PAXIL CR (paroxetine hydrochloride) is an orally administered psychotropic drug with a chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic, or other available antidepressant or antipanic agents. 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 C₁₉H₂₀FNO₃•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.

Each enteric, film-coated, controlled-release tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 12.5 mg-yellow, 25 mg-pink, 37.5 mg-blue. One layer of the tablet consists of a degradable barrier layer and the other contains the active material in a hydrophilic matrix.

Inactive ingredients consist of hypromellose, polyvinylpyrrolidone, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, glyceryl behenate, methacrylic acid copolymer type C, sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate, and 1 or more of the following colorants: Yellow ferric oxide, red ferric oxide, D&C Red No. 30, D&C Yellow No. 6, D&C Yellow No. 10, FD&C Blue No. 2.

Major Depressive Disorder: PAXIL CR is indicated for the treatment of major depressive disorder.

The efficacy of PAXIL CR in the treatment of a major depressive episode was established in two 12-week controlled trials of outpatients whose diagnoses corresponded to the DSM-IV category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least 5 of the following 9 symptoms during the same 2-week period: Depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation.

The antidepressant action of paroxetine in hospitalized depressed patients has not been adequately studied.

PAXIL CR has not been systematically evaluated beyond 12 weeks in controlled clinical trials; however, the effectiveness of immediate-release paroxetine hydrochloride in maintaining a response in major depressive disorder for up to 1 year has been demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). The physician who elects to use PAXIL CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Panic Disorder: PAXIL CR 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 CR controlled-release tablets was established in two 10-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IV 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 with the immediate-release formulation of paroxetine was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to immediate-release paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who prescribes PAXIL CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Social Anxiety Disorder: PAXIL CR 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 CR as a treatment for social anxiety disorder has been established, in part, on the basis of extrapolation from the established effectiveness of the immediate-release formulation of paroxetine. In addition, the efficacy of PAXIL CR was established in a 12-week trial, in adult outpatients with social anxiety disorder (DSM-IV). PAXIL CR has not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY—Clinical Trials).

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

Premenstrual Dysphoric Disorder: PAXIL CR is indicated for the treatment of PMDD.

The efficacy of PAXIL CR in the treatment of PMDD has been established in 3 placebo-controlled trials (see CLINICAL PHARMACOLOGY—Clinical Trials).

The essential features of PMDD, according to DSM-IV, include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following the onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.

The effectiveness of PAXIL CR in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use PAXIL CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Major Depressive Disorder: Usual Initial Dosage: PAXIL CR should be administered as a single daily dose, usually in the morning, with or without food. The recommended initial dose is 25 mg/day. Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials demonstrating the effectiveness of PAXIL CR in the treatment of major depressive 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 25-mg dose may benefit from dose increases, in 12.5-mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at intervals of at least 1 week.

Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be swallowed whole.

Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with PAXIL CR 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 of an antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Systematic evaluation of the efficacy of immediate-release paroxetine hydrochloride has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg, which corresponds to a 37.5-mg dose of PAXIL CR, based on relative bioavailability considerations (see CLINICAL PHARMACOLOGY-Pharmacokinetics).

Panic Disorder: Usual Initial Dosage: PAXIL CR should be administered as a single daily dose, usually in the morning. Patients should be started on 12.5 mg/day. Dose changes should occur in 12.5-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of PAXIL CR. The maximum dosage should not exceed 75 mg/day.

Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be swallowed whole.

Maintenance Therapy: Long-term maintenance of efficacy with the immediate-release formulation of paroxetine was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to immediate-release paroxetine demonstrated a lower relapse rate compared to patients on placebo. 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 CR should be administered as a single daily dose, usually in the morning, with or without food. The recommended initial dose is 12.5 mg/day. Patients were dosed in a range of 12.5 mg to 37.5 mg/day in the clinical trial demonstrating the effectiveness of PAXIL CR in the treatment of social anxiety disorder. If the dose is increased, this should occur at intervals of at least 1 week, in increments of 12.5 mg/day, up to a maximum of 37.5 mg/day.

Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be swallowed whole.

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

Premenstrual Dysphoric Disorder: Usual Initial Dosage: PAXIL CR should be administered as a single daily dose, usually in the morning, with or without food. PAXIL CR may be administered either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment. The recommended initial dose is 12.5 mg/day. In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective. Dose changes should occur at intervals of at least 1 week.

Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be swallowed whole.

Maintenance/Continuation Therapy: The effectiveness of PAXIL CR for a period exceeding 3 menstrual cycles has not been systematically evaluated in controlled trials. However, women commonly report that symptoms worsen with age until relieved by the onset of menopause. Therefore, it is reasonable to consider continuation of a responding patient. Patients should be periodically reassessed to determine the need for continued treatment.

Special Populations: Treatment of Pregnant Women During the Third Trimester: Neonates exposed to PAXIL CR 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 of PAXIL CR is 12.5 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 50 mg/day.

Switching 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 CR. Similarly, at least 14 days should be allowed after stopping PAXIL CR before starting an MAOI.

Discontinuation of Treatment With PAXIL CR: Symptoms associated with discontinuation of immediate-release paroxetine hydrochloride or PAXIL CR have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which PAXIL CR 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.

PAXIL CR is supplied as an enteric film-coated, controlled-release, round tablet, as follows:

12.5-mg yellow tablets, engraved with PAXIL CR and 12.5

NDC 0029-3206-13 Bottles of 30

25-mg pink tablets, engraved with PAXIL CR and 25

NDC 0029-3207-13 Bottles of 30

37.5 mg blue tablets, engraved with PAXIL CR and 37.5

NDC 0029-3208-13 Bottles of 30

Store at or below 25°C (77°F) [see USP].

PAXIL CR is a registered trademark of GlaxoSmithKline. GEOMATRIX is a trademark of Jago Pharma, Muttenz, Switzerland. GlaxoSmithKline. Research Triangle Park, NC 27709. June 2007. FDA Rev date: 8/2/2007

The information included under the "Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With PAXIL CR" subsection of ADVERSE REACTIONS is based on data from 11 placebo-controlled clinical trials. Three of these studies were conducted in patients with major depressive disorder, 3 studies were done in patients with panic disorder, 1 study was conducted in patients with social anxiety disorder, and 4 studies were done in female patients with PMDD. Two of the studies in major depressive disorder, which enrolled patients in the age range 18 to 65 years, are pooled. Information from a third study of major depressive disorder, which focused on elderly patients (60 to 88 years), is presented separately as is the information from the panic disorder studies and the information from the PMDD studies. Information on additional adverse events associated with PAXIL CR and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events).

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With PAXIL CR:

Adverse Events Associated With Discontinuation of Treatment: Major Depressive Disorder: Ten percent (21/212) of patients treated with PAXIL CR discontinued treatment due to an adverse event in a pool of 2 studies of patients with major depressive disorder. 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 CR compared to placebo) included the following:

	PAXIL CR (n = 212)	Placebo (n = 211)
Nausea	3.7%	0.5%
Asthenia	1.9%	0.5%
Dizziness	1.4%	0.0%
Somnolence	1.4%	0.0%

In a placebo-controlled study of elderly patients with major depressive disorder, 13% (13/104) of patients treated with PAXIL CR discontinued due to an adverse event. Events meeting the above criteria included the following:

	PAXIL CR (n = 104)	Placebo (n = 109)
Nausea	2.9%	0.0%
Headache	1.9%	0.9%
Depression	1.9%	0.0%
LFT's abnormal	1.9%	0.0%

Panic Disorder: Eleven percent (50/444) of patients treated with PAXIL CR in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

	PAXIL CR (n = 444)	Placebo (n = 445)
Nausea	2.9%	0.4%
Insomnia	1.8%	0.0%
Headache	1.4%	0.2%
Asthenia	1.1%	0.0%

Social Anxiety Disorder: Three percent (5/186) of patients treated with PAXIL CR in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

	PAXIL CR (n = 186)	Placebo (n = 184)
Nausea	2.2%	0.5%
Headache	1.6%	0.5%
Diarrhea	1.1%	0.5%

Premenstrual Dysphoric Disorder: Spontaneously reported adverse events were monitored in studies of both continuous and intermittent dosing of PAXIL CR in the treatment of PMDD. Generally, there were few differences in the adverse event profiles of the 2 dosing regimens. Thirteen percent (88/681) of patients treated with PAXIL CR in PMDD studies of continuous dosing discontinued treatment due to an adverse event.

The most common events (≥ 1%) associated with discontinuation in either group treated with PAXIL CR with an incidence rate that is at least twice that of placebo in PMDD trials that employed a continuous dosing regimen are shown in the following table. This table also shows those events that were dose dependent (indicated with an asterisk) as defined as events having an incidence rate with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the placebo group).

	PAXIL CR 25 mg (n = 348)	PAXIL CR 12.5 mg (n = 333)	Placebo 25 (n = 349)
TOTAL	15%	9.9%	6.3%
Nausea*	6.0%	2.4%	0.9%
Asthenia	4.9%	3.0%	1.4%
Somnolence*	4.3%	1.8%	0.3%
Insomnia	2.3%	1.5%	0.0%
Concentration Impaired*	2.0%	0.6%	0.3%
Dry mouth*	2.0%	0.6%	0.3%
Dizziness*	1.7%	0.6%	0.6%
Decreased Appetite*	1.4%	0.6%	0.0%
Sweating*	1.4%	0.0%	0.3%
Tremor*	1.4%	0.3%	0.0%
Yawn*	1.1%	0.0%	0.0%
Diarrhea	0.9%	1.2%	0.0%
* Events considered to be dose dependent are defined as events having an incidence rate with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the placebo group).

Commonly Observed Adverse Events: Major Depressive Disorder: The most commonly observed adverse events associated with the use of PAXIL CR in a pool of 2 trials (incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo, derived from Table 2) were: Abnormal ejaculation, abnormal vision, constipation, decreased libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma, tremor, and yawning.

Using the same criteria, the adverse events associated with the use of PAXIL CR in a study of elderly patients with major depressive disorder were: Abnormal ejaculation, constipation, decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.

Panic Disorder: In the pool of panic disorder studies, the adverse events meeting these criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating, and female genital disorders (generally anorgasmia or difficulty achieving orgasm).

Social Anxiety Disorder: In the social anxiety disorder study, the adverse events meeting these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence, insomnia, and libido decreased.

Premenstrual Dysphoric Disorder: The most commonly observed adverse events associated with the use of PAXIL CR either during continuous dosing or luteal phase dosing (incidence of 5% or greater and incidence for PAXIL CR at least twice that for placebo, derived from Table 6) were: Nausea, asthenia, libido decreased, somnolence, insomnia, female genital disorders, sweating, dizziness, diarrhea, and constipation.

In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day of PAXIL CR limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the 3 off-drug phases were combined, the following adverse events were reported at an incidence of 2% or greater for PAXIL CR and were at least twice the rate of that reported for placebo: Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%), sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).

Incidence in Controlled Clinical Trials: Table 2 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with PAXIL CR, aged 18 to 65, who participated in 2 short-term (12-week) placebo-controlled trials in major depressive disorder in which patients were dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse events reported at an incidence of 5% or greater among elderly patients (ages 60 to 88) treated with PAXIL CR who participated in a short-term (12-week) placebo-controlled trial in major depressive disorder in which patients were dosed in a range of 12.5 mg to 50 mg/day. Table 4 enumerates adverse events reported at an incidence of 1% or greater among patients (19 to 72 years) treated with PAXIL CR who participated in short-term (10-week) placebo-controlled trials in panic disorder in which patients were dosed in a range of 12.5 mg to 75 mg/day. Table 5 enumerates adverse events reported at an incidence of 1% or greater among adult patients treated with PAXIL CR who participated in a short-term (12-week), double-blind, placebo-controlled trial in social anxiety disorder in which patients were dosed in a range of 12.5 to 37.5 mg/day. Table 6 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with PAXIL CR who participated in three, 12-week, placebo-controlled trials in PMDD in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses (luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Table 2. Treatment-Emergent Adverse Events Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Pool of 2 Studies in Major Depressive Disorder^1,2

Body System/Adverse Event	% Reporting Event
	PAXIL CR (n = 212)	Placebo (n = 211)
Body as a Whole
Headache	27%	20%
Asthenia	14%	9%
Infection3	8%	5%
Abdominal Pain	7%	4%
Back Pain	5%	3%
Trauma4	5%	1%
Pain5	3%	1%
Allergic Reaction6	2%	1%
Cardiovascular System
Tachycardia	1%	0%
Vasodilatation7	2%	0%
Digestive System
Nausea	22%	10%
Diarrhea	18%	7%
Dry Mouth	15%	8%
Constipation	10%	4%
Flatulence	6%	4%
Decreased Appetite	4%	2%
Vomiting	2%	1%
Nervous System
Somnolence	22%	8%
Insomnia	17%	9%
Dizziness	14%	4%
Libido Decreased	7%	3%
Tremor	7%	1%
Hypertonia	3%	1%
Paresthesia	3%	1%
Agitation	2%	1%
Confusion	1%	0%
Respiratory System
Yawn	5%	0%
Rhinitis	4%	1%
Cough Increased	2%	1%
Bronchitis	1%	0%
Skin and Appendages
Sweating	6%	2%
Photosensitivity	2%	0%
Special Senses
Abnormal Vision8	5%	1%
Taste Perversion	2%	0%
Urogenital System
Abnormal Ejaculation9,10	26%	1%
Female Genital Disorder9,11	10%	< 1%
Impotence9	5%	3%
Urinary Tract Infection	3%	1%
Menstrual Disorder9	2%	< 1%
Vaginitis9	2%	0%
1. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the placebo incidence are not included. These events are: Abnormal dreams, anxiety, arthralgia, depersonalization, dysmenorrhea, dyspepsia, hyperkinesia, increased appetite, myalgia, nervousness, pharyngitis, purpura, rash, respiratory disorder, sinusitis, urinary frequency, and weight gain. 2. < 1% means greater than zero and less than 1%. 3. Mostly flu. 4. A wide variety of injuries with no obvious pattern. 5. Pain in a variety of locations with no obvious pattern. 6. Most frequently seasonal allergic symptoms. 7. Usually flushing. 8. Mostly blurred vision. 9. Based on the number of males or females. 10. Mostly anorgasmia or delayed ejaculation. 11. Mostly anorgasmia or delayed orgasm.

Table 3. Treatment-Emergent Adverse Events Occurring in ≥ 5% of Patients Treated With PAXIL CR in a Study of Elderly Patients With Major Depressive Disorder^1,2

Body System/Adverse Event	% Reporting Event
	PAXIL CR (n = 104)	Placebo (n = 109)
Body as a Whole
Headache	17%	13%
Asthenia	15%	14%
Trauma	8%	5%
Infection	6%	2%
Digestive System
Dry Mouth	18%	7%
Diarrhea	15%	9%
Constipation	13%	5%
Dyspepsia	13%	10%
Decreased Appetite	12%	5%
Flatulence	8%	7%
Nervous System
Somnolence	21%	12%
Insomnia	10%	8%
Dizziness	9%	5%
Libido Decreased	8%	< 1%
Tremor	7%	0%
Skin and Appendages
Sweating	10%	< 1%
Urogenital System
Abnormal Ejaculation3,4	17%	3%
Impotence3	9%	3%
1. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the placebo incidence are not included. These events are nausea and respiratory disorder. 2. < 1% means greater than zero and less than 1%. 3. Based on the number of males. 4. Mostly anorgasmia or delayed ejaculation.

Table 4. Treatment-Emergent Adverse Events Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Pool of 3 Panic Disorder Studies^1,2

Body System/Adverse Event	% Reporting Event
	PAXIL CR (n = 444)	Placebo (n = 445)
Body as a Whole
Asthenia	15%	10%
Abdominal Pain	6%	4%
Trauma3	5%	4%
Cardiovascular System
Vasodilation4	3%	2%
Digestive System
Nausea	23%	17%
Dry Mouth	13%	9%
Diarrhea	12%	9%
Constipation	9%	6%
Decreased Appetite	8%	6%
Metabolic/Nutritional Disorders
Weight Loss	1%	0%
Musculoskeletal System
Myalgia	5%	3%
Nervous System
Insomnia	20%	11%
Somnolence	20%	9%
Libido Decreased	9%	4%
Nervousness	8%	7%
Tremor	8%	2%
Anxiety	5%	4%
Agitation	3%	2%
Hypertonia5	2%	< 1%
Myoclonus	2%	< 1%
Respiratory System
Sinusitis	8%	5%
Yawn	3%	0%
Skin and Appendages
Sweating	7%	2%
Special Senses
Abnormal Vision6	3%	< 1%
Urogenital System
Abnormal Ejaculation7,8	27%	3%
Impotence7	10%	1%
Female Genital Disorders9,10	7%	1%
Urinary Frequency	2%	< 1%
Urination Impaired	2%	< 1%
Vaginitis9	1%	< 1%
1. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the placebo rate are not included. These events are: Abnormal dreams, allergic reaction, back pain, bronchitis, chest pain, concentration impaired, confusion, cough increased, depression, dizziness, dysmenorrhea, dyspepsia, fever, flatulence, headache, increased appetite, infection, menstrual disorder, migraine, pain, paresthesia, pharyngitis, respiratory disorder, rhinitis, tachycardia, taste perversion, thinking abnormal, urinary tract infection, and vomiting. 2. < 1% means greater than zero and less than 1%. 3. Various physical injuries. 4. Mostly flushing. 5. Mostly muscle tightness or stiffness. 6. Mostly blurred vision. 7. Based on the number of male patients. 8. Mostly anorgasmia or delayed ejaculation. 9. Based on the number of female patients. 10. Mostly anorgasmia or difficulty achieving orgasm.

Table 5. Treatment-Emergent Adverse Effects Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Social Anxiety Disorder Study^1,2

Body System/Adverse Event	% Reporting Event
	PAXIL CR (n = 186)	Placebo (n = 184)
Body as a Whole
Headache	23%	17%
Asthenia	18%	7%
Abdominal Pain	5%	4%
Back Pain	4%	1%
Trauma3	3%	< 1%
Allergic Reaction4	2%	< 1%
Chest Pain	1%	< 1%
Cardiovascular System
Hypertension	2%	0%
Migraine	2%	1%
Tachycardia	2%	1%
Digestive System
Nausea	22%	6%
Diarrhea	9%	8%
Constipation	5%	2%
Dry Mouth	3%	2%
Dyspepsia	2%	< 1%
Decreased Appetite	1%	< 1%
Tooth Disorder	1%	0%
Metabolic/Nutritional Disorders
Weight Gain	3%	1%
Weight Loss	1%	0%
Nervous System
Insomnia	9%	4%
Somnolence	9%	4%
Libido Decreased	8%	1%
Dizziness	7%	4%
Tremor	4%	2%
Anxiety	2%	1%
Concentration Impaired	2%	0%
Depression	2%	1%
Myoclonus	1%	< 1%
Paresthesia	1%	< 1%
Respiratory System
Yawn	2%	0%
Skin and Appendages
Sweating	14%	3%
Eczema	1%	0%
Special Senses
Abnormal Vision5	2%	0%
Abnormality of Accommodation	2%	0%
Urogenital System
Abnormal Ejaculation6,7	15%	1%
Impotence6	9%	0%
Female Genital Disorders8,9	3%	0%
1. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the placebo rate are not included. These events are: Dysmenorrhea, flatulence, gastroenteritis, hypertonia, infection, pain, pharyngitis, rash, respiratory disorder, rhinitis, and vomiting. 2. < 1% means greater than zero and less than 1%. 3. Various physical injuries. 4. Most frequently seasonal allergic symptoms. 5. Mostly blurred vision. 6. Based on the number of male patients. 7. Mostly anorgasmia or delayed ejaculation. 8. Based on the number of female patients. 9. Mostly anorgasmia or difficulty achieving orgasm.

Table 6. Treatment-Emergent Adverse Events Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Pool of 3 Premenstrual Dysphoric Disorder Studies with Continuous Dosing or in 1 Premenstrual Dysphoric Disorder Study with Luteal Phase Dosing^1,2,3

Body System/Adverse Event	% Reporting Event
	Continuous Dosing		Luteal Phase Dosing
	PAXIL CR (n = 681)	Placebo (n = 349)	PAXIL CR (n = 246)	Placebo (n = 120)
Body as a Whole
Asthenia	17%	6%	15%	4%
Headache	15%	12%	-	-
Infection	6%	4%	-	-
Abdominal pain	-	-	3%	0%
Cardiovascular System
Migraine	1%	< 1%	-	-
Digestive System
Nausea	17%	7%	18%	2%
Diarrhea	6%	2%	6%	0%
Constipation	5%	1%	2%	< 1%
Dry Mouth	4%	2%	2%	< 1%
Increased Appetite	3%	< 1%	-	-
Decreased Appetite	2%	< 1%	2%	0%
Dyspepsia	2%	1%	2%	2%
Gingivitis	-	-	1%	0%
Metabolic and Nutritional Disorders
Generalized Edema	-	-	1%	< 1%
Weight Gain	-	-	1%	< 1%
Musculoskeletal System
Arthralgia	2%	1%	-	-
Nervous System
Libido Decreased	12%	5%	9%	6%
Somnolence	9%	2%	3%	< 1%
Insomnia	8%	2%	7%	3%
Dizziness	7%	3%	6%	3%
Tremor	4%	< 1%	5%	0%
Concentration Impaired	3%	< 1%	1%	0%
Nervousness	2%	< 1%	3%	2%
Anxiety	2%	1%	-	-
Lack of Emotion	2%	< 1%	-	-
Depression	-	-	2%	< 1%
Vertigo	-	-	2%	< 1%
Abnormal Dreams	1%	< 1%	-	-
Amnesia	-	-	1%	0%
Respiratory System
Sinusitis	-	-	4%	2%
Yawn	2%	< 1%	-	-
Bronchitis	-	-	2%	0%
Cough Increased	1%	< 1%	-	-
Skin and Appendages
Sweating	7%	< 1%	6%	< 1%
Special Senses
Abnormal Vision	-	-	1%	0%
Urogenital System
Female Genital Disorders4	8%	1%	2%	0%
Menorrhagia	1%	< 1%	-	-
Vaginal Moniliasis	1%	< 1%	-	-
Menstrual Disorder	-	-	1%	0%
1. Adverse events for which the reporting rate of PAXIL CR was less than or equal to the placebo rate are not included. These events for continuous dosing are: Abdominal pain, back pain, pain, trauma, weight gain, myalgia, pharyngitis, respiratory disorder, rhinitis, sinusitis, pruritis, dysmenorrhea, menstrual disorder, urinary tract infection, and vomiting. The events for luteal phase dosing are: Allergic reaction, back pain, headache, infection, pain, trauma, myalgia, anxiety, pharyngitis, respiratory disorder, cystitis, and dysmenorrhea. 2. < 1% means greater than zero and less than 1%. 3. The luteal phase and continuous dosing PMDD trials were not designed for making direct comparisons between the 2 dosing regimens. Therefore, a comparison between the 2 dosing regimens of the PMDD trials of incidence rates shown in Table 5 should be avoided. 4. Mostly anorgasmia or difficulty achieving orgasm.

Dose Dependency of Adverse Events: The following table shows results in PMDD trials of common adverse events, defined as events with an incidence of ≥ 1% with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR and with placebo.

Incidence of Common Adverse Events in Placebo, 12.5 mg and 25 mg of PAXIL CR in a Pool of 3 Fixed-Dose PMDD Trials

Common Adverse Event	PAXIL CR 25 mg (n = 348)	PAXIL CR 12.5 mg (n = 333)	Placebo (n = 349)
Sweating	8.9%	4.2%	0.9%
Tremor	6.0%	1.5%	0.3%
Concentration Impaired	4.3%	1.5%	0.6%
Yawn	3.2%	0.9%	0.3%
Paresthesia	1.4%	0.3%	0.3%
Hyperkinesia	1.1%	0.3%	0.0%
Vaginitis	1.1%	0.3%	0.3%

A comparison of adverse event rates in a fixed-dose study comparing immediate-release paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with the use of immediate-release paroxetine.

Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain; however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.

The percentage of patients reporting symptoms of sexual dysfunction in the pool of 2 placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of 3 placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients with social anxiety disorder, and in the intermittent dosing and the pool of 3 placebo-controlled continuous dosing trials in female patients with PMDD are as follows:

	Major Depressive Disorder		Panic Disorder		Social Anxiety Disorder		PMDD Continuous Dosing		PMDD Luteal Phase Dosing
	PAXIL CR	Placebo	PAXIL CR	Placebo	PAXIL CR	Placebo	PAXIL CR	Placebo	PAXIL CR	Placebo
n (males)	78	78	162	194	88	97	n/a	n/a	n/a	n/a
Decreased Libido	10%	5%	9%	6%	13%	1%	n/a	n/a	n/a	n/a
Ejaculatory Disturbance	26%	1%	27%	3%	15%	1%	n/a	n/a	n/a	n/a
Impotence	5%	3%	10%	1%	9%	0%	n/a	n/a	n/a	n/a
n (females)	134	133	282	251	98	87	681	349	246	120
Decreased Libido	4%	2%	8%	2%	4%	1%	12%	5%	9%	6%
Orgasmic Disturbance	10%	< 1%	7%	1%	3%	0%	8%	1%	2%	0%

There are no adequate, controlled studies examining sexual dysfunction with paroxetine treatment.

Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials with PAXIL CR or the immediate-release formulation, had minimal weight loss (about 1 pound). No significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature) were observed in patients treated with PAXIL CR, or immediate-release paroxetine hydrochloride, in controlled clinical trials.

ECG Changes: In an analysis of ECGs obtained in 682 patients treated with immediate-release paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group.

Liver Function Tests: In a pool of 2 placebo-controlled clinical trials, patients treated with PAXIL CR or placebo exhibited abnormal values on liver function tests at comparable rates. In particular, the controlled-release paroxetine-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities.

In a study of elderly patients with major depressive disorder, 3 of 104 patients treated with PAXIL CR and none of 109 placebo patients experienced liver transaminase elevations of potential clinical concern.

Two of the patients treated with PAXIL CR dropped out of the study due to abnormal liver function tests; the third patient experienced normalization of transaminase levels with continued treatment. Also, in the pool of 3 studies of patients with panic disorder, 4 of 444 patients treated with PAXIL CR and none of 445 placebo patients experienced liver transaminase elevations of potential clinical concern. Elevations in all 4 patients decreased substantially after discontinuation of PAXIL CR. The clinical significance of these findings is unknown.

In placebo-controlled clinical trials with the immediate-release formulation of paroxetine, patients exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients.

Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving drug and in 4 of 3,187 patients receiving placebo.

Other Events Observed During the Clinical Development of Paroxetine: The following adverse events were reported during the clinical development of PAXIL CR and/or the clinical development of the immediate-release formulation of paroxetine.

Adverse events for which frequencies are provided below occurred in clinical trials with the controlled-release formulation of paroxetine. During its premarketing assessment in major depressive disorder, panic disorder, social anxiety disorder, and PMDD, multiple doses of PAXIL CR were administered to 1,627 patients in phase 3 double-blind, controlled, outpatient studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of the 1,627 patients exposed to PAXIL CR who experienced an event of the type cited on at least 1 occasion while receiving PAXIL CR. All reported events are included except those already listed in Tables 2 through 6 and those events where a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was deleted or, when possible, replaced with a more informative term. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.

Adverse events for which frequencies are not provided occurred during the premarketing assessment of immediate-release paroxetine in phase 2 and 3 studies of major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to immediate-release paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. Only those events not previously listed for controlled-release paroxetine are included. The extent to which these events may be associated with PAXIL CR is unknown.

Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in the PRECAUTIONS section.

Body as a Whole: Infrequent were chills, face edema, fever, flu syndrome, malaise; rare were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed were adrenergic syndrome, neck rigidity, sepsis.

Cardiovascular System: Infrequent were angina pectoris, bradycardia, hematoma, hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia, syncope; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation, cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.

Digestive System: Infrequent were bruxism, dysphagia, eructation, gastritis, gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function test abnormal, melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis, glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction, peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue edema.

Endocrine System: Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus, hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis.

Hemic and Lymphatic System: Infrequent were anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis, lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.

Metabolic and Nutritional Disorders: Infrequent were generalized edema, hyperglycemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare were bilirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperphosphatemia, hypocalcemia, hypoglycemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.

Musculoskeletal System: Infrequent were arthritis, bursitis, tendonitis; rare were myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis, tenosynovitis, tetany.

Nervous System: Frequent were depression; infrequent were amnesia, convulsion, depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis, vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis, withdrawal syndrome; also observed were abnormal gait, akathisia, akinesia, aphasia, choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction, manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus.

Respiratory System: Frequent were pharyngitis; infrequent were asthma, dyspnea, epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema, hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum increased.

Skin and Appendages: Frequent were rash; infrequent were acne, alopecia, dry skin, eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash, seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.

Special Senses: Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis, photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss.

Urogenital System: Frequent were dysmenorrhea*; infrequent were albuminuria, amenorrhea*, breast pain*, cystitis, dysuria, prostatitis*, urinary retention; rare were breast enlargement*, breast neoplasm*, female lactation, hematuria, kidney calculus, metrorrhagia*, nephritis, nocturia, pregnancy and puerperal disorders*, salpingitis, urinary incontinence, uterine fibroids enlarged*; also observed were breast atrophy, ejaculatory disturbance, endometrial disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria, urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage. *Based on the number of men and women as appropriate.

Postmarketing Reports: Voluntary reports of adverse events in patients taking immediate-release paroxetine hydrochloride that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barre syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea, neuroleptic malignant syndrome-like events, serotonin syndrome; 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-Schonlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when immediate-release paroxetine was added to chronic metoprolol treatment.

Drug Abuse And Dependence

Controlled Substance Class: PAXIL CR is not a controlled substance.

Physical and Psychologic Dependence: PAXIL CR 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 CR (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 immediate-release paroxetine. Consequently, concomitant use of PAXIL CR with tryptophan is not recommended (see WARNINGS-Serotonin Syndrome).

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.

Pimozide: In a controlled study of healthy volunteers, after immediate-release paroxetine hydrochloride was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and PAXIL CR 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 CR 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 CR 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 CR 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 CR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS-Serotonin Syndrome)

Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.

Cimetidine: Cimetidine inhibits many cytochrome P₄₅₀ (oxidative) enzymes. In a study where immediate-release paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of PAXIL CR after the starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine's pharmacokinetics was not studied.

Phenobarbital: Phenobarbital induces many cytochrome P₄₅₀ (oxidative) enzymes. When a single oral 30-mg dose of immediate-release paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T_½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment with PAXIL CR is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Phenytoin: When a single oral 30-mg dose of immediate-release paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T_½ were reduced (by an average of 50% and 35%, respectively) compared to immediate-release paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when PAXIL CR is coadministered with phenytoin; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS-Postmarketing Reports).

Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs, and many tricyclics), are metabolized by the cytochrome P₄₅₀ isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In 1 study, daily dosing of immediate-release paroxetine (20 mg once daily) under steady-state conditions increased single-dose desipramine (100 mg) Cmax, AUC, and T_½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when given with paroxetine.

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

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

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

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 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 TCAs with PAXIL CR, 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 CR (see PRECAUTIONS-Drugs Metabolized by Cytochrome CYP2D6).

Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of PAXIL CR 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 (NSAIDs, Aspirin, Warfarin, etc.): 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 potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with paroxetine.

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

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

Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of PAXIL CR and digoxin should be undertaken with caution.

Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.

Procyclidine: Daily oral dosing of immediate-release paroxetine (30 mg once daily) increased steady-state 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 immediate-release paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS- Postmarketing Reports).

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

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

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