Paroxetin: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

Paroxetine tablets, USP are available as:

• 10 mg yellow colored film-coated modified capsule shaped, biconvex tablets debossed with ‘C 55’ on one side and a deep breakline on the other side.
• 20 mg pink colored film-coated modified capsule shaped, biconvex tablets debossed with ‘56’ on one side and ‘C’ with a deep breakline on the other side.
• 30 mg blue colored film-coated modified capsule shaped, biconvex tablets debossed with ‘F’ on one side and ‘12’ on the other side.
• 40 mg pink colored film-coated modified capsule shaped, biconvex tablets debossed with ‘A 59’ on one side and plain on the other side.

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

• Hypersensitivity reactions to paroxetine [see Contraindications (4)]
• Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Embryofetal Toxicity [see Warnings and Precautions (5.4)]
• Increased Risk of Bleeding [see Warnings and Precautions (5.5)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]
• Discontinuation Syndrome [see Warnings and Precautions (5.7)]
• 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
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.
| MDD | OCD | PD | SAD | GAD | PTSD
Paroxetine % | Placebo % | Paroxetine % | Placebo % | Paroxetine % | Placebo % | Paroxetine % | Placebo % | Paroxetine % | Placebo % | Paroxetine % | Placebo %
CNS Somnolence Insomnia Agitation Tremor Anxiety Dizziness | 2.3 — 1.1 1.1 — — | 0.7 — 0.5 0.3 — — | — 1.7 — — — 1.5 | 0 0 | 1.9 1.3 | 0.3 0.3 | 3.4 3.1 1.7 1.1 1.9 | 0.3 0 0 0 0 | 2.0 1.0 | 0.2 0.2 | 2.8 — — 1.0 — — | 0.6 — — 0.2 — —
Gastrointestinal Constipation Nausea Diarrhea Dry mouth Vomiting Flatulence | — 3.2 1.0 1.0 1.0 | 1.1 0.3 0.3 0.3 | 1.1 1.9 — — — | 0 0 | 3.2 | 1.2 | 4.0 1.0 1.0 | 0.3 0 0.3 | 2.0 | 0.2 | — 2.2 — — — | — 0.6 — — —
Other Asthenia Abnormal Ejaculationa Sweating Impotencea Libido Decreased | 1.6 1.6 1.0 — | 0.4 0 0.3 | 1.9 2.1 — 1.5 | 0.4 0 0 | | | 2.5 4.9 1.1 1.0 | 0.6 0.6 0 0 | 1.8 2.5 1.1 | 0.2 0.5 0.2 | 1.6 — — — — | 0.2 — — — —

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) %
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.”
Body as a Whole Headache Asthenia | 18 15 | 17 6
Cardiovascular Palpitation Vasodilation | 3 3 | 1 1
Dermatologic Sweating Rash | 11 2 | 2 1
Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite Flatulence Oropharynx Disordera Dyspepsia | 26 18 14 12 6 4 2 2 | 9 12 9 8 2 2 0 1
Musculoskeletal Myopathy Myalgia Myasthenia | 2 2 1 | 1 1 0
Nervous System Somnolence Dizziness Insomnia Tremor Nervousness Anxiety Paresthesia Libido Decreased Drugged Feeling Confusion | 23 13 13 8 5 5 4 3 2 1 | 9 6 6 2 3 3 2 0 1 0
Respiration Yawn | 4 | 0
Special Senses Blurred Vision Taste Perversion | 4 2 | 1 0
Urogenital System Ejaculatory Disturbanceb,c Other Male Genital Disordersb,d Urinary Frequency Urination Disordere Female Genital Disordersb,f | 13 10 3 3 2 | 0 0 1 0 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
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) %
a. Percentage corrected for gender.
Body as a Whole Asthenia Abdominal Pain Chest Pain Back Pain Chills Trauma | 22 - 3 - 2 — | 14 - 2 - 1 — | 14 4 - 3 2 — | 5 3 - 2 1 — | 22 — - - — 3 | 14 — - - — 1
Cardiovascular Vasodilation Palpitation | 4 2 | 1 0 | — — | — — | — — | — —
Dermatologic Sweating Rash | 9 3 | 3 2 | 14 — | 6 — | 9 — | 2 —
Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite Dyspepsia Flatulence Increased Appetite Vomiting | 23 18 16 10 9 - - 4 - | 10 9 6 10 3 - - 3 - | 23 18 8 12 7 - - 2 - | 17 11 5 7 3 - - 1 - | 25 9 5 9 8 4 4 - 2 | 7 3 2 6 2 2 2 - 1
Musculoskeletal Myalgia | — | — | — | — | 4 | 3
Nervous System Insomnia Somnolence Dizziness Tremor Nervousness Libido Decreased Agitation Anxiety Abnormal Dreams Concentration Impaired Depersonalization Myoclonus Amnesia | 24 24 12 11 9 7 — — 4 3 3 3 2 | 13 7 6 1 8 4 — — 1 2 0 0 1 | 18 19 14 9 — 9 5 5 — — — 3 - | 10 11 10 1 — 1 4 4 — — — 2 - | 21 22 11 9 8 12 3 5 — 4 — 2 - | 16 5 7 1 7 1 1 4 — 1 — 1 -
Respiratory System Rhinitis Pharyngitis Yawn | - — - | - — - | 3 — - | 0 — - | - 4 5 | - 2 1
Special Senses Abnormal Vision Taste Perversion | 4 2 | 2 0 | — - | — - | 4 - | 1 -
Urogenital System Abnormal Ejaculationa Dysmenorrhea Female Genital Disordera Impotencea Urinary Frequency Urination Impaired Urinary Tract Infection | 23 — 3 8 3 3 2 | 1 — 0 1 1 0 1 | 21 — 9 5 2 — 2 | 1 — 1 0 0 — 1 | 28 5 9 5 — — — | 1 4 1 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 PTSDa
Body System/Preferred Term | Generalized Anxiety Disorder | Posttraumatic Stress Disorder
Paroxetine (n = 735) % | Placebo (n = 529) % | Paroxetine (n = 676) % | Placebo (n = 504) %
a. Percentage corrected for gender.
Body as a Whole Asthenia Headache Infection Abdominal Pain Trauma | 14 17 6 | 6 14 3 | 12 — 5 4 6 | 4 — 4 3 5
Cardiovascular Vasodilation | 3 | 1 | 2 | 1
Dermatologic Sweating | 6 | 2 | 5 | 1
Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite Vomiting Dyspepsia | 20 11 10 9 5 3 — | 5 5 2 7 1 2 — | 19 10 5 11 6 3 5 | 8 5 3 5 3 2 3
Nervous System Insomnia Somnolence Dizziness Tremor Nervousness Libido Decreased Abnormal Dreams | 11 15 6 5 4 9 | 8 5 5 1 3 2 | 12 16 6 4 — 5 3 | 11 5 5 1 — 2
Respiratory System Respiratory Disorder Sinusitis Yawn | 7 4 4 | 5 3 — | — — 2 | — — <1
Special Senses Abnormal Vision | 2 | 1 | 3 | 1
Urogenital System Abnormal Ejaculationa Female Genital Disordera Impotence a | 25 4 4 | 2 1 3 | 13 5 9 | 2 1 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 n = 51 % | Paroxetine
10 mg n = 102 % | 20 mg n = 104 % | 30 mg n = 101 % | 40 mg n = 102 %
Body as a Whole Asthenia | 0.0 | 2.9 | 10.6 | 13.9 | 12.7
Dermatology Sweating | 2.0 | 1.0 | 6.7 | 8.9 | 11.8
Gastrointestinal | | | | |
Constipation | 5.9 | 4.9 | 7.7 | 9.9 | 12.7
Decreased Appetite | 2.0 | 2.0 | 5.8 | 4.0 | 4.9
Diarrhea | 7.8 | 9.8 | 19.2 | 7.9 | 14.7
Dry Mouth | 2.0 | 10.8 | 18.3 | 15.8 | 20.6
Nausea | 13.7 | 14.7 | 26.9 | 34.7 | 36.3
Nervous System | | | | |
Anxiety | 0.0 | 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 Senses Blurred 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 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 to 15 | 0 to 5
Ejaculatory Disturbance | 13 to 28 | 0 to 2
Impotence | 2 to 9 | 0 to 3
n (females) | 1822 % | 1340 %
Decreased Libido | 0 to 9 | 0 to 2
Orgasmic Disturbance | 2 to 9 | 0 to 1

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.

6.2 Postmarketing Experience

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

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

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2.

Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients
Age Range | Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients Treated
| Increases Compared to Placebo
<18 years old | 14 additional cases
18 to 24 years old | 5 additional cases
| Decreases Compared to Placebo
25 to 64 years old | 1 fewer case
≥65 years old | 6 fewer cases

Paroxetine is not approved for use in pediatric patients.

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

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

5.2 Serotonin Syndrome

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

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

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

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

5.3 Drug Interactions Leading to QT Prolongation

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

5.4 Embryofetal Toxicity

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

5.5 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including 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 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 coadministration. However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

5.12 Bone Fracture

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

5.13 Sexual Dysfunction

Use of SSRIs, including paroxetine, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.
It is important for prescribers to inquire about sexual function prior to initiation of paroxetine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

Table 9 presents clinically significant drug interactions with paroxetine.

Table 9 : Clinically Significant Drug Interactions with Paroxetine
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact | The concomitant use of SSRIs, including paroxetine, and MAOIs increases the risk of serotonin syndrome.
Intervention | Paroxetine is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.5) , Contraindications (4) , Warnings and Precautions (5.2) ].
Examples | selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide and Thioridazine
Clinical Impact | Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias.
Intervention | Paroxetine is contraindicated in patients taking pimozide or thioridazine [see Contraindications (4) ].
Other Serotonergic Drugs
Clinical Impact | The concomitant use of serotonergic drugs with paroxetine increases the risk of serotonin syndrome.
Intervention | Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of paroxetine and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2) ].
Examples | other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort.
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact | The concurrent use of an antiplatelet agent or anticoagulant with paroxetine may potentiate the risk of bleeding.
Intervention | Inform patients of the increased risk of bleeding associated with the concomitant use of paroxetine and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions (5.5) ].
Examples | aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact | Paroxetine is highly bound to plasma protein. The concomitant use of paroxetine with another drug that is highly bound to plasma protein may increase free concentrations of paroxetine or other tightly-bound drugs in plasma.
Intervention | Monitor for adverse reactions and reduce dosage of paroxetine or other protein-bound drugs as warranted.
Examples | Warfarin
Drugs Metabolized by CYP2D6
Clinical Impact | Paroxetine is a CYP2D6 inhibitor [see Clinical Pharmacology (12.3) ]. The concomitant use of paroxetine with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention | Decrease the dosage of a CYP2D6 substrate if needed with concomitant paroxetine use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if paroxetine is discontinued.
Examples | propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone.
Tamoxifen
Clinical Impact | Concomitant use of tamoxifen with paroxetine may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen
Intervention | Consider use of an alternative antidepressant with little or no CYP2D6 inhibition [see Warnings and Precautions (5.11) ].
Fosamprenavir/Ritonavir
Clinical Impact | Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine.
Intervention | Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including paroxetine, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

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].

Paroxetine is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. While individual epidemiological studies on the association between paroxetine use and cardiac malformations have reported inconsistent findings, some meta-analyses of epidemiological studies have identified an increased risk of cardiovascular malformations (see Data). There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including paroxetine during pregnancy. There also are risks associated with untreated depression in pregnancy (see Clinical Considerations). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options.

No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 60 mg) on an mg/m² basis. When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m² basis (See Data).

The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum.

Maternal Adverse Reactions

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

Fetal/Neonatal adverse reactions

Neonates exposed to paroxetine and other SSRIs 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, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs 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)].

Data

Human Data

Published epidemiological studies on the association between first trimester paroxetine use and cardiovascular malformations have reported inconsistent results; however, meta-analyses of population-based cohort studies published between 1996 to 2017 indicate a less than 2-fold increased risk for overall cardiovascular malformations. Specific cardiac malformations identified in two meta-analyses include an approximately 2 to 2.5-fold increased risk for right ventricular outflow tract defects. One meta-analysis also identified an increased risk (less than 2-fold) for bulbus cordis anomalies and anomalies of cardiac septal closure, and an increased risk for atrial septal defect (pooled OR 2.38, 95% CI 1.14 to 4.97). Important limitations of the studies included in these meta-analyses include potential confounding by indication, depression severity, and potential exposure misclassification.

Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality.

Animal Data

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 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 60 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 less 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.

8.2 Lactation

Risk Summary

Data from the published literature report the presence of paroxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to paroxetine through breast milk (see Clinical Considerations). There are no data on the effect of paroxetine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for paroxetine and any potential adverse effects on the breastfed child from paroxetine or from underlying maternal condition.

Clinical Considerations

Infants exposed to paroxetine should be monitored for agitation, irritability, poor feeding and poor weight gain.

Data

Published literature suggests the presence of paroxetine in human milk with relative infant doses ranging between 0.4% to 2.2%, and a milk/plasma ratio of <1. No significant amounts were detected in the plasma of infants after breastfeeding.

8.3 Females and Males of Reproductive Potential

Infertility

Male

Based on findings from clinical studies, paroxetine may affect sperm quality which may impair fertility; it is not known if this effect is reversible [see Nonclinical Toxicology (13.1)].

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 selfharm, 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)].

The following have been reported with paroxetine tablet overdosage:

• Seizures, which may be delayed, and altered mental status including coma.
• Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
• Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk).

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose.

Consider contacting a poison center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

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 tablets 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 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 and tablet.

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 tablets daily for 30 days of paroxetine.