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SIDE EFFECTS

Associated with Discontinuation of Treatment

Twenty percent (1199/6145) of patients treated with paroxetine in worldwide clinical trials in MDD and 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine in worldwide trials in OCD, PD, and GAD, respectively, discontinued treatment due to an adverse event. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) included the following:

  MDD OCD PD GAD
Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo
CNS
Somnolence 2.3% 0.7% - - 1.9% 0.3% 2.0% 0.2%
Insomnia - - 1 .7% 0% 1.3% 0.3% - -
Agitation 1.1% 0.5% - - - - - -
Tremor 1.1% 0.3% -
Dizziness - - 1.5% 0% - - 1.0% 0.2%
Gastrointestinal
Constipation - - 1.1% 0% - - - -
Nausea 3.2% 1.1% 1.9% 0% 3.2% 1 .2% 2.0% 0.2%
Diarrhea 1.0% 0.3% - - - - - -
Dry mouth 1.0% 0.3% - - - - - -
Vomiting 1.0% 0.3% - - - - - -
Other
Asthenia 1 .6% 0.4% 1 .9% 0.4% - - 1.8% 0.2%
Abnormal Ejaculation1 1 .6% 0% 2.1% 0% - - 2.5% 0.5%
Sweating 1.0% 0.3% - - - - 1.1% 0.2%
Impotence1 - - 1.5% 0% - - - -
Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not > 1% or was not greater than or equal to two times the incidence of placebo.
1 Incidence corrected for gender.

Commonly Observed Adverse Events

Major Depressive Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 2 below) were: asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders.

Obsessive Compulsive Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that of placebo, derived from Table 3 below) were: nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.

Panic Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 3 below) were: asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.

Generalized Anxiety Disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 4) were: asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.

Incidence in Controlled Clinical Trials

The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied.

Major Depressive Disorder

Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

TABLE 2: Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for MDD1

Body System Preferred Term 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 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 3,4 13% 0%
Other Male Genital Disorders 3,5 10% 0%
Urinary Frequency 3% 1%
Urination Disorder 6 3% 0%
Female Genital Disorders 3,7 2% 0%
1 Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”), trauma, and vomiting.
2 Includes mostly “lump in throat” and “tightness in throat.”
3 Percentage corrected for gender.
4 Mostly “ejaculatory delay.”
5 Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction” and “impotence.”
6 Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7 Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”

Obsessive Compulsive Disorder and Panic Disorder

Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 to 60 mg/day or among patients with PD on paroxetine who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 to 60 mg/day.

TABLE 3: Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder and Panic Disorder1

Body System Preferred Term Paroxetine
(n=542)
Placebo
(n=265)
Paroxetine
(n=469)
Placebo
(n=324)
Body as a Whole Asthenia 22% 14% 14% 5%
Abdominal Pain - - 4% 3%
Chest Pain 3% 2% - -
Back Pain - - 3% 2%
Chills 2% 1% 2% 1%
Cardiovascular Vasodilation 4% 1% - -
Palpitation 2% 0% - -
Dermatologic Sweating 9% 3% 14% 6%
Rash 3% 2% - -
Gastrointestinal Nausea 23% 10% 23% 17%
Dry Mouth 18% 9% 18% 11%
Constipation 16% 6% 8% 5%
Diarrhea 10% 10% 12% 7%
Decreased Appetite 9% 3% 7% 3%
Increased Appetite 4% 3% 2% 1%
Nervous System Insomnia 24% 13% 18% 10%
Somnolence 24% 7% 19% 11%
Dizziness 12% 6% 14% 10%
Tremor 11% 1% 9% 1%
Nervousness 9% 8% - -
Libido Decreased 7% 4% 9% 1%
Agitation - - 5% 4%
Anxiety - - 5% 4%
Abnormal Dreams 4% 1% - -
Concentration Impaired 3% 2% - -
Depersonalization 3% 0% - -
Myoclonus 3% 0% 3% 2%
Amnesia 2% 1% - -
Respiratory System Rhinitis - - 3% 0%
Special Senses Abnormal Vision 4% 2%
Taste Perversion 2% 0% - -
Urogenital System Abnormal Ejaculation 2 23% 1% 21% 1%
Female Genital Disorder 2 3% 0% 9% 1%
Impotence 2 8% 1% 5% 0%
Urinary Frequency 3% 1% 2% 0%
Urination Impaired 3% 0% - -
  Urinary Tract Infection 2% 1% 2% 1%
1 Events reported by at least 2% of OCD or PD paroxetine-treated patients are included, except the following events which had an incidence on placebo ≥ paroxetine [OCD]: abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [PD]: abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation.
2 Percentage corrected for gender.

Generalized Anxiety Disorder

Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day.

TABLE 4: Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized Anxiety Disorder1

Body System Preferred Term Paroxetine
(n=735)
Placebo
(n=529)
Body as a Whole Asthenia 14% 6%
Headache 17% 14%
Infection 6% 3%
Cardiovascular Vasodilation 3% 1%
Dermatologic Sweating 6% 2%
Gastrointestinal Nausea 20% 5%
Dry Mouth 11% 5%
Constipation 10% 2%
Diarrhea 9% 7%
Decreased Appetite 5% 1%
Vomiting 3% 2%
Nervous System Insomnia 11% 8%
Somnolence 15% 5%
Dizziness 6% 5%
Tremor 5% 1%
Nervousness 4% 3%
Libido Decreased 9% 2%
Respiratory System Respiratory Disorder 7% 5%
Sinusitis 4% 3%
Yawn 4% -
Special Senses Abnormal Vision 2% 1%
Urogenital System Abnormal Ejaculation 2 25% 2%
Female Genital Disorder 4% 1%
Impotence 2 4% 3%
1 Events reported by at least 2% of GAD patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis.
2 Percentage corrected for gender.

Dose Dependency of Adverse Events

A comparison of adverse event rates in a fixed-dose study comparing paroxetine 10, 20, 30, and 40 mg/day with placebo in the treatment of MDD revealed a clear dose dependency for some of the more common adverse events associated with paroxetine use, as shown in the following table:

TABLE 5: Treatment-Emergent Adverse Experience Incidence 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%
*Rule for including adverse events in table: incidence at least 5% for one of paroxetine groups and ≥ twice the placebo incidence for at least one paroxetine group.

In a fixed-dose study comparing placebo and paroxetine 20, 40, and 60 mg in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned. No new adverse events were observed in the paroxetine 60 mg dose group compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and paroxetine 10, 20, and 40 mg in the treatment of PD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of GAD, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for the following adverse events: asthenia, constipation, and abnormal ejaculation.

In flexible dose studies, no new adverse events were observed in patients receiving paroxetine 60 mg compared to any of the other treatment groups.

Adaptation to Certain Adverse Events

Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia).

Male and Female Sexual Dysfunction with SSRIs

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 pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

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 physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.

In placebo-controlled clinical trials involving more than 3200 patients the ranges for the reported incidence of sexual side effects in males and females with MDD, OCD, PD, social anxiety disorder, GAD, and post traumatic stress disorder (PTSD) are displayed in Table 6.

TABLE 6: Incidence of Sexual Adverse Events in Controlled Clinical Trials

  Paroxetine Placebo
n (males) 1446 1042
  Decreased Libido 6% - 15% 0% - 5%
  Ejaculatory Disturbance 13% - 28% 0% - 2%
  Impotence 2% -9% 0% -3%
n (females) 1822 1340
  Decreased Libido 0% -9% 0% -2%
  Orgasmic Disturbance 2% -9% 0% -1%

There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment. Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Weight and Vital Sign Changes

Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss vs. smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature) were observed in patients treated with paroxetine in controlled clinical trials.

ECG Changes

In an analysis of ECGs obtained in 682 patients treated with paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group.

Liver Function Tests

In placebo-controlled clinical trials, patients treated with paroxetine exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine vs. placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities.

Hallucinations

In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo.

Other Events Observed During the Premarketing Evaluation of Paroxetine

During its premarketing assessment in MDD, multiple doses of paroxetine were administered to 6145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. During premarketing clinical trials in OCD, PD, and GAD, 542, 469, and 735 patients, respectively, received multiple doses of paroxetine. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9089 patients exposed to multiple doses of paroxetine who experienced an event of the type cited on at least one occasion while receiving paroxetine. All reported events are included except those already listed in Tables 2 to 4, those reported in terms so general as to be uninformative, and those events where a drug cause was remote.

It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section.

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 infarction, 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, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; rare: aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, chlolelithiasis, 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, hallucinations, 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, pyuria, polyuria, 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.

Postmarketing Reports

Voluntary reports of adverse events in patients taking paroxetine that have been received since market introduction and not listed above that may have no causal relationship with the drug include 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, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide, tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women.

There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

Drug Abuse And Dependence

Controlled Substance Class

Paroxetine is not a controlled substance.

Physical and Psychologic Dependence

Paroxetine has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of PEXEVA® (paroxetine mesylate) misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

Read the Pexeva (paroxetine mesylate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Tryptophan

As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine with tryptophan is not recommended.

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS and WARNINGS.

Pimozide

In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, coadministration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see CONTRAINDICATIONS).

Serotonergic Drugs

Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS-Serotonin Syndrome). The concomitant use of paroxetine with other SSRIs, SNRIs, or tryptophan is not recommended (see PRECAUTIONS-DRUG INTERACTIONS, Tryptophan).

Thioridazine

See CONTRAINDICATIONS and WARNINGS.

Warfarin

Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere With Hemostasis).

Triptans

There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS-Serotonin Syndrome).

Drugs Affecting Hepatic Metabolism

The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.

Cimetidine-Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where paroxetine (30 mg qd) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg tid) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine's pharmacokinetics was not studied.

Phenobarbital-Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine was administered at phenobarbital steady state (100 mg qd for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial paroxetine dosage adjustment is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Phenytoin-When a single oral 30 mg dose of paroxetine was administered at phenytoin steady state (300 mg qd for 14 days), paroxetine AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg qd for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS-Postmarketing Reports).

Drugs Metabolized by Cytochrome CYP2D6

Many drugs, including most drugs effective in the treatment of MDD (paroxetine, other SSRIs, and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients ( > 90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In one study, daily dosing of paroxetine (20 mg qd) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate, has also been evaluated. In one study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine.

Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug.

Therefore, coadministration of PEXEVA® (paroxetine mesylate) with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of MDD (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.

However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine, and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS).

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS).

At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes, which, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONSTricyclic Antidepressants).

Drugs Metabolized by Cytochrome CYP3A4

An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome 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. Based on the assumption that the relationship between paroxetine's in vitro Ki and its lack of effect on terfenadine's in vivo clearance predicts its effect on other 3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic Antidepressants (TCA)

Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with PEXEVA® (paroxetine mesylate), because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced, if a TCA is coadministered with PEXEVA® (paroxetine mesylate). (See PRECAUTIONS Drugs Metabolized by Cytochrome CYP2D6).

Drugs Highly Bound to Plasma Protein

Because paroxetine is highly bound to plasma protein, administration of PEXEVA® (paroxetine mesylate) to a patient taking another drug that is highly protein-bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when PEXEVA® (paroxetine mesylate) is initiated or discontinued.

Alcohol - Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PEXEVA® (paroxetine mesylate).

Lithium - A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, the concurrent administration of paroxetine and lithium should be undertaken with caution.

Digoxin - The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.

Diazepam - Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.

Procyclidine - Daily oral dosing of paroxetine (30 mg qd) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral qd) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.

Beta-Blockers - In a study where propranolol (80 mg bid) was dosed orally for 18 days, the established steadystate plasma concentrations of propranolol were unaltered during coadministration with paroxetine (30 mg qd) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS-Postmarketing Reports).

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.

Fosamprenavir/Ritonavir - Coadministration of fosamprenavir/ ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of ECT and paroxetine.

Read the Pexeva Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 1/23/2013
This monograph has been modified to include the generic and brand name in many instances.

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