Gastrointestinal side effects are some of the most commonly reported adverse events to SSRIs, including paroxetine. In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, nausea/vomiting occurred in 4.3% of paroxetine-treated patients and 2.3% of placebo-treated patients; abdominal pain lead to discontinuation of treatment in 0.3% of patients.[55186] In adult trials, nausea (17 to 26%), xerostomia (3 to 18%), constipation (5 to 16%), diarrhea (6 to 18%), abdominal pain (3 to 7%), anorexia (1 to 9%), appetite stimulation (2 to 4%), weight gain (1 to 3%), weight loss (1%), flatulence (4 to 6%), oropharynx disorder (2%), vomiting (2 to 3%), dyspepsia (2 to 5%), gingivitis (1%), and tooth disorder (1%) were reported. Thirst was reported infrequently (1% or less) and may be associated with dry mouth (xerostomia). In pediatric paroxetine trials, decreased appetite (anorexia) was reported in 2% or more of patients and at a rate at least twice that of placebo. With continued treatment over several weeks, adaptation to some GI adverse events (e.g., nausea) may occur, but other effects (e.g., dry mouth) may continue. Most GI effects appear to be dose-related and may respond well to dosage reduction. Other GI effects reported in 1% of adult patients during premarketing evaluation include teeth grinding (bruxism), colitis, dysphagia, eructation, gastritis, gastroenteritis, gastroesophageal reflux, glossitis, hypersalivation, hemorrhoids, melena, rectal hemorrhage, dental pain, and ulcerative stomatitis. Rare (less than 0.1%) were gingival hyperplasia, GI obstruction, peptic ulcer, stomach ulcer, and throat tightness. Also observed were aphthous stomatitis, bloody diarrhea, bulimia, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impaction, fecal incontinence, gum hemorrhage, hematemesis, ileitis, ileus, oral ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue edema, and dental caries. During postmarketing use, laryngospasm has been reported; however, the frequency is unknown and causality to the drug has not been established. Significant weight loss may be an undesirable result of treatment for some patients, but on average, patients in controlled trials had minimal (roughly 0.45 kg) weight loss vs. smaller changes on placebo or active control. However, because decreased appetite and weight loss have been observed during use of SSRIs, periodic monitoring of weight and height are recommended in pediatric patients or other patients at risk receiving paroxetine.[28260] [43998] [43999]

In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, extrapyramidal effects were not reported.[55186] During adult clinical trial evaluation, hypertonia (2 to 3%), tremor (4 to 11%), and myoclonia (1 to 3%) occurred more frequently in patients receiving paroxetine than placebo. Extrapyramidal effects or movement disorders infrequently reported (0.1 to 1%) include ataxia, dystonia, dyskinesia, hypokinesia, and muscle paralysis. Extrapyramidal effects or movement disorders rarely reported (less than 0.1%) include akathisia, choreoathetosis, incoordination, fasciculations, abnormal gait, hyperkinesis, bradykinesia, akinesia, hyporeflexia, hyperreflexia, pseudoparkinsonism (cogwheel rigidity), dystonic reaction (e.g., torticollis, trismus), dysarthria, and nystagmus. Oculogyric crisis has occurred when paroxetine has been used in conjunction with pimozide. Tremor and hyperkinesis were reported in 2% or more of pediatric patients at a rate at least twice that of placebo during clinical trials..[28260] [43998] [43999]

Neurologic side effects are common with paroxetine therapy. In clinical trials of paroxetine for the treatment of depression and other psychiatric or mood disorders, drowsiness (9 to 24%), headache (15 to 27%), migraine (1 to 2%), dizziness (6 to 14%), insomnia (8 to 24%), vertigo (2%), yawning (4 to 5%), paresthesias (1 to 4%), abnormal dreams (1 to 4%), impaired concentration (2 to 4%), memory impairment (2%), drugged feeling (2%), amnesia (1%), and confusion (1%) occurred in paroxetine-treated patients. Premarketing adverse effects reported in 0.1% to 1% of patients included abnormal thinking, hypoesthesia, neuralgia, neuropathy (neuropathic pain), and seizures. Rare events (less than 0.1%) included aphasia, circumoral paresthesias, coma, grand mal seizures, hyperalgesia, meningitis, myelitis, neuralgia, peripheral neuritis, and stupor. Guillain-Barre syndrome, restless legs syndrome (RLS), and status epilepticus have been reported postmarketing. Limited data suggest that paroxetine may increase seizure length in patients undergoing electroconvulsive therapy (ECT). In clinical trials for vasomotor symptoms associated with menopause, headache was reported in 6.3% of paroxetine-treated patients and attention disturbances lead to discontinuation of the drug in 0.3% of patients.[28260] [43998] [43999] [55186]

In adult trials, psychiatric effects reported more frequently in patients receiving paroxetine than placebo included nervousness (2% to 9%), anxiety (2% to 5%), agitation (2% to 5%), lack of emotion (apathy, 2%), and emotional lability (1% or more). Other effects reported in 0.1% to 1% of patients included abnormal thinking, euphoria, hallucinations, hostility, neurosis, and paranoia. Rare events (less than 0.1%) included antisocial reaction, delirium, delusions, hysteria, psychosis, psychotic depression, and stupor. Mania can occur in predisposed patients during treatment with an antidepressant. Hypomania or mania occurred in approximately 1% of paroxetine-treated adult patients with major depressive disorder and mania was reported in 2.2% of a subset of patients classified as bipolar. Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over 24 years of age; there was a reduction in risk with antidepressant use in patients aged 65 and older. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. During the clinical evaluation of paroxetine to treat vasomotor symptoms associated with menopause (7.5 mg/day dosing), suicidal ideation was reported in 3 paroxetine-treated patients, and 1 patient receiving the drug reported a suicide attempt.[28260] [43998] [43999] [55186]

Hyponatremia was reported rarely (less than 0.1%) during premarketing evaluation of paroxetine in adult patients. Several cases of hyponatremia have been reported with the use of SSRIs. While the cases were complex, some instances may have been due to the syndrome of inappropriate antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Like with all SSRIs, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) presents as hyposmolarity of serum and urine, and hyponatremia. The hyponatremia appeared to be reversible when paroxetine was discontinued. The majority of cases have been seen in patients that are elderly, in patients taking diuretics, or in patients who are volume depleted. In a prospective cohort study, 9 of 75 (12%) elderly patients age 63 to 90 years taking paroxetine developed hyponatremia (plasma sodium less than 135 mEq/L). The median time to development of hyponatremia after initiation of paroxetine was 9 days (range 1 to 14 days). Predictors for development of hyponatremia included lower baseline plasma sodium (less than 138 mEq/L) and lower body mass index. Hyponatremia does not appear to be associated with plasma concentrations of paroxetine.[27868] Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness. More severe cases may cause hallucinations, fainting, seizures, coma, respiratory arrest, and death. Discontinuation of paroxetine may be necessary in those with symptomatic hyponatremia.[28260] [43998] [43999]

Platelet dysfunction (i.e., impaired platelet aggregation) may occur during treatment with selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., GI bleeding, ecchymosis, epistaxis, hematoma, petechiae, hemorrhage). Hematologic and lymphatic effects reported in 0.1 to 1% of patients during premarketing evaluation of 1 or more paroxetine formulations included anemia, ecchymosis, eosinophilia, hematoma, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, and purpura. Rare events (less than 0.1%) reported during use of one or more paroxetine formulations included abnormal erythrocytes, anisocytosis, basophilia, ecchymosis, prolonged bleeding time, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, and thrombocytopenia. During postmarketing use, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, bone marrow aplasia, agranulocytosis, and vasculitic syndromes such as Henoch-Schonlein purpura and vasculitis have been reported. An increased risk of bleeding complications is possible in patients receiving antiplatelet or anticoagulant medications concurrently with paroxetine.[28260] [43998] [43999]

Cardiovascular events may occur during paroxetine treatment. In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause (Brisdelle), adverse cardiac effects were not reported.[55186] Clinical data from all other conditions studied indicate that the following cardiovascular effects occurred more frequently in those receiving immediate-release paroxetine mesylate or hydrochloride formulations than placebo: palpitations (2 to 3%), chest pain (unspecified) (3%), and unspecified peripheral vasodilation (3 to 4%). The following cardiac effects occurred more frequently in those receiving controlled-release paroxetine than placebo during all conditions studied: sinus tachycardia (1 to 2%), hypertension (2%), chest pain (unspecified) (1%), and vasodilation (2 to 3%). Hypertension and sinus tachycardia occurred in at least 1% of patients receiving immediate-release formulations. Other effects reported in 0.1 to 1% of patients during premarketing evaluation of one or more paroxetine formulations included angina, bradycardia, hypotension, orthostatic hypotension, supraventricular tachycardia (SVT), and syncope. Rare events (less than 0.1%) reported during use of 1 or more paroxetine formulations included angina pectoris, arrhythmia nodal, atrial fibrillation, bundle-branch block, cerebral ischemia, cerebrovascular accident (stroke), congestive heart failure, heart block (unspecified), low cardiac output, myocardial infarction, myocardial ischemia, pallor, phlebitis, pulmonary embolism, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headaches, and ventricular extrasystoles. No significant changes in ECG patterns were observed in patients treated with paroxetine versus placebo in controlled clinical trials. During postmarketing use, pulmonary hypertension, ventricular fibrillation, and ventricular tachycardia (including torsade de pointes) have been reported.[28260] [43998] [43999]

Clinical data from clinical studies indicate that the following general effects occurred more frequently in those receiving immediate-release paroxetine mesylate or hydrochloride formulations than placebo: asthenia (12 to 22%), chills (2%), and unspecified trauma (3 to 6%). The following general effects occurred more frequently in those receiving controlled-release paroxetine than placebo during all conditions studied: asthenia (14 to 18%), unspecified trauma (3 to 5%), and generalized edema (1%). General effects reported in 0.1 to 1% of adult patients during premarketing evaluation for all conditions include chills, face edema, malaise, and neck pain. Rare events (less than 0.1%) reported include adrenergic syndrome, cellulitis, candidiasis, neck rigidity, peritonitis, ulcer, and sepsis.[28260] [43998] [43999] In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, fatigue, malaise, or lethargy occurred in 4.9% of paroxetine-treated patients and 2.8% of placebo-treated patients.[55186]

Hypersensitivity and allergic reactions (2% or less) have been reported with paroxetine use. The most common dermatologic reactions reported during adult clinical trials include hyperhidrosis (6 to 14%), rash (unspecified) (2 to 3%), flushing (1 to 4%), atopic dermatitis (1%), and pruritus (1% or more). During pediatric trials, hyperhidrosis occurred in 2% or more of patients at a rate at least twice that of placebo. The following allergic reactions occurred more frequently in those receiving immediate-release paroxetine than placebo in clinical trials: allergic reaction (unspecified, 2%). Serious reactions are not common; during clinical trials, anaphylaxis/anaphylactoid reactions (0.1 to 1%) were infrequent and angioedema, erythema multiforme, and exfoliative dermatitis were rare (less than 0.1%). Other infrequent (0.1 to 1%) dermatologic events reported include acne vulgaris, alopecia, contact dermatitis, xerosis, eczema, herpes simplex, photosensitivity, and urticaria. Rare events (less than 0.1%) included erythema nodosum, fungal dermatitis, furunculosis, herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, decreased sweating, and vesiculobullous rash (vesicular rash or bullous rash). During postmarketing use, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), laryngospasm, and allergic alveolitis (also known as hypersensitivity pneumonitis) have been reported; however, the frequencies are unknown and causality to the drug has not been established.[28260] [43998] [43999] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported during postmarketing use of paroxetine according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).[62974] Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Paroxetine should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with a rash or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified.[62975] [62976] In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, dermatologic effects were not reported.[55186]

Rhinitis (3 to 4%), pharyngitis (4%), infection (unspecified) (5 to 8%), unspecified respiratory disorder (7%), increased cough (1 to 2%), bronchitis (1 to 2%), pharyngitis (more than 1%), and sinusitis (4 to 8%) have been reported during adult clinical trials of paroxetine. Respiratory/infectious effects reported in 0.1 to 1% of patients during premarketing evaluation include asthma (bronchospasm), bronchitis, dyspnea, flu syndrome, hyperventilation, fever, laryngitis, pneumonia, and sepsis. Rare events (less than 0.1%) reported include emphysema, hemoptysis, hiccups, pulmonary fibrosis, pulmonary edema, increased sputum, stridor, and voice alteration (dysphonia). Hypersensitivity reactions affecting the airway including laryngismus and allergic alveolitis/pneumonitis have been reported with postmarketing use.[28260] [43998] [43999] These respiratory effects and infections were not reported in clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause (Brisdelle).[55186] However, anosmia and hyposmia have also been reported with postmarketing use of all paroxetine formulations.[28260] [43998] [43999] [55186]

Infrequently, alterations in special senses such as blurred vision (2 to 4%), unspecified abnormal vision or visual impairment (1 to 5%), and dysgeusia (2%) were reported during adult clinical trials of paroxetine. Tinnitus occurred in at least 1% of patients. Other effects reported in 0.1 to 1% of adult patients include abnormal accommodation, conjunctivitis, ear pain (otalgia), ocular pain, keratoconjunctivitis, mydriasis, and otitis media. Rare events (less than 0.1%) included amblyopia, diplopia, anisocoria, blepharitis, cataracts, conjunctival edema, corneal edema, corneal ulcer, deafness (hearing loss), exophthalmos, ocular hemorrhage, glaucoma (ocular hypertension), hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, and visual field defects occurred. During postmarketing use, optic neuritis has been reported although the frequency is unknown and causality to the drug has not been established. Due to reports of narrow-angle glaucoma with paroxetine and other SSRIs, use paroxetine with caution in patients with narrow angle glaucoma.[28260] [43998] [43999] In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, adverse effects related to the special senses were not reported.[55186]

Paroxetine is extensively metabolized in the liver. Adverse hepatobiliary effects reported infrequently (0.1 to 1%) in adult patients during premarketing evaluation of paroxetine included abnormal liver function tests (elevated hepatic enzymes). Rare events (less than 0.1%) included pancreatitis, hyperbilirubinemia, hepatomegaly and splenomegaly combined (hepatosplenomegaly), hepatitis, and jaundice. During postmarketing use, acute pancreatitis, porphyria, and elevated hepatic enzymes (in severe cases resulting in death due to hepatic necrosis, and grossly elevated transaminases associated with severe liver dysfunction) have been reported.[28260] [43998] [43999] Adverse hepatic effects were not reported in clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause.[55186]

Genital and reproductive disorders have occurred in femal and male patients receiving paroxetine. Unspecified female (2 to 10%) and male (2 to 10%) genital and reproductive disordershave been reported. Most frequently, specific adverse events such as menstrual disorder (2% or less), dysmenorrhea (5% or less), menorrhagia (1% or less), vaginal moniliasis/candidiasis ( 1% or less), and vaginitis (1 to 2%) were reported in female patients. Infrequently (0.1 to 1%) amenorrhea and mastalgia occurred. Rare events (less than 0.1%) reported include breast enlargement, breast neoplasm, female lactation or breast discharge, metrorrhagia, salpingitis, pelvic pain, and enlarged uterine fibroids. Also observed were breast atrophy, endometrial disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, uterine spasm, and vaginal bleeding. Symptoms suggestive of galactorrhea, gynecomastia, and hyperprolactinemia have been reported during postmarketing use with SSRIs including paroxetine; hyperprolactinemia can induce some reproductive/genital symptoms. Sexual effects have also been reported in both males and females receiving paroxetine. Clinical data from all other conditions studied indicate that the following sexual effects occurred more frequently in those receiving immediate-release paroxetine than placebo: ejaculation dysfunction, reported primarily as delayed ejaculation (13 to 28%), male genital disorders (10%), impotence (erectile dysfunction) (4 to 9%), libido decrease (3 to 9%), and female genital disorders including orgasm dysfunction (reported as anorgasmia, 2 to 9%). The following effects occurred more frequently in those receiving controlled-release paroxetine than placebo during all conditions studied: abnormal ejaculation (15 to 27%), libido decrease (7 to 12%), and impotence (erectile dysfunction) (5 to 10%). Other effects reported in 0.1 to 1% of patients during premarketing evaluation included libido increase. Rare events (less than 0.1%) reported during use of 1 or more paroxetine formulations included spontaneous fetal abortion, ejaculatory disturbance, uterine fibroids enlarged, and vaginal candidiasis. Eclampsia has been reported during postmarketing use of the drug. Some studies have shown that SSRIs may affect sperm quality; fertility may be affected in some men. Although the initial frequency of sexual side effects was reported to be relatively low from clinical trial data, postmarketing experience has suggested that the frequency of sexual adverse events is actually much higher than previously recognized.[28260] [43999] [43998] In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, sexual dysfunction was not reported.[55186] Priapism, a medical emergency in males, has been reported rarely with all SSRIs, including paroxetine, during postmarketing use. If priapism develops during treatment with an SSRI, the drug should be discontinued and appropriate medical interventions should be initiated.[28260] [43999] [43998]

Clinical data from all other conditions studied indicate that the following urinary or renal effects occurred more frequently in those receiving immediate-release paroxetine mesylate or hydrochloride formulations than placebo: increased urinary frequency (2 to 3%), urination disorder/dysuria (3%), impaired urination (3%), and urinary tract infection (2%). The following effects occurred more frequently in those receiving controlled-release paroxetine than placebo during all conditions studied: urinary tract infection (3%), increased urinary frequency (2%), and impaired urination (2%). Other effects reported in 0.1 to 1% of patients during premarketing evaluation of 1 or more paroxetine formulations included albuminuria (proteinuria), cystitis, dysuria, hematuria, nocturia, polyuria, urinary incontinence, urinary retention, and urinary urgency. Rare events (less than 0.1%) reported during use of one or more paroxetine formulations included kidney calculus (nephrolithiasis), kidney flank pain, nephritis, prostatitis, epididymitis, oliguria, pyuria, urethritis, urinary casts, and urolithiasis. Acute renal failure (unspecified) has been reported during postmarketing use of the drug.[28260] [43999] [43998] In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, urinary and renal effects were not reported.[55186]

Clinical data from all other conditions studied indicate that the following musculoskeletal effects occurred more frequently in those receiving immediate-release paroxetine than placebo: myopathy (2%), myalgia (2 to 4%), myasthenia (1%), and back pain (3%). The following musculoskeletal effects occurred more frequently in those receiving controlled-release paroxetine than placebo during all conditions studied: back pain (4 to 5%), unspecified pain (3%), arthralgia (2%), and myalgia (5%). Arthralgia occurred in at least 1% of patients receiving immediate-release formulations. Other effects reported in 0.1 to 1% of patients during premarketing evaluation of one or more paroxetine formulations included arthritis, arthrosis, bursitis, neck pain, and tendonitis. Rare events (less than 0.1%) reported during use of 1 or more paroxetine formulations included bursitis, generalized muscle spasm (muscle cramps), myasthenia, myopathy, myositis, tenosynovitis, and tetany.[28260] [43998] [43999] In clinical trials of the 7.5 mg/day dose for vasomotor symptoms associated with menopause, musculoskeletal effects were not reported.[55186]

Rare metabolic and nutritional events (less than 0.1%) reported during use of 1 or more paroxetine formulations included hyperglycemia and hypoglycemia. Endocrine effects reported rarely (less than 0.1%) included diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, and thyroiditis.[28260] [43998] [43999]

Metabolic and nutritional effects reported in 0.1 to 1% of patients during premarketing evaluation of one or more paroxetine formulations included thirst (polydipsia) and peripheral edema. Rare events (less than 0.1%) reported during use of 1 or more paroxetine formulations included increased alkaline phosphatase, hyperbilirubinemia, increased BUN, increased creatinine phosphokinase, dehydration, increased gamma globulins, gout, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypokalemia, ketosis, increased lactic dehydrogenase, and increased non-protein nitrogen (NPN).[28260] [43998] [43999]

Serotonin syndrome has been reported during use of SSRIs alone, during concurrent use of other medications known to increase CNS or peripheral serotonin levels, or during SSRI overdose. Serotonin syndrome has been noted in postmarketing reports with paroxetine. Signs and symptoms of serotonin syndrome with paroxetine include nausea, vomiting, excessive sedation, dizziness, diaphoresis (sweating), facial flush, mental status changes, myoclonus, restlessness, shivering, increased heart rate, and tremor. If serotonin syndrome becomes evident during treatment, the SSRI and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.[28260] [43998] [43999]

During pre-marketing evaluation of paroxetine, osteoporosis was reported rarely. Use selective serotonin reuptake inhibitors (SSRIs) with caution in patients with osteopenia or risk factors for osteopenia. Epidemiological studies suggest an association between the use of selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, and bone fractures.[28260] Some data suggest that chronic treatment with SSRIs may be associated with reduced bone density. Serotonin (5-HT) receptors and the serotonin reuptake transporter (5-HTT) have been found in osteoblasts and osteoclasts, and 5-HT functioning appears to be involved in bone architecture, bone mass, and bone density.[42688] Results of one observational retrospective study assessing the association between the degree of 5-HTT inhibition among antidepressants and the risk of osteoporotic and non-osteoporotic fractures indicated that use of antidepressants considered to have a high affinity for 5-HTT was associated with a higher risk of osteoporotic fractures than antidepressants with a moderate or low affinity for 5-HTT (OR 1.86, CI 1.63 to 2.13). There was no trend with increasing affinity for 5-HTT in non-osteoporotic fractures, although antidepressant use in general resulted in a 50% increase in this fracture type.[42688] In a separate prospective population-based cohort study, the risk of non-vertebral fractures was 2.35 in users of SSRIs compared to nonusers of antidepressants. A sub-analysis was conducted, which included current and prior antidepressant users only. The results showed that current users of SSRIs had a 2.07-fold increased risk of fracture compared to past users of tricyclic antidepressants or SSRIs, and this risk further increased with prolonged use.[42690]

A withdrawal syndrome was reported rarely (less than 0.1%) during pre-marketing evaluation of paroxetine. The most commonly reported withdrawal symptoms from SSRI discontinuation include fatigue, abdominal pain or nausea, dizziness/light-headedness, tremor, chill, diaphoresis, and incoordination. Other reported symptoms include impaired memory, insomnia, shock sensations, ringing in the ears, dysphoric mood, irritability, anxiety, confusion, lethargy, emotional lability, hypomania, headaches, and agitation or aggression. Withdrawal symptoms usually begin 1 to 3 days after abrupt discontinuation of the SSRI and remit within 1 to 2 weeks. While these adverse events are usually transient, some may be severe. Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of withdrawal symptoms. Even with gradual tapering, self-limited withdrawal events occurring in at least 2% of patients and greater than placebo have included: abnormal dreams, paresthesia, and dizziness. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the clinician may continue decreasing the dose but at a more gradual rate.[28260] [43998] [43999] Certain symptoms were seen more frequently in women at the time of discontinuation of low dose paroxetine compared to women discontinuing placebo; however, no specific tapering recommendations are available.[55186]

Epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of teratogenesis (i.e., cardiovascular malformations, primarily ventricular and atrial septal defects). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously.[28260] [43998] [43999] In addition, non-teratogenic risks have been reported in the neonate. A neonatal abstinence syndrome has been reported in infants exposed to paroxetine in utero.[26455] After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) were noted. Such complications can arise immediately upon delivery. Other symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, and constant crying. Serum concentrations of paroxetine were measurable in the infants affected. Several other symptoms (bloody stools, necrotizing enterocolitis) may have been attributable to rebound platelet activation on withdrawal of the exposure to the SSRI. Neonatal symptoms generally improved over several days. A cohort study of 55 women revealed that 22% (12/55) of neonates exposed to paroxetine in the third trimester had complications requiring treatment or extended hospitalization compared with 6% in comparison groups. Complications included respiratory distress (n = 9), hypoglycemia (n = 2) and jaundice (n = 1). The incidence of prematurity in the third trimester paroxetine group was significant at 20% vs. 3.7% of controls.[27398] These features are consistent with either a direct toxic effect of serotonergic agents, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with the serotonin syndrome. A case-controlled epidemiologic report has been published that suggests a significant association between maternal use of SSRIs after 20 weeks of pregnancy and the development of persistent pulmonary hypertension of the newborn (PPHN) (odds ratio (OR) 5.1; 95% CI, 1.9 to 13.3). The study population consisted of 377 women whose infants had PPHN and 836 matched control women and their infants. There was no increased risk of PPHN when SSRI use was restricted to the first half of the pregnancy (OR = 0.3; 95% CI, 0.1 to 1.1). Additionally, the use of non-SSRI antidepressant drugs at any time during pregnancy was not associated with an increased risk of PPHN. The SSRIs that were used by women 20 weeks or more of gestation in the study included fluoxetine, paroxetine and sertraline. However, the numbers were too small to permit examination of the effects of dose size, specific SSRI used, or reduction of the length of exposure before delivery.[32025] More recent retrospective studies have not shown an increased risk of PPHN with SSRI exposure.[47179] [47180] [47181] In December 2011, the FDA issued a safety announcement stating that based on conflicting data, an increased risk of PPHN from SSRI exposure cannot be determined. The FDA advises that healthcare professionals should not alter their current practice of treating depression in pregnancy at this time.[47182] When treating a pregnant woman with an SSRI or other serotonergic agent, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the half-life into consideration, tapering of the serotonergic agent prior to delivery may be considered as an alternative.

As with other SSRIs, decreased weight gain has been observed in children and adolescents receiving paroxetine. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition, but height and weight should be monitored periodically throughout therapy. In controlled clinical trials of paroxetine, patients had an average minimal weight loss of approximately 1 pound (2.2 kg) compared to smaller changes in those receiving placebo or active control. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.[27238] [28260] [43998] [43999]

Avoid abrupt discontinuation of any SSRI, like paroxetine, if possible. Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of potential discontinuation symptoms. The product labeling offers some guidance to taper paroxetine prior to discontinuation to limit withdrawal-type effects. The taper phase regimen used in some clinical trials of paroxetine involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, this dose was continued for 1 week before treatment was stopped. In controlled trials of paroxetine CR, patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose by 12.5 mg/day for 1 week before treatment was stopped. For patients receiving 12.5 or 25 mg/day, treatment was stopped without a taper. Adverse events were reported in some patients, even with this gradual taper regimen. Patients should be monitored when discontinuing treatment, regardless of the indication for which the SSRI is being prescribed. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, continue decreasing the dose but at a more gradual rate.[28260] [43999] [43998] When used for hot flashes at a dose of 7.5 mg/day, a taper during discontinuation has not been recommended.[55186]

The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, paroxetine should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or emergence of suicidality.[28260] [43999]

Paroxetine is not FDA-approved for use in pediatric patients. The efficacy of paroxetine for major depressive disorder (MDD) was not established in 3 well-controlled trials in pediatric patients. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. Prescribe paroxetine in the smallest quantity consistent with good patient management to reduce the risk of overdose. Monitor all patients receiving antidepressants for any indication closely for clinical worsening, suicidal ideation, and unusual behavioral changes, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania, especially during the first few months of therapy and after any dosage adjustment. Instruct caregivers and patients to immediately notify the prescriber of changes in behavior or suicidal ideation. Consider changing the therapeutic regimen or discontinuing the medication in patients with persistent or worrisome symptoms, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. In a pooled analysis of placebo-controlled trials of antidepressants (n = more than 4,400 pediatric patients and 77,000 adult patients), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults older than 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide. It is unknown if the suicidality risk extends to long-term use (i.e., more than 4 months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression, a known risk factor for suicidal thoughts and behaviors. In addition to suicide risk, monitor pediatric patients for the potential for growth inhibition during SSRI therapy. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving SSRIs. Monitor height and weight periodically while the patient is receiving paroxetine. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.[27238] [28260] [32127]

Concomitant use of MAOI therapy with paroxetine or within 14 days of stopping treatment with paroxetine is contraindicated because of an increased risk of serotonin syndrome. The use of paroxetine within 14 days of stopping MAOI therapy is also contraindicated. Starting paroxetine in a patient who is being treated with linezolid or intravenous methylene blue, both of which inhibit monoamine oxidase, is also contraindicated because of an increased risk of serotonin syndrome.[28260] [43999] [55186] Starting paroxetine in a patient being treated with an MAOI such as linezolid or methylene blue is also contraindicated; however, there may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or methylene blue in a patient taking paroxetine. If acceptable alternatives are not available and benefits are judged to outweigh the risks of serotonin syndrome, paroxetine should be promptly discontinued before initiating treatment with the MAOI. Monitor the patient closely for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of MAOI, whichever comes first. Therapy with paroxetine may be resumed 24 hours after the last dose of MAOI.[28260] [43999] [55186] The development of a potentially life-threatening serotonin syndrome has been reported with the use of SSRIs such as paroxetine alone, but particularly with concomitant use of other serotonergic drugs. If concomitant use of paroxetine with certain other serotonergic drugs (i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort) is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with paroxetine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.[28260] [43999] [55186]

Paroxetine should be used with caution in patients with a history of seizure disorder. Seizures have been reported rarely in patients taking SSRIs; however, they have occurred primarily in cases of overdose. Paroxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date.

Selective serotonin reuptake inhibitors (SSRIs), like paroxetine, may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Older patients (65 years of age or more), those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of the SSRI, as well as implementation of the appropriate medical interventions.

Paroxetine should be used with caution in patients with severe renal impairment or renal failure because paroxetine clearance is reduced. Specific dosage adjustments are recommended in adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute). A lower starting dose should be used in patients receiving most paroxetine formulations. The exception is those patients receiving the the 7.5 mg dose for menopause (e.g., Brisdelle) for which no dose adjustment is considered necessary. Quantitative guidelines are not available for pediatric patients.[28260] [43999] [55186]

Paroxetine should be used cautiously in patients with hepatic disease. Adult patients with severe hepatic impairment have about a 2-fold increase in plasma concentrations of paroxetine compared to patients without hepatic impairment. Specific dosage adjustments are recommended in adult patients with severe hepatic impairment receiving all formulations except the 7.5 mg dose for menopause (e.g., Brisdelle) for which no dose adjustment is considered necessary. Quantitative guidelines are not available for pediatric patients.[28260] [43999] [55186]

Monitor patients taking an SSRI such as paroxetine for signs and symptoms of bleeding. Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). 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. In published observational studies, pregnant patients taking SSRIs, particularly in the month before obstetric delivery, were at an increased risk of postpartum hemorrhage. Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase the risk of bleeding complications. Patients should be instructed to promptly report any bleeding events to their health care provider.[28260] [43999] [55186]

Although clinical trial data indicate that paroxetine is not associated with the development of clinically significant ECG abnormalities in adults, the use of paroxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable cardiac disease. Evaluation of electrocardiograms (ECGs) of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Paroxetine should be used with caution in patients with congenital heart disease or in those who are taking other medications concomitantly that might result in drug interactions. For example, QT prolongation, tachycardias, and other side effects have been reported in children taking clomipramine in combination with paroxetine for the treatment of obsessive-compulsive disorder (OCD), or in adult patients taking paroxetine (a CYP2D6 inhibitor) along with medications known to prolong the QT interval that are metabolized by CYP2D6. Additional monitoring may be necessary, especially when a patient receives combined treatments.[25690] [28260] [43999] [55186]

Use selective serotonin reuptake inhibitors (SSRIs), including paroxetine, with caution in patients with osteoporosis. Epidemiological studies on bone fracture risk following exposure to SSRIs have reported an association between SSRI treatment and bone fractures. It is unknown to what extent fracture risk is directly attributable to SSRI treatment. If a paroxetine-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising, consider the possibility of a fragility fracture.[28260] [42688] [42690] [55186] Patients at risk for osteoporosis, such as postmenopausal females, may benefit from more frequent monitoring of bone density during long-term use of an SSRI. 

Caution is recommended when prescribing paroxetine to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.[28260] [43999] [55186]

The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.[28260]

Decreased appetite and weight loss have been observed during administration of SSRIs.[28260] Therefore, caution is advisable when administering paroxetine to patients with anorexia nervosa or other conditions where weight loss is undesirable.

Because any psychoactive drug may impair judgment, thinking, or motor skills, patients should use caution when driving or operating machinery, until they are reasonably certain that paroxetine does not affect them adversely. Although paroxetine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid ethanol ingestion while taking paroxetine.[28260] [43999] [55186]

Sexual dysfunction can occur in individuals taking paroxetine. For males, these effects may present as ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Females may experience decreased libido and delayed or absent orgasm. Prescribers should discuss sexual function prior to initiating treatment with paroxetine and throughout treatment and obtain a detailed history and timeline of any changes in sexual function to determine whether the changes are medication-related or may be attributed to the underlying psychiatric disorder. Clinicians should also discuss management strategies and treatment options with patients.[28260] [43998] [43999] [55186]

Paroxetine may cause fetal harm during human pregnancy; the paroxetine capsule for treatment of menopause (e.g., Brisdelle) is contraindicated for use during pregnancy because menopausal vasomotor symptoms do not occur during pregnancy. Unless the benefits of continuing treatment with paroxetine outweigh the potential risks to the infant, either discontinue paroxetine or switch to another antidepressant. For those who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after careful consideration of the risks and ruling out the possibility of other treatment options.[28260] [43998] [43999] [55186] [46229] Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular (CV) malformations. A retrospective, epidemiologic study derived from the Swedish National Registry comprised of 6896 women prescribed antidepressants in early pregnancy (5,123 of these women exposed to SSRIs; 815 to paroxetine) suggests an increased risk of CV malformations, primarily ventricular (VSDs) and atrial (ASDs) septal defects in those with exposure to paroxetine. This increased risk was seen compared to the entire registry population (OR 1.8; 95% CI 1.1 to 2.8). The rate of CV malformations following paroxetine exposure was 2% vs. 1% in the entire registry population; however, there was no increase in the overall risk for congenital malformations in either group. In another retrospective, cohort study (a US health insurance claims database), that evaluated outcomes of infants exposed to antidepressants in the first trimester (n = 5,956 total; 815 for paroxetine), a 1.5-fold elevated risk for cardiac malformations and a 1.8-fold elevated risk for overall congenital malformations was seen in the paroxetine group compared to infants exposed to other antidepressants (OR 1.5; 95% CI 0.8 to 2.9). The prevalence of cardiac malformations when drug was received in the first trimester was 1.5% for paroxetine and 1% for other antidepressants. Nine out of 12 newborns with cardiac malformations whose mothers received paroxetine in the first trimester had VSDs. There was an increased risk of overall major congenital malformations (inclusive of the CV defects) for paroxetine compared to other antidepressants (OR 1.8; 95% CI 1.2 to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants. Results from 2 large case-control studies (each with more than 9,000 birth defect cases and more than 4,000 controls) showed a 2- to 3-fold increased risk of right ventricular outflow tract obstructions from infant exposures to paroxetine in utero during the first trimester of pregnancy, with 7 exposed in one study (OR 2.5; 95% CI, 1 to 6), and 6 exposed in the other study (OR 3.3; 95% CI 1.3 to 8.8). All of these studies were limited to first trimester exposure only, therefore the risk of fetal exposure to paroxetine in the second and third trimesters is not known.[28260] [46229] There have been postmarketing reports of premature births in pregnant patients exposed to paroxetine; however, causality has not been established. A prospective, cohort study was conducted to evaluate the outcome of newborns born to 267 women who took an SSRI during pregnancy (of whom 97 took paroxetine). Compared with a neonatal control group, SSRI-exposed neonates had similar rates of major malformation, spontaneous and elective abortion, stillbirth; mean birth weight and gestational age at birth were also similar.[25007] There are also risks associated with SSRI use during the third trimester of pregnancy, particularly the risk of persistent pulmonary hypertension of the newborn (PPHN). Some neonates exposed to SSRIs late in the third trimester have also experienced poor neonatal adaptation resulting in complications requiring prolonged hospitalization, respiratory support, and tube feeding upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with direct SSRI toxicity, serotonin syndrome, or a drug discontinuation syndrome. Data from published observational studies have reported that exposure to SSRIs, particularly in the month before obstetric delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to paroxetine; information about the registry can be obtained at information about the registry can be obtained at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ or by calling 1-866-961-2388.[28260] [43998] [43999] [55186] [47180] [47181] [47182] [62732]

Paroxetine is considered to be compatible with breast-feeding, due to its low concentrations in milk.[70365] As with other SSRI agents, infants exposed to paroxetine via breast-feeding should be monitored for agitation, irritability, poor feeding, and poor weight gain. In one small trial, mothers ingested up to 50 mg/day PO of paroxetine for more than 10 days. Paroxetine was excreted into the breast milk, but at low concentrations (less than 2 ng/mL). None of the breastfed infants had detectable serum concentrations, and no infant experienced adverse effects from the medication.[26980] A pooled analysis found that maternal use of paroxetine, along with nortriptyline and sertraline, usually produced undetectable or low drug concentrations in infant serum, and these agents may be the preferred antidepressants in breast-feeding individuals.[45642] [62732]

The selective serotonin reuptake inhibitors (SSRIs) are often a preferred antidepressant group for treatment of depression or other behavioral symptoms in the geriatric adult, including patients with dementia.[65503] [70290] There are some precautions related to use of paroxetine in the geriatric adult. Although no difference in safety or effectiveness has been recorded, slow titration of paroxetine dosage is recommended in the geriatric adult as pharmacokinetic data indicate that paroxetine clearance is reduced in the elderly. SSRIs may cause hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH); geriatric adults appear to be at greater risk.[28260] [43998] [43999] [55186] Paroxetine also exhibits anticholinergic activity; anticholinergic effects may be additive with other anticholinergic medications in any patient, but the geriatric adult may be more susceptible.[64280] According to the Beers Criteria, SSRIs are considered potentially inappropriate medications (PIMs) in older adults with a history of falls or fractures; SSRIs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an SSRI must be used, consider reducing the use of other CNS-active medications and implement other strategies to reduce fall risk. Paroxetine use should be avoided particularly in older adults with selected conditions that may be aggravated by anticholinergic effects of the drug. Also, SSRIs may cause hyponatremia and SIADH; closely monitor sodium concentrations when initiating treatment or changing doses in older adults.[63923] The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities (LTCFs). When used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the antidepressant as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. Dosages and durations of treatment used in the geriatric adult should be in accordance with prescribing labels, published literature recommendations, and expert guidelines.[60742]