Paroxetine: Package Insert and Label Information (Page 2 of 6)

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 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 co-administration. 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:

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
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.
*
Incidence corrected for gender.

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

Gastrointestinal

 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  Ejaculation *

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

 Impotence *

1.5

0

 Libido  Decreased

1

0

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 (≥ l% of Paroxetine-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD
*
Includes mostly “lump in throat” and “tightness in throat.”
Percentage corrected for gender.
Mostly “ejaculatory delay.”
§
Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.”
Includes mostly “difficulty with micturition” and “urinary hesitancy.”
#
Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”

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 Disorder *

2

0

 Dyspepsia

2

1

Musculoskeletal

 Myopathy

2

1

 Myalgia

2

1

 Myasthenia

1

0

Nervous System

 Somnolence

23

9

 Dizziness

13

6

 Insomnia

13

6

 Tremor

8

2

 Nervousness

5

3

 Anxiety

5

3

 Paresthesia

4

2

 Libido Decreased

3

0

 Drugged Feeling

2

1

 Confusion

1

0

Respiration

 Yawn

4

0

Special Senses

 Blurred Vision

4

1

 Taste Perversion

2

0

Urogenital System

 Ejaculatory Disturbance ,

13

0

 Other Male Genital Disorders , §

10

0

 Urinary Frequency

3

1

 Urinary Disorder

3

0

 Female Genital Disorders , #

2

0

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
*
Percentage corrected for gender.

Body System/  Preferred Term

Obsessive Compulsive Disorder

Panic Disorder

Social Anxiety Disorder

Paroxetine

Placebo

Paroxetine

Placebo

Paroxetine

Placebo

(n = 542)

(n = 265)

(n = 469)

(n = 324)

(n = 425)

(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 Ejaculation *

23

1

21

1

28

1

 Dysmenorrhea

5

4

 Female Genital Disorders *

3

0

9

1

9

1

 Impotence *

8

1

5

0

5

1

 Urinary Frequency

3

1

2

0

 Urination Impaired

3

0

 Urinary Tract Infection

2

1

2

1

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 *
*
Percentage corrected for gender.

Body System/  Preferred Term

Generalized Anxiety Disorder

Posttraumatic Stress Disorder

Paroxetine

Placebo

Paroxetine

Placebo

(n = 735)

(n = 529)

(n = 676)

(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 *

25

2

13

2

 Female Genital Disorder *

4

1

5

1

 Impotence *

4

3

9

1

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

Paroxetine Tablets

n=51

10 mg n=102

20 mg n=104

30 mg n=101

40 mg n=102

%

%

%

%

%

Body As A Whole

 Asthenia

0

2.9

10.6

13.9

12.7

Dermatology

 Sweating

2

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)

1,446

1,042

%

%

 Decreased Libido

6 to15

0 to 5

 Ejaculatory Disturbance

13 to 28

0 to 2

 Impotence

2 to 9

0 to 3

n (females)

1,822

1,340

%

%

 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 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.

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