAXIL does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.

Lithium

A multiple-dose study has shown that there is no pharmacokinetic interaction between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when PAXIL is coadministered with lithium.

Digoxin

The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine 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 PAXIL (30 mg once daily) increased steady-state AUC_0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.

Beta-Blockers

In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS - Postmarketing Reports).

Theophylline

Reports of elevated theophylline levels associated with treatment with PAXIL have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.

Fosamprenavir/Ritonavir

Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Electroconvulsive Therapy (ECT)

There are no clinical studies of the combined use of ECT and PAXIL.

Last updated on RxList: 3/20/2009

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 behavior (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 4,400 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 77,000 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 1,000 patients treated) are provided in Table 1.

Table 1

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 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, i.e., 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 PAXIL, for a description of the risks of discontinuation of PAXIL).

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 PAXIL 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 PAXIL is not approved for use in treating bipolar depression.

Potential for Interaction With Monoamine Oxidase Inhibitors

In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with PAXIL, 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 PAXIL not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI (see CONTRAINDICATIONS). At least 2 weeks should be allowed after stopping PAXIL before starting an 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 treatment with PAXIL, 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 PAXIL with MAOIs intended to treat depression is contraindicated.

If concomitant treatment of PAXIL 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 PAXIL with serotonin precursors (such as tryptophan) is not recommended.

Treatment with PAXIL 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 QT_c interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be dose related.

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

Usage in Pregnancy

Teratogenic Effects

Epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS - Discontinuation of Treatment with PAXIL). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options.

A study based on Swedish national registry data evaluated infants of 6,896 women exposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population. Among the same paroxetine exposed infants, an examination of the data showed no increase in the overall risk for congenital malformations.

A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815for 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 riskof overall major congenital malformations (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR 1.8; 95% confidence interval 1.2-2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants.

Animal Findings

Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m² basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m² basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.

Nonteratogenic Effects

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

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately sixfold higher for infants exposed to SSRIs after the 20^th 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.

General

Activation of Mania/Hypomania

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

Seizures

During premarketing testing, seizures occurred in 0.1% of patients treated with PAXIL, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. PAXIL 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 PAXIL

Recent clinical trials supporting the various approved indications for PAXIL 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 at an incidence of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention.

During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with PAXIL. 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 PAXIL 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 PAXIL. 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 PAXIL should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Abnormal Bleeding

SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation.

Use in Patients With Concomitant Illness

Clinical experience with PAXIL in patients with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with PAXIL. 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 PAXIL is prescribed for patients with narrow angle glaucoma.

PAXIL 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 PAXIL in double-blind, placebo-controlled trials, however, did not indicate that PAXIL is associated with the development of significant ECG abnormalities. Similarly, PAXIL 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

PAXIL 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 PAXIL and triptans, tramadol, or other serotonergic agents.

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

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Interference With Cognitive and Motor Performance

Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with PAXIL does not affect their ability to engage in such activities.

Completing Course of Therapy

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

Concomitant Medication

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

Alcohol

Although PAXIL 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 PAXIL.

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 breastfeeding an infant (see PRECAUTIONS - Nursing Mothers).

Laboratory Tests

There are no specific laboratory tests recommended.

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 MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD on a mg/m² basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.

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 major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m² basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m² basis).

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 PAXIL 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 PAXIL, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of PAXIL 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 PAXIL 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 PAXIL in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received PAXIL 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 PAXIL).

Geriatric Use

SSRIs and SNRIs, including PAXIL, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).

In worldwide premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL (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).

Last updated on RxList: 3/20/2009

Human Experience

Since the introduction of PAXIL in the United States, 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 that 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 2,000 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 major depressive disorder.

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 PRECAUTIONS - Drugs Metabolized by Cytochrome CYP2D6).

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).

Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs), including linezolid, an antibiotic which is a reversible non-selective MAOI, or thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).

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

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

Last updated on RxList: 3/20/2009

Pharmacodynamics

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

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

Pharmacokinetics

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

Absorption and Distribution

Paroxetine is equally bioavailable from the oral suspension and tablet.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC_0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.

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

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

Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL.

Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

Metabolism and Excretion

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS).

Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.

Other Clinical Pharmacology Information

Specific Populations

Renal and Liver Disease

Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. were 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 PAXIL as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor.

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

Obsessive Compulsive Disorder

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

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

Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1

Outcome Classification	Placebo (n = 74)	PAXIL 20 mg (n = 75)	PAXIL 40 mg (n = 66)	PAXIL 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 PAXIL 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 PAXIL in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, PAXIL was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score.

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

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

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

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

Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.

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

Social Anxiety Disorder

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

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

Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.

Generalized Anxiety Disorder

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

Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of PAXIL 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. PAXIL 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 PAXIL over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.

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

In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of PAXIL, were randomized to continuation of PAXIL 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 PAXIL experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.

Posttraumatic Stress Disorder

The effectiveness of PAXIL in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved).

Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. 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 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo. PAXIL was demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.

A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo, demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS-2 total score, but not on proportion of responders on the CGI-I.

The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively.

Last updated on RxList: 3/20/2009

Medication Guide

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

PAXIL®
(PAX-il)
(paroxetine hydrochloride) Tablets and Oral Suspension

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 action?

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

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. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
• 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.

Last updated on RxList: 3/20/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PAROXETINE - ORAL

(pair-OX-eh-teen)

COMMON BRAND NAME(S): Paxil

WARNING: Antidepressant medications are used to treat a variety of conditions, including depression and other mental/mood disorders. These medications can help prevent suicidal thoughts/attempts and provide other important benefits. However, studies have shown that a small number of people (especially people younger than 25) who take antidepressants for any condition may experience worsening depression, other mental/mood symptoms, or suicidal thoughts/attempts. Therefore, it is very important to talk with the doctor about the risks and benefits of antidepressant medication (especially for people younger than 25), even if treatment is not for a mental/mood condition.

Tell the doctor immediately if you notice worsening depression/other psychiatric conditions, unusual behavior changes (including possible suicidal thoughts/attempts), or other mental/mood changes (including new/worsening anxiety, panic attacks, trouble sleeping, irritability, hostile/angry feelings, impulsive actions, severe restlessness, very rapid speech). Be especially watchful for these symptoms when a new antidepressant is started or when the dose is changed.

USES: Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used to treat depression, panic attacks, obsessive-compulsive disorder (OCD), anxiety disorders, post-traumatic stress disorder, and a severe form of premenstrual syndrome (premenstrual dysphoric disorder).

SSRIs work by helping to restore the balance of certain natural substances in the brain (neurotransmitters such as serotonin). Paroxetine may improve your mood, sleep, appetite, and energy level and may help restore your interest in daily living. It may decrease anxiety/unreasonable fears, persistent/troubling thoughts (obsessions), and unwanted urges that keep returning (compulsions). It may decrease the number and severity of panic attacks. Paroxetine may lessen premenstrual symptoms such as irritability, increased appetite, and depression.

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using paroxetine and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily or as directed by your doctor. Taking this medication with food may decrease nausea. This medication may make you either sleepy or wakeful. Therefore, depending on how this medication affects you, your doctor may direct you to take the entire dose once daily in either the morning or evening.

The dosage is based on your medical condition and response to treatment. To reduce your risk of side effects, your doctor may start you at a low dose and gradually increase your dose. Follow your doctor's instructions carefully. Do not take more or less medication or take it more frequently than prescribed. Your condition will not improve any faster and your risk of side effects will increase. Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time each day.

If you are taking paroxetine for premenstrual problems, your doctor may direct you to take it every day of the month or just for the 2 weeks before your period through the first full day of your period.

It is important to continue taking this medication as prescribed even if you feel well. Do not stop taking this medication without first consulting your doctor.

This medication may cause dependence, especially if it has been used regularly for an extended time or if it has been used in high doses. In such cases, withdrawal reactions (e.g., mood swings, headache, tiredness, sleep changes, "shock-like" feelings) may occur if you suddenly stop this drug. To prevent withdrawal when stopping extended/regular treatment with this drug, gradually reduce the dosage as directed. Consult your doctor or pharmacist for more details. Report any withdrawal reactions or worsening symptoms immediately.

You should see some improvement in 1 to 2 weeks. It may take several weeks before you feel the full benefit.

Tell your doctor if your condition does not improve or if it worsens.

SIDE EFFECTS: See also Warning section.

Nausea, drowsiness, dizziness, trouble sleeping, loss of appetite, weakness, tiredness, dry mouth, sweating, yawning, or headache may occur. If any of these effects persist or worsen, tell your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual or severe mental/mood changes (e.g., agitation, thoughts of suicide), shakiness (tremor), restlessness, inability to keep still, decreased interest in sex, changes in sexual ability, blurred vision, numbness/tingling.

Tell your doctor immediately if any of these rare but very serious side effects occur: bloody/black/tarry stools, vomit that looks like coffee grounds, easy bruising/bleeding, fainting, fast/irregular heartbeat, muscle weakness/spasm, seizures, change in amount of urine.

This medication may rarely cause a very serious condition called serotonin syndrome. The risk increases when this medication is used with certain other drugs such as "triptans" used to treat migraine headaches (e.g., sumatriptan, eletriptan), certain antidepressants including other SSRIs (e.g., citalopram, fluoxetine) and SNRIs (e.g., duloxetine, venlafaxine), lithium, tramadol, tryptophan, or a certain drug to treat obesity (sibutramine). Before taking this drug, tell your doctor if you take any of these medications. Serotonin syndrome may be more likely when you start or increase the dose of any of these medications. Seek immediate medical attention if you develop some of the following symptoms: hallucinations, unusual restlessness, loss of coordination, fast heartbeat, severe dizziness, unexplained fever, severe nausea/vomiting/diarrhea, twitchy muscles.

For males, in the very unlikely event you have a painful or prolonged erection lasting 4 or more hours, stop using this drug and seek immediate medical attention, or permanent problems could occur.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking paroxetine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: personal or family history of bipolar/manic-depressive disorder, personal or family history of suicide attempts, liver problems, kidney problems, low sodium in the blood, severe loss of body water (dehydration), seizures, stomach/intestinal ulcers, glaucoma (narrow-angle type).

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any other activity that requires alertness. Avoid alcoholic beverages.

Caution is advised when using this product in the elderly because they may be more sensitive to its effects. The elderly are more likely to lose too much salt (hyponatremia), especially if they are also taking "water pills" (diuretics) with this medication.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. Also, babies born to mothers who have used this drug during the last 3 months of pregnancy may infrequently develop withdrawal symptoms such as feeding/breathing difficulties, seizures, muscle stiffness, or constant crying. If you notice any of these symptoms in your newborn, tell the doctor promptly.

Since untreated depression can be a serious condition, do not stop taking this medication unless directed by your doctor. If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately discuss the benefits and risks of using this medication during pregnancy with your doctor.

This drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Certain medications taken with this product could result in serious (rarely fatal) drug interactions. Avoid taking sibutramine or MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) for 2 weeks before, during, or after treatment with this medication. Consult your doctor or pharmacist for additional information.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: pimozide, sibutramine, thioridazine.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting paroxetine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs removed from your body by certain liver enzymes (e.g., aripiprazole, atomoxetine, fluoxetine, phenothiazines, procyclidine, risperidone, tamoxifen, antiarrhythmics such as propafenone, flecainide, TCA antidepressants such as desipramine, amitriptyline), cimetidine, digoxin, fosamprenavir/ritonavir, metoprolol, quinidine, theophylline, tramadol, "water pills" (diuretics such as furosemide), drugs that can cause bleeding/bruising (e.g., aspirin, antiplatelet drugs such as clopidogrel, NSAIDs such as ibuprofen, "blood thinners" such as heparin, warfarin).

Aspirin can increase the risk of bleeding when used with this medication (see above). If your doctor has directed you to take low-dose aspirin for heart attack or stroke prevention (usually at dosages of 81-325 milligrams a day), you should continue taking it unless your doctor instructs you otherwise. Discuss the risks and benefits with your doctor.

Also tell your doctor if you take any other drugs that increase serotonin, such as bromocriptine, buspirone, dextromethorphan, lithium, meperidine, propoxyphene, phentermine, SSRIs, SNRIs, tryptophan, St. John's wort, drugs used to treat migraines such as "triptans" and dihydroergotamine, street drugs such as MDMA/"ecstasy," amphetamine. (See also Side Effects section.)

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, quetiapine, nortriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

Cimetidine is a nonprescription drug that is commonly used to treat extra stomach acid. Because it may cause undesirable interactions when used with paroxetine, ask your pharmacist about other products to treat stomach acid.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: irregular heartbeat, fainting, severe dizziness, seizures.

NOTES: Do not share this medication with others.

Psychiatric/medical check-ups should be done periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.