PAROXETINE (paroxetine hydrochloride anhydrous 30 mg) Dailymed

Recent Major Changes

Warnings and Precautions (5.2, 5.5) 8/2023  

1 Indications And Usage

Paroxetine tablets are indicated in adults for the treatment of:

• • Major depressive disorder (MDD)
• •Obsessive compulsive disorder (OCD)
• •Panic disorder (PD)
• •Social anxiety disorder (SAD)
• •Generalized anxiety disorder (GAD)
• •Posttraumatic stress disorder (PTSD)

Paroxetine tablets is a selective serotonin reuptake inhibitor (SSRI) indicated in adults for the treatment of (1):

• •Major Depressive Disorder (MDD)
• •Obsessive Compulsive Disorder (OCD)
• •Panic Disorder (PD)
• •Social Anxiety Disorder (SAD)
• •Generalized Anxiety Disorder (GAD)
• •Posttraumatic Stress Disorder (PTSD)

2 Dosage And Administration

• •Recommended starting and maximum daily dosage for MDD, OCD, PD, and PTSD: (2.2)

Indication	Starting Daily Dose	Maximum Daily Dose
MDD	20 mg	50 mg
OCD	20 mg	60 mg
PD	10 mg	60 mg
PTSD	20 mg	50 mg

• •Recommended starting dosage for SAD and GAD is 20 mg daily. (2.3)
• •Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dosage is 10 mg daily. Maximum dosage is 40 mg daily. (2.4)
• •When discontinuing paroxetine tablets, reduce dosage gradually. (2.6, 5.7)

2.1 Administration Information

Administer paroxetine tablets as a single daily dose in the morning, with or without food. 

2.2 Recommended Dosage for MDD, OCD, PD, and PTSD

The recommended starting dosages and maximum dosages of paroxetine tablets in patients with MDD, OCD, PD, and PTSD are presented in Table 1. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability.

Table 1: Recommended Daily Dosage of Paroxetine tablets in Patients with MDD, OCD, PD, and PTSD

Indication	Starting Dose	Maximum Dose
MDD	20 mg	50 mg
OCD	20 mg	60 mg
PD	10 mg	60 mg
PTSD	20 mg	50 mg

2.3 Recommended Dosage for SAD and GAD

SAD

The starting and recommended dosage in patients with SAD is 20 mg daily. In clinical trials the effectiveness of paroxetine was demonstrated in patients dosed in a range of 20 mg to 60 mg daily. While the safety of paroxetine has been evaluated in patients with SAD at doses up to 60 mg daily, available information does not suggest any additional benefit for doses above 20 mg daily [see Clinical Studies (14.4)].

GAD

The starting and recommended dosage in patients with GAD is 20 mg daily. In clinical trials the effectiveness of paroxetine in GAD was demonstrated in patients dosed in a range of 20 mg to 50 mg daily. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg daily [see Clinical Studies (14.5)]. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability.

2.4 Screen for Bipolar Disorder Prior to Starting Paroxetine Tablets

Prior to initiating treatment with paroxetine tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)].

2.5 Recommended Dosage for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment

The recommended initial dosage is 10 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Dosage should not exceed 40 mg/day.

2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI)

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI and initiation of paroxetine tablets. In addition, at least 14 days must elapse after stopping paroxetine tablets before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)].

2.7 Discontinuation of Treatment with Paroxetine Tablets

Adverse reactions may occur upon discontinuation of paroxetine tablets [see Warnings and Precautions (5.7)]. Gradually reduce the dosage rather than stopping paroxetine tablets abruptly whenever possible.

• • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue paroxetine tablets and serotonergic agents and initiate supportive measures. (5.2)
• • Embryofetal and Neonatal Toxicity: Can cause fetal and neonatal harm. Increased risk of cardiovascular malformations with exposure during the first trimester. Exposure in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn. (5.4, 8.1)
• • Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti- inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5)
• • Activation of Mania/Hypomania: Screen patients 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: Paroxetine 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 included 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 in 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 1,000 patients treated are provided in Table 2.

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

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

Paroxetine is not approved for use in pediatric 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 four 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 for 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 paroxetine, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

SSRIs, including paroxetine 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 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). 

The concomitant use of paroxetine with MAOIs is contraindicated. In addition, do not initiate paroxetine 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) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine discontinue paroxetine before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)]. 

Monitor all patients taking paroxetine for the emergence of serotonin syndrome. Discontinue treatment with paroxetine  and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic  treatment. If concomitant use of paroxetine 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 paroxetine is contraindicated in combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)].

5.4 Embryofetal and Neonatal Toxicity

Paroxetine can cause fetal harm when administered to a pregnant woman. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of cardiovascular malformations. Exposure to paroxetine in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn (PPNH) and/or neonatal complications  requiring  prolonged hospitalization, respiratory support, and tube feeding. 

If paroxetine are used during  pregnancy,  or if the patient becomes pregnant while taking paroxetine, the patient should be apprised of the  potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.5 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including paroxetine, 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 use of 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 paroxetine and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

5.6 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with paroxetine tablet or another antidepressant may precipitate a  mixed/manic episode. During controlled clinical trials of paroxetine, 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 paroxetine, 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 (2.7)].

During clinical trials of GAD and PTSD, gradual 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 adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of paroxetine in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)].

5.8 Seizures

Paroxetine tablets have not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies, seizures occurred in 0.1% of patients treated with paroxetine. Paroxetine should be prescribed with caution in patients with a seizure disorder. Discontinue paroxetine in any patient who develops seizures.

5.9 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine 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 have been reported. Avoid use of antidepressants, including paroxetine in patients with untreated anatomically narrow angles.

5.10 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs, including paroxetine. Cases with serum sodium lower than 110 mmol/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 result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue paroxetine tablet 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 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 with concomitant use of paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions (7)]. One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. 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 during 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 paroxetine, 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 paroxetine 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 and Neonatal 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)]
• •Seizures [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)]
• •Sexual Dysfunction [see Warnings and Precautions (5.13)]

Most common adverse reactions (≥5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, yawn. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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 be directly 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
• •12-week clinical trials in SAD patients who received paroxetine 20 mg to 50 mg once daily
• •8-week clinical trials in GAD patients who received paroxetine 10 mg to 50 mg once daily
• •12-week clinical trials in PTSD patients who received paroxetine 20 mg to 50 mg once daily

Adverse Reactions Leading to Discontinuation

Twenty percent (1,199/6,145) of patients treated with paroxetine in clinical trials in MDD and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with paroxetine in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (≥1%) associated with discontinuation (i.e., those adverse reactions associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) are presented in Table 3:

Table 3: Adverse Reactions Reported as Leading to Discontinuation (≥1% of Paroxetine Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD Trials

	MDD		OCD		PD		SAD		GAD		PTSD
	PAROXETINE %	Placebo%	PAROXETINE %	Placebo%	PAROXETINE %	Placebo%	PAROXETINE %	Placebo%	PAROXETINE %	Placebo%	PAROXETINE %	Placebo%
CNS
Somnolence	2.3	0.7	—		1.9	0.3	3.4	0.3	2	0.2	2.8	0.6
Insomnia	—	—	1.7	0	1.3	0.3	3.1	0			—	—
Agitation	1.1	0.5	—								—	—
Tremor	1.1	0.3	—				1.7	0			1	0.2
Anxiety	—	—	—				1.1	0			—	—
Dizziness	—	—	1.5	0			1.9	0	1	0.2	—	—
Gastroin-
testinal
Constipation	—		1.1	0							—	—
Nausea	3.2	1.1	1.9	0	3.2	1.2	4	0.3	2	0.2	2.2	0.6
Diarrhea	1	0.3	—
Dry mouth	1	0.3	—								—	—
Vomiting	1	0.3	—				1	0			—	—
Flatulence							1	0.3			—	—
Other
Asthenia	1.6	0.4	1.9	0.4			2.5	0.6	1.8	0.2	1.6	0.2
Abnormal
Ejaculationa	1.6	0	2.1	0			4.9	0.6	2.5	0.5	—	—
Sweating	1	0.3	—				1.1	0	1.1	0.2	—	—
Impotencea	—		1.5	0							—	—
Libido Decreased							1	0			---	---

Where numbers are not provided the incidence of the adverse reactions in patients treated with paroxetine was not >1% or was not greater than or equal to 2 times the incidence of placebo. ^a. Incidence corrected for gender. 

Most Common Adverse Reactions

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

MDD: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. 

OCD: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.

PD: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.

SAD: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence.

GAD: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. 

PTSD: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence.

Adverse Reactions in Patients with MDD

Table 4 presents the 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

Body System/ Adverse Reaction	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	1
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	2	0
Dyspepsia	2	1
Musculoskeletal
Myopathy	2	1
Myalgia	2	0
Myasthenia	1	1
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 Prevention	2	0
Urogenital System
Ejaculatory Disturbance b,c	13	0
Other Male Genital Disorders b,d	10	0
Urinary Frequency	3	1
Urination Disorder e	3	0
Female Genital Disorders b,f	2	0

^a Includes mostly “lump in throat” and “tightness in throat.”

^b Percentage corrected for gender.

^c Mostly “ejaculatory delay.”

^d Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,”  and “impotence.”

^e Includes mostly “difficulty with micturition” and “urinary hesitancy.”

^f Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” 

Adverse Reactions in Patients with OCD, PD, and SAD

Table 5 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD, PD, and SAD.

Table 5. Adverse Reactions (≥2% of Paroxetine -Treated Patients and Greater than Placebo) in 10 to 12-Week Clinical Trials for OCD, PD, and SAD

Body System/Preferred Term	Obsessive Compulsive Disorder		Panic Disorder		Social Anxiety Disorder
	PAROXETINE (n = 542 %	Placebo (n = 265) %	PAROXETINE (n = 469) %	Placebo (n = 324) %	PAROXETINE (n = 425) %	Placebo (n = 339) %
Body as a Whole
Asthenia	22	14	14	5	22	14
Abdominal Pain	-	-	4	3	—	—
Chest Pain	3	2	-	-	-	-
Back Pain	-	-	3	2	-	-
Chills	2	1	2	1	—	—
Trauma	—	—	—	—	3	1
Cardiovascular
Vasodilation	4	1	—	—	—	—
Palpitation	2	0	—	—	—	—
Dermatologic
Sweating	9	3	14	6	9	2
Rash	3	2	-	-	-	-
Gastrointestinal
Nausea	23	10	23	17	25	7
Dry Mouth	18	9	18	11	9	3
Constipation	16	6	8	5	5	2
Diarrhea	10	10	12	7	9	6
Decreased Appetite	9	3	7	3	8	2
Dyspepsia	-	-	-	-	4	2
Flatulence	-	-	-	-	4	2
Increased Appetite	4	3	2	1	-	-
Vomiting	-	-	-	-	2	1
Musculoskeletal
Myalgia	-	-	-	-	4	3
Nervous System
Insomnia	24	13	18	10	21	16
Somnolence	24	7	19	11	22	5
Dizziness	12	6	14	10	11	7
Tremor	11	1	9	1	9	1
Nervousness	9	8	—	—	8	7
Libido Decreased	7	4	9	1	12	1
Agitation	—	—	5	4	3	1
Anxiety	—	—	5	4	5	4
Abnormal Dreams	4	1	—	—	—	—
Concentration Impaired	3	2	—	—	4	1
Depersonalization	3	0	—	—	—	—
Myoclonus	3	0	3	2	2	1
Amnesia	2	1	-	-	-	-
Respiratory System
Rhinitis	-	-	3	0	-	-
Pharyngitis	-	-	-	-	4	2
Yawn	-	-	-	-	5	1
Special Senses
Abnormal Vision	4	2	—	—	4	1
Taste Perversion	2	0	-	-	-	-
Urogenital System
Abnormal Ejaculationa	23	1	21	1	28	1
Dysmenorrhea	—	—	—	—	5	4
Female Genital Disordera	3	0	9	1	9	1
Impotencea	8	1	5	0	5	1
Urinary Frequency	3	1	2	0	—	—
Urination Impaired	3	0	—	—	—	—
Urinary Tract Infection	2	1	2	1	—	—

^a Percentage corrected for gender. 

Adverse Reactions in Patients with GAD and PTSD

Table 6 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with GAD and PTSD 

Table 6. Adverse Reactions (≥2% of Paroxetine -Treated Patients and Greater than Placebo) in 8- to 12-Week Clinical Trials for GAD and PTSD^a

BodySystem/Preferr ed Term	Generalized Anxiety Disorder		Posttraumatic Stress Disorder
	Paroxetine  (n = 735)%	Placebo (n = 529)%	Paroxetine (n = 676)%	Placebo (n = 504)%
Body as a Whole
Asthenia	14	6	12	4
Headache	17	14	—	—
Infection	6	3	5	4
Abdominal Pain			4	3
Trauma			6	5
Cardiovascular Vasodilation	3	1	2	1
Dermatologic Sweating	6	2	5	1
Gastrointestinal
Nausea	20	5	19	8
Dry Mouth	11	5	10	5
Constipation	10	2	5	3
Diarrhea	9	7	11	5
Decreased
Appetite	5	1	6	3
Vomiting	3	2	3	2
Dyspepsia	—	—	5	3
Nervous System
Insomnia	11	8	12	11
Somnolence	15	5	16	5
Dizziness	6	5	6	5
Tremor	5	1	4	1
Nervousness	4	3	-	-
Libido Decreased	9	2	5	2
Abnormal Dreams	-	-	3	-
Respiratory System
Respiratory Disorder	7	5	-	-
Sinusitis	4	3	-	-
Yawn	4	-	2	≤1
Special Senses
Abnormal Vision	2	1	3	1
Urogenital System
Abnormal Ejaculation a	25	2	13	2
Female Genital Disorder a	4	1	5	1
Impotence a	4	3	9	1

^a. Percentage corrected for gender. 

Dose Dependent Adverse Reactions 

MDD

A comparison of adverse reaction rates in a fixed-dose study comparing paroxetine 10 mg, 20 mg, 30 mg, and 40 mg once daily with placebo in the treatment of MDD revealed dose dependent adverse reactions, as shown in Table 7: 

Table 7. Adverse Reactions (≥5% of Paroxetine -Treated Patients and ≥ Twice the Rate of  Placebo) (in a Dose-Comparison Trial in the Treatment of MDD

Body System/Preferred Term	Placebo n = 51%	PAROXETINE10 mg 20 mg 30 mg 40 mgn = 102 n = 104 n = 101 n = 102% % % %
Body as a Whole Asthenia	0	2.9	10.6	13.9	12.7
Dermatology Sweating	2	1	6.7	8.9	11.8
Gastrointestinal
Constipation	5.9	4.9	7.7	9.9	12.7
Decreased Appetite	2	2	5.8	4	4.9
Diarrhea	7.8	9.8	19.2	7.9	14.7
Dry Mouth	2	10.8	18.3	15.8	20.6
Nausea	13.7	14.7	26.9	34.7	36.3
Nervous System
Anxiety	0	2	5.8	5.9	5.9
Dizziness	3.9	6.9	6.7	8.9	12.7
Nervousness	0	5.9	5.8	4	2.9
Paresthesia	0	2.9	1	5	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	2.9	2.9	2	7.8
Urogenital System
Abnormal Ejaculation	0	5.8	6.5	10.6	13
Impotence	0	1.9	4.3	6.4	1.9
Male Genital Disorders	0	3.8	8.7	6.4	3.7

OCD

In a fixed-dose study comparing placebo and paroxetine 20 mg, 40 mg, 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. 

PD

In a fixed-dose study comparing placebo and paroxetine 10 mg, 20 mg, and 40 mg in the treatment of PD, the following adverse reactions were shown to be dose-dependent: asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation.  

SAD

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

GAD

In a fixed-dose study comparing placebo and paroxetine 20 mg and 40 mg in the treatment of GAD, the following adverse reactions were shown to be dose-dependent: asthenia, constipation, and abnormal ejaculation. 

PTSD

In a fixed-dose study comparing placebo and paroxetine 20 mg and 40 mg in the treatment of PTSD, the following adverse reactions were shown to be dose-dependent: impotence 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, however, 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 labeling may underestimate their actual incidence. The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, SAD, GAD, and PTSD are displayed in Table 8.

Table 8. Adverse Reactions Related to Sexual Dysfunction in Patients Treated with Paroxetine in Clinical Trials of MDD, OCD, PD, SAD, GAD, and PTSD

	PAROXETINE	Placebo
n (males)	1446%	1042%
Decreased Libido	6 to15	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

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

Hallucinations

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

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 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 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 infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.

Digestive System

Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.

Endocrine System

Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. 

Hemic and Lymphatic Systems

Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia.

Metabolic and Nutritional

Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.

Musculoskeletal System

Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.

Nervous System

Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome.

Respiratory System

Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration.

Skin and Appendages

Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.

Special Senses

Frequent: Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect.

Urogenital System

Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis.

6.2 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), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; 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.