PAROXETINE (Page 3 of 9)

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) ]

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
Ejaculation a 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 a 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 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 a 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 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
Ejaculation a 23 1 21 1 28 1
Dysmenorrhea 5 4
Female Genital
Disorder a 3 0 9 1 9 1
Impotence a 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

Body System/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 Trail in the Treatment of MDD

Body System/Preferred Term Placebo n = 51 % PAROXETINE 10 mg 20 mg 30 mg 40 mg n = 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 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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