PEXEVA (paroxetine mesylate 30 mg) Dailymed

• Serotonin Syndrome:Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue PEXEVA and serotonergic agents and initiate supportive measures ( 5.2)
• Embryofetal Toxicity:May cause fetal harm. Meta-analyses of epidemiological studies have shown increased risk (less than 2-fold) of cardiovascular malformations with exposure during the first trimester. ( 5.4, 8.1)
• Increased Risk of Bleeding:Concomitant use of aspirin, nonsteroidal antiinflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. ( 5.5)
• Activation of Mania/Hypomania:Screen for bipolar disorder ( 5.6)
• Seizures:Use with caution in patients with seizure disorders ( 5.8)
• Angle-Closure Glaucoma:Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5 .9)
• Sexual Dysfunction: Pexeva may cause symptoms of sexual dysfunction ( 5.13)

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that include approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

TABLE 2: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trails of Antidepressants in Pediatric and Adult Patients

Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated
	Increases Compared to Placebo
<18 years old	14 additional patients
18-24 years old	5 additional patients
	Decreases Compared to Placebo
25-64 years old	1 fewer patient
≥65 years old	6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond 4 months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing PEXEVA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts and behaviors.

5.2 Serotonin Syndrome

SSRIs, including PEXEVA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4), Drug Interactions ( 7.1)] . Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of PEXEVA with MAOIs is contraindicated. In addition, do not initiate PEXEVA in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking PEXEVA, discontinue PEXEVA before initiating treatment with the MAOI [see Contraindications ( 4), Drug Interactions ( 7)] .

Monitor all patients taking PEXEVA for the emergence of serotonin syndrome. Discontinue treatment with PEXEVA and any concomitant serotonergic agents immediately if the above symptoms occur and initiate symptomatic treatment. If concomitant use of PEXEVA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Drug Interactions Leading to QT Prolongation

The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of PEXEVA is contraindicated in combination with thioridazine and pimozide [see Contraindications ( 4), Drug Interactions ( 7), Clinical Pharmacology ( 12.3)] .

5.4 Embryofetal and Neonatal Toxicity

Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants. For women who intend to become pregnant or who are in their first trimester of pregnancy, PEXEVA, should be initiated only after consideration of the other available treatment options [see Use in Specific Populations ( 8.1)] .

5.5 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including PEXEVA, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet 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 drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1)] . Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of PEXEVA and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

5.6Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with PEXEVA or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately 1% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with PEXEVA, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.7 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration ( 2)] .

Adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of PEXEVA in pediatric patients has not been established. [see Boxed Warning, Warnings and Precautions ( 5.1), Use in Specific Populations ( 8.4)] .

During clinical trials of paroxetine in GAD and another indication, incremental decreases in the daily dose by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness.

5.8 Seizures

During clinical studies, seizure occurred in 0.1% of patients treated with PEXEVA. PEXEVA should be prescribed with caution in patients with a seizure disorder. Discontinue PEXEVA in any patient who develops seizures.

5.9 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including PEXEVA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of paroxetine hydrochloride tables have been reported. Avoid use of antidepressants, including PEXEVA, in patients with untreated anatomically narrow angles.

5.10 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs, including PEXEVA. Cases with serum sodium lower than 110mmol/L have been reported. 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. In many cases, this hyponatremia appears to be the results of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue PEXEVA and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with and SSRIs [see Use in Specific Populations ( 8.5)] .

5.11 Reduction of Efficacy of Tamoxifen

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug interactions ( 7.1) . One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

5.12 Bone Fracture

Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation, and it is unknown to what extent fracture risk is directly attributable to SSRI treatment.

5.13 Sexual Dysfunction

Use of SSRIs, including PEXEVA, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1)] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of PEXEVA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 Adverse Reactions

The following adverse reactions are included in more detail in other sections of the prescribing information:

• Hypersensitivity reactions to paroxetine [see Contraindications ( 4)]
• Suicidal Thoughts and Behaviors [see Warnings and Precautions ( 5.1)]
• Serotonin syndrome [see Warnings and Precautions ( 5.2)]
• Embryofetal Toxicity [see Warnings and Precautions ( 5.4)]
• Increased Risk of Bleeding [see Warnings and Precautions ( 5.5)]
• Activation of Mania/Hypomania [see Warnings and Precautions ( 5.6)]
• Discontinuation Syndrome [see Warnings and Precautions ( 5.7)]
• Seizure [see Warnings and Precautions ( 5.8)]
• Angle-closure Glaucoma [see Warnings and Precautions ( 5.9)]
• Hyponatremia [see Warnings and Precautions ( 5.10)]
• Bone Fracture [see Warnings and Precautions ( 5.12)]

Most common adverse reactions (≥5% and at least twice placebo): asthenia, sweating, nausea, decreased appetite, dry mouth, constipation, somnolence, dizziness, insomnia, tremor, nervousness, libido decreased, female genital disorders, impotence, ejaculatory disturbance, other male genital disorders, orgasmic disturbance, and infection ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Sebela Pharmaceuticals Inc. at 1-844-732-3521 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot directly be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data for paroxetine are from:

• 6-week clinical trials in MDD patients who received paroxetine 20 mg to 50 mg once daily
• 12-week clinical trials in OCD patients who received paroxetine 20 mg to 60 mg once daily
• 10- to 12-week clinical trials in PD patients who received paroxetine 10 mg to 60 mg once daily
• 8-week clinical trials in GAD patients who received paroxetine 10 mg to 50 mg once daily

Adverse Reactions Leading to Discontinuation

Twenty percent (1199/6145) of patients treated with paroxetine in clinical trials in MDD and 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine in clinical trials in OCD, PD, and GAD, respectively, discontinued treatment due to an adverse reaction. Table 3 shows the most common reactions (≥1%) associated with discontinuation and considered to be drug related (i.e., those reactions associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo).

TABLE 3: Adverse Reactions Reported as Leading to Discontinuation (≥1% of Paroxetine-Treated Patients and (≥2% Placebo) in MDD, OCD, PD, and GAD Trials

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

Most Common Adverse Reactions in MDD, OCD, PD, and GAD

The most commonly observed adverse reactions associated with the use of PEXEVA (incidence of 5% or greater and at least twice that for placebo) were:

Major Depressive Disorder:  asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders.

Obsessive Compulsive Disorder: nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.

Panic Disorder: asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.

Generalized Anxiety Disorder: asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.

Adverse Reactions Occurring at an Incidence of 1% or More in Paroxetine Treated Patients

Major Depressive Disorder: Table 4 enumerates adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine-treated patients with MDD.

TABLE 4: Adverse Reactions (≥1% of Paroxetine-treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD

1Includes mostly “lump in throat” and “tightness in throat.”
2Percentage corrected for gender.
3Mostly “ejaculatory delay.”
4Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction” and “impotence.”
5Includes mostly “difficulty with micturition” and “urinary hesitancy.”
6Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
Body System	Preferred Term	Paroxetine (n=421) %	Placebo (n=421) %
Body as a Whole	Headache	18	17
	Asthenia	15	6
Cardiovascular	Palpitation	3	1
	Vasodilation	3	1
Dermatologic	Sweating	11	2
	Rash	2	1
Gastrointestinal	Nausea	26	9
	Dry Mouth	18	12
	Constipation	14	9
	Diarrhea	12	8
	Decreased Appetite	6	2
	Flatulence	4	2
	Oropharynx Disorder 1	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 Disturbance 2,3	13	0
	Other Male Genital Disorders 2,4	10	0
	Urinary Frequency	3	1
	Urination Disorder 5	3	0
	Female Genital Disorders 2,6	2	0

Obsessive Compulsive Disorder and Panic Disorder: Table 5 enumerates adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD and PD.

1Percentage corrected for gender.
TABLE 5: Adverse Reactions (≥2% of Paroxetine-Treated Patients and Greater than Placebo) in 10- to 12-Week Clinical Trials for OCD and PD
		Obsessive Compulsive Disorder		Panic Disorder
Body System	Preferred Term	Paroxetine (n=542) %	Placebo (n=265) %	Paroxetine (n=469) %	Placebo (n=324) %
Body as a Whole	Asthenia	22	14	14	5
	Abdominal Pain	-	-	4	3
	Chest Pain	3	2	-	-
	Back Pain	-	-	3	2
	Chills	2	1	2	1
Cardiovascular	Vasodilation	4	1	-	-
	Palpitation	2	0	-	-
Dermatologic	Sweating	9	3	14	6
	Rash	3	2%	-	-
Gastrointestinal	Nausea	23	10	23	17
	Dry Mouth	18	9	18	11
	Constipation	16	6	8	5
	Diarrhea	10	10	12	7
	Decreased Appetite	9	3	7	3
	Increased Appetite	4	3	2	1
Nervous System	Insomnia	24	13	18	10
	Somnolence	24	7	19	11
	Dizziness	12	6	14	10
	Tremor	11	1	9	1
	Nervousness	9	8	-	-
	Libido Decreased	7	4	9	1
	Agitation	-	-	5	4
	Anxiety	-	-	5	4
	Abnormal Dreams	4	1	-	-
	Concentration Impaired	3	2	-	-
	Depersonalization	3	0	-	-
	Myoclonus	3	0	3	2
	Amnesia	2	1	-	-
Respiratory System	Rhinitis	-	-	3	0
Special Senses	Abnormal Vision	4	2	-	-
	Taste Perversion	2	0	-	-
Urogenital System	Abnormal Ejaculation 1	23	1	21	1
	Female Genital Disorder 1	3	0	9	1
	Impotence 1	8	1	5	0
	Urinary Frequency	3	1	2	0
	Urination Impaired	3	0	-	-
	Urinary Tract Infection	2	1	2	1

Generalized Anxiety Disorder: Table 6 enumerates adverse reactions that occurred at a frequency of 2% or more among GAD patients on paroxetine who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day.

1Percentage corrected for gender.
TABLE 6: Adverse Reactions (≥2% of Paroxetine-Treated Patients and Greater than Placebo) in 8-Week Clinical Trials for GAD
Body System	Preferred Term	Paroxetine (n=735) %	Placebo (n=529) %
Body as a Whole	Asthenia	14	6
	Headache	17	14
	Infection	6	3
Cardiovascular	Vasodilation	3	1
Dermatologic	Sweating	6	2
Gastrointestinal	Nausea	20	5
	Dry Mouth	11	5
	Constipation	10	2
	Diarrhea	9	7
	Decreased Appetite	5	1
	Vomiting	3	2
Nervous System	Insomnia	11	8
	Somnolence	15	5
	Dizziness	6	5
	Tremor	5	1
	Nervousness	4	3
	Libido Decreased	9	2
Respiratory System	Respiratory Disorder	7	5
	Sinusitis	4	3
	Yawn	4	-
Special Senses	Abnormal Vision	2	1
Urogenital System	Abnormal Ejaculation 1	25	2
	Female Genital Disorder 1	4	1
	Impotence 1	4	3

Dose Dependency of Adverse Reactions:A comparison of adverse reaction rates in a fixed-dose study comparing paroxetine 10, 20, 30, and 40 mg/day with placebo in the treatment of MDD revealed a clear dose dependency for some of the more common adverse reactions associated with paroxetine use, as shown in Table 7:

TABLE 7: Adverse Reactions (≥5% of Paroxetine-Treated Patients and Twice that of Placebo) in a Dose-Comparison Trial in the Treatment of MDD*
Body System/    Preferred Term	Placebo	Paroxetine
	n=51 %	10 mg n=102 %	20 mg n=104 %	30 mg n=101 %	40 mg n=102 %
Body as a Whole
Asthenia	0	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	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	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	5.8	6.5	10.6	13.0
Impotence	0	1.9	4.3	6.4	1.9
Male Genital Disorders	0	3.8	8.7	6.4	3.7

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

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

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

Male and Female Sexual Dysfunction

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 SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and healthcare providers 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 males and females with MDD, OCD, PD, , GAD, and two other indications are displayed in Table 8.

Table 8: Incidence of Sexual Adverse Reactions in Controlled Clinical Trials
	Paroxetine	Placebo
n (males)	1446	1042
	%	%
Decreased Libido	6 to 15	0 to 5
Ejaculatory Disturbance	13 to 28	0 to 2
Impotence	2 to 9	0 to 3
n (females)	1822	1340
	%	%
Decreased Libido	0 to 9	0 to 2
Orgasmic Disturbance	2 to 9	0 to 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, healthcare providers should routinely inquire about such possible side effects.

Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 0.2% of paroxetine-treated patients compared to 0.1% of patients receiving placebo.

6.2 Other Reactions Observed During the Premarketing Evaluation of Paroxetine

Less Common Adverse Reactions

The following adverse reactions occurred during the clinical studies of paroxetine and are not included elsewhere in the labeling.

Adverse reactions are categorized by body system and uled in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients.

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

6.3 Postmarketing Experience

The following reactions have been identified during post approval use of paroxetine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), priapism, syndrome of inappropriate ADH secretion (SIADH), 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; trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura) and premature births in pregnant women. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.