2.1 Administration Information

Administer paroxetine oral suspension as a single daily dose in the morning, with or without food. Shake the oral suspension well before administration.

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

The recommended starting dosages and maximum dosages of paroxetine 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 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 oral suspension was demonstrated in patients dosed in a range of 20 mg to 60 mg daily. While the safety of  paroxetine oral suspension 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 oral suspension 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 oral suspension

Prior to initiating treatment with  paroxetine oral suspension 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 oral suspension. In addition, at least 14 days must elapse after stopping paroxetine oral suspension before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)].

2.7 Discontinuation of Treatment With Paroxetine oral suspension

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

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 inthe 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 oral suspension, 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 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  is 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  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 oral suspension has 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  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 oral suspension, 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 oral suspension 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.

6.1 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 oral suspension are from:

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

Adverse Reactions Leading to Discontinuation

Twenty percent (1,199/6,145) of patients treated with  paroxetine oral suspension 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 oral suspension 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 oral suspension 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	0.2	2.8	0.6
Insomnia	—	—	1.7	0.0	1.3	0.3	3.1	0.0			—	—
Agitation	1.1	0.5	—								—	—
Tremor	1.1	0.3	—				1.7	0.0			1.0	0.2
Anxiety	—	—	—				1.1	0.0			—	—
Dizziness	—	—	1.5	0.0			1.9	0.0	1.0	0.2	—	—
Gastroin-
testinal
Constipation	—		1.1	0.0							—	—
Nausea	3.2	1.1	1.9	0.0	3.2	1.2	4.0	0.3	2.0	0.2	2.2	0.6
Diarrhea	1.0	0.3	—
Dry mouth	1.0	0.3	—								—	—
Vomiting	1.0	0.3	—				1.0	0			—	—
Flatulence							1.0	0.3			—	—
Other
Asthenia	1.6	0.4	1.9	0.4			2.5	0.6	1.8	0.2	1.6	0.2
Abnormal
Ejaculationa	1.6	0.0	2.1	0.0			4.9	0.6	2.5	0.5	—	—
Sweating	1.0	0.3	—				1.1	0.0	1.1	0.2	—	—
Impotencea	—		1.5	0.0							—	—
Libido Decreased							1.0	0.0			---	---

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 oral suspension (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	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 Disordera	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 Perversion	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	-—-	-—-	3—-	0—-
System
Rhinitis					-	-
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 PTSDa

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
Cardiovascula rVasodilation	3	1	2	1
DermatologicSweating	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

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 WholeAsthenia	0.0	2.9	10.6	13.9	12.7
DermatologySweating	2.0	1.0	6.7	8.9	11.8
Gastrointestinal
Constipation	5.9	4.9	7.7	9.9	12.7
Decreased Appetite	2.0	2.0	5.8	4.0	4.9
Diarrhea	7.8	9.8	19.2	7.9	14.7
Dry Mouth	2.0	10.8	18.3	15.8	20.6
Nausea	13.7	14.7	26.9	34.7	36.3
Nervous System
Anxiety	0.0	2.0	5.8	5.9	5.9
Dizziness	3.9	6.9	6.7	8.9	12.7
Nervousness	0.0	5.9	5.8	4.0	2.9
Paresthesia	0.0	2.9	1.0	5.0	5.9
Somnolence	7.8	12.7	18.3	20.8	21.6
Tremor	0.0	0.0	7.7	7.9	14.7
Special SensesBlurred Vision	2.0	2.9	2.9	2.0	7.8
Urogenital System
Abnormal Ejaculation	0.0	5.8	6.5	10.6	13.0
Impotence	0.0	1.9	4.3	6.4	1.9
Male Genital Disorders	0.0	3.8	8.7	6.4	3.7

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 paroxetineto 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 oral suspension 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 listed 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 oral suspension.  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.

8.1 Pregnancy

Risk Summary

Based on data from 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 Warnings and Precautions (5.5) and Clinical Considerations].

Clinical Considerations

Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant [see Warnings and Precautions (5.7)]. For

• A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery.
• A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).
• Two large case-control studies using separate databases, each with >9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, 7.0 exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).

Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations. 

Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant [see Warnings and Precautions (5.7)]. For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options [see Warnings and Precautions (5.4)]. 

Treatment of Pregnant Women During Their Third Trimester: Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including  paroxetine, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. 

Exposure to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs. 

When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment. A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy. The women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. 

Maternal Adverse Reactions

Use of paroxetine oral solution in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)].

Animal Findings

Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 6 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 75 mg) on an mg/m2 basis. These studies have revealed no evidence of developmental effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day which is than the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.

8.3 Nursing Mothers

Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from  paroxetine, a decision should be made whether to discontinue nursing infants or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of  paroxetine in pediatric patients have not been established [see Box Warning]. Effectiveness was not demonstrated in three placebo-controlled trials in 752  paroxetine treated pediatric patients with MDD. 

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)]. Decreased appetite and weight loss have been observed in association with the use of SSRIs. 

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

Adverse reactions upon discontinuation of treatment with  paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain.

8.5 Geriatric Use

In premarketing clinical trials with  paroxetine, 17% of patients treated with  paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended, however, no overall differences in safety or effectiveness were observed between elderly and younger patients [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 

SSRIs including  paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.7)].

8.6 Renal and Hepatic Impairment

Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage of  paroxetine should be reduced in patients with severe renal impairment and in patients with severe hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

The mechanism of action of  paroxetine in the treatment of MDD, SAD, OCD\, PD, GAD, and PTSD is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine,5-HT).

12.2 Pharmacodynamics

Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake (SSRI) and has only very weak effects on norepinephrine and dopamine neuronal reuptake.

12.3 Pharmacokinetics

Nonlinearity in pharmacokinetics is observed with increasing doses of  paroxetine. In a meta analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females.

Absorption 

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable. Paroxetine is equally bioavailable from the oral suspension. 

Effect of Food

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

Distribution

Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. 

Elimination

Metabolism

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg daily for 30 days of  paroxetine. 

In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. 

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions [see Drug Interactions (7)]. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). 

Excretion

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

Drug Interaction Studies

There are clinically significant, known drug interactions between paroxetine and other drugs [see Drug Interactions (7)].

Figure 1. Impact of Paroxetine on the Pharmacokinetics of Co-Administered Drugs (logscale)

Figure 2. Impact of Co-Administered Drugs on the Pharmacokinetics of Paroxetine

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

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. Paroxetine’s extent of inhibition of CYP3A4 activity is not expected to be of clinical significance. 

Specific Populations

The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3. The recommended starting dosage and maximum dosage of  paroxetine is reduced in elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment [see Dosage and Administration (2.4)].

Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale)

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.0 (mouse) and 3.2 (rat) times the MRHD of 75 mg on a mg/m2 basis. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. 

Mutagenesis

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

Impairment of Fertility

Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.4 times the MRHD of 75 mg on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (8.2 and 4.1 times the MRHD of 75 mg on a mg/m2 basis).

14.1 Major Depressive Disorder

The efficacy of  paroxetine as a treatment for major depressive disorder (MDD) has been established in 6 placebo-controlled studies of patients with MDD (aged 18 to 73). In these studies,  paroxetine was shown to be statistically significantly more effective than placebo in treating MDD by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness.  paroxetine was statistically significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. Long-term efficacy of  paroxetine for treatment of MDD in outpatients was demonstrated in a randomized withdrawal study. Patients who responded to  paroxetine (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue  paroxetine or placebo, for up to 1 year. Patients treated with  paroxetine demonstrated a statistically significant lower relapse rate during the withdrawal phase (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.

14.2 Obsessive Compulsive Disorder

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

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

Table 10: Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1 in Patients with OCD

Outcome	Placebo	PAROXETINE 20 mg	PAROXETINE  40 mg	PAROXETINE 60 mg
Classification	(n = 74)	(n = 75)	(n = 66)	(n = 66)
	%	%	%	%
Worse	14	7	7	3
No Change	44	35	22	19
Minimally Improved	24	33	29	34
Much Improved	11	18	22	24
Very Much Improved	7	7	20	20

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

The long-term efficacy of  paroxetine for the treatment of OCD was established in a long-term extension to Study 1. Patients who responded to  paroxetine during the 3-month double-blind phase and a 6-month extension on open-label  paroxetine 20 mg to 60 mg daily were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were statistically significantly less likely to relapse than placebo-treated patients.

14.3 Panic Disorder

The effectiveness of  paroxetine in the treatment of panic disorder (PD) was demonstrated in three 10 to 12 week multicenter, placebo-controlled studies of adult outpatients (Studies 1, 2, and 3). 

Patients had PD (DSM-IIIR), with or without agoraphobia. In these studies,  paroxetine was shown to be statistically significantly more effective than placebo in treating PD by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. 

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

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

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

In Studies 2 and 3, the mean  paroxetine dose for completers at endpoint was approximately 40 mg daily. 

Long-term efficacy of  paroxetine in PD was demonstrated in an extension to Study 1. Patients who responded to  paroxetine during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either  paroxetine 10 mg, 20 mg, or 40 mg daily or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to  paroxetine were statistically significantly less likely to relapse than placebo-treated patients. 

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

14.4 Social Anxiety Disorder

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

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

Study 3 was a 12-week study comparing fixed doses of  paroxetine 20 mg, 40 mg, or 60 mg daily with placebo.  paroxetine 20 mg was statistically significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the  paroxetine 40 mg and 60 mg daily dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg daily. 

Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.

14.5 Generalized Anxiety Disorder

The effectiveness of  paroxetine in the treatment of generalized anxiety disorder (GAD) was demonstrated in two 8 week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with GAD (DSM-IV). 

Study 1 was an 8-week study comparing fixed doses of  paroxetine 20 mg or 40 mg daily with placebo. Doses of  paroxetine 20 mg or 40 mg were both demonstrated to be statistically significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score.

There was not sufficient evidence in this study to suggest a greater benefit for the  paroxetine 40 mg daily dose compared to the 20 mg daily dose. 

Study 2 was a flexible-dose study comparing  paroxetine 20 mg to 50 mg daily and placebo. paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. 

A third study, a flexible-dose study comparing  paroxetine 20 mg to 50 mg daily to placebo, did not demonstrate statistically significant superiority of  paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. 

Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a long-term trial, 566 patients meeting DSM-IV criteria for GAD, who had responded during a single-blind, 8-week acute treatment phase with  paroxetine 20 mg to 50 mg daily, were randomized to continuation of  paroxetine at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or withdrawal due to lack of efficacy. Patients continuing to receive  paroxetine experienced a statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.

14.6 Posttraumatic Stress Disorder

The effectiveness of  paroxetine in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from 0.1 year to 57 years). The percentage of patients with secondary MDD or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (1) the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (2) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The 2 primary outcomes for each trial were (1) change from baseline to endpoint on the CAPS-2 total score (17 items), and (2) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). 

Study 1 was a 12-week study comparing fixed doses of  paroxetine 20 mg or 40 mg daily to placebo. Doses of  paroxetine 20 mg and 40 mg were demonstrated to be statistically significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg daily dose compared to the 20 mg daily dose.

Study 2 was a 12-week flexible-dose study comparing  paroxetine 20 mg to 50 mg daily to placebo. paroxetine was demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. 

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

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