PAROXETINE HCL (Generic for PAXIL)

General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

Route-Specific Administration

Oral Administration
-Administer as a single dose, usually in the morning. May be administered without regard to meals, however, food may minimize GI adverse effects.
Oral Solid Formulations
-Controlled-release tablets: Patient should swallow tablets whole. Do not cut, chew, or crush. Do not administer concomitantly with antacids; the tablets are enteric-coated.

Oral Liquid Formulations
-Oral suspension: Shake well before each use. To ensure accurate dosing, measure dosage with a calibrated measuring device.

Several pediatric studies have been published, including 3 placebo-controlled trials in 752 pediatric patients with major depressive disorder (MDD). In general, while safety and efficacy have not been established, the adverse event profile in pediatric patients is expected to be similar to that in adults.

Gastrointestinal (GI) side effects are among the most commonly reported adverse events of SSRIs, including paroxetine. 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. 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). 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. 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 receiving paroxetine.

Tremor and hyperkinesis were reported in 2% or more of pediatric patients at a rate at least twice that of placebo during clinical trials. 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 rarely reported (less than 1%) include akathisia, ataxia, hypertonia, choreoathetosis, incoordination, fasciculations, muscle paralysis, abnormal gait, dyskinesia, hyperkinesis, bradykinesia, akinesia, hyporeflexia, hyperreflexia, pseudoparkinsonism (cogwheel rigidity), dystonic reaction (e.g., torticollis, trismus), dysarthria, nystagmus, and tremor. Oculogyric crisis has occurred when paroxetine has been used in conjunction with pimozide.

Neurologic adverse effects are commonly reported with paroxetine therapy. 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%) were reported in adult patients receiving paroxetine during clinical trials for treatment of depression and other psychiatric or mood disorders. Other effects reported in 0.1% to 1% of patients during premarketing evaluation include abnormal thinking, hypoesthesia, neuralgia, neuropathy (neuropathic pain), and seizures. Rare events (less than 0.1%) reported during use of paroxetine 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.

Emotional lability (including self-harm, suicidal ideation, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, and agitation were reported in 2% or more of patients receiving paroxetine during pediatric clinical trials. In adult trials, nervousness (2 to 9%), anxiety (2 to 5%), agitation (2 to 5%), lack of emotion (apathy, 2%), emotional lability (1% or more), and depersonalization (3%) were reported. Other effects reported in 0.1 to 1% of patients during premarketing evaluation included abnormal thinking, euphoria, hallucinations, hostility, neurosis, and paranoia. Rare events (less than 0.1%) reported during use of paroxetine included antisocial reaction, delirium, delusions, hysteria, psychosis, psychotic depression, and stupor. Antidepressants can precipitate mania in susceptible individuals, and manic symptoms and suicidal ideation appear to be more prevalent in children with or at high risk for bipolar disorder on antidepressants. 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. In a study of 52 patients (mean age: 15 years, range: 7 to 22 years) with bipolar disorder or subthreshold manic symptoms and exposure to antidepressants, 50% developed antidepressant-induced mania and 25.5% had new-onset suicidal ideation. Depression or worsening of depression may also occur (0.1% to 2% of adults in clinical trials). 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. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation.

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, 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. 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.

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 adult patients during premarketing evaluation of paroxetine included anemia, ecchymosis, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, and purpura. Rare events (less than 0.1%) reported in adult patients 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.

Cardiovascular events may occur during paroxetine treatment. Palpitations (2 to 3%), chest pain (unspecified) (1 to 3%), sinus tachycardia (1% or more), hypertension (1% or more), and unspecified peripheral vasodilation (2 to 4%) were reported more frequently in adult patients receiving paroxetine than placebo during clinical trials. Other effects reported in 0.1 to 1% of patients during premarketing evaluation include bradycardia, hypotension, orthostatic hypotension, supraventricular tachycardia (SVT), and syncope. Rare events (less than 0.1%) reported include 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.

Clinical data from all conditions and formulations studied indicate that the following general effects occurred more frequently in adult patients receiving paroxetine than placebo: asthenia (12 to 22%), chills (2%), edema (1%), and unspecified trauma (3 to 6%). General effects reported in 0.1 to 1% of adult patients during premarketing evaluation include chills, face edema, malaise, and generalized edema. Rare events (less than 0.1%) reported include adrenergic syndrome, cellulitis, candidiasis, and sepsis.

Hypersensitivity and allergic reactions (2% or less) have been reported with paroxetine use. During pediatric trials, hyperhidrosis occurred in 2% or more of patients at a rate at least twice that of placebo. 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). 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. 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). 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.

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). In postmarketing use, anosmia, hyposmia, and hypersensitivity reactions affecting the airway (including laryngismus and allergic alveolitis/pneumonitis) have been reported.

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. Rarely (less than 0.1%), 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.

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.

Unspecified female (2 to 10%) and male (2 to 10%) genital disorders have been reported with paroxetine use during adult clinical trials. Most frequently, 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 and hyperprolactinemia have been reported during post-marketing use. Priapism, a medical emergency, has been reported rarely with all of the SSRIs; in those cases with a known outcome, the male patients recovered without sequelae after drug discontinuation and appropriate treatment. If priapism occurs, the patient should discontinue the drug and seek immediate medical assistance.

Increased urinary frequency (2 to 3%), urination disorder/dysuria (3%), impaired urination (e.g., urinary retention) (2 to 3%), urinary tract infection (2 to 3%), and prostatitis (1% or more) have been reported during adult clinical trials of paroxetine. Other urogenital effects reported in 0.1 to 1% of adult patients during premarketing evaluation include albuminuria (proteinuria), cystitis, dysuria, hematuria, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, and urinary urgency. Rarely (less than 0.1%), epididymitis, kidney calculus (nephrolithiasis), kidney flank pain, nephritis, oliguria, urethritis, urinary casts, and urolithiasis have occurred. Acute renal failure (unspecified) has been reported during postmarketing use of paroxetine; however, frequency and causality have not been established.

Myopathy (2% or less), myalgia (5% or less), arthralgia (1% or more), myasthenia (1% or less), back pain (3 to 5%), bursitis (1% or less) were reported in association with paroxetine use during adult clinical trials. Other effects reported in 0.1 to 1% of patients during premarketing evaluation include arthritis, arthrosis, neck pain, and tendonitis. Rarely (less than 0.1%), generalized muscle cramps or spasm, myositis, tenosynovitis, tetany, and neck rigidity have occurred.

Paroxetine has been associated with altered glycemic control, including hyperglycemia and hypoglycemia, although these effects appear to be uncommon. During premarketing adult trials, endocrine-related effects were rare (less than 0.1%) and included diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, and thyroiditis.

Metabolic effects reported 1% or less of adult patients during premarketing evaluation of paroxetine include thirst (polydipsia), peripheral edema, increased alkaline phosphatase, hyperbilirubinemia, increased BUN, increased creatinine phosphokinase, dehydration, increased gamma globulins, gout, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, ketosis, increased lactic dehydrogenase, and increased non-protein nitrogen (NPN).

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 specifically noted in post-marketing reports with paroxetine. Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome. Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. If serotonin syndrome becomes evident during treatment, the SSRI and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.

Epidemiological studies have reported an association between antidepressant treatment and bone fractures; however, it is unknown to what extent the fracture risk is directly attributable to antidepressant use. Rarely (less than 0.1%), osteoporosis was reported during pre-marketing evaluation of paroxetine. The possibility of a fracture produced by minimal trauma in a patient with osteopenia should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising.

A drug discontinuation syndrome was reported rarely (less than 0.1%) during premarketing evaluation of paroxetine in adult patients. 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.

A neonatal abstinence syndrome has been reported in infants exposed to paroxetine in utero, with features consistent with either a direct toxic effect of serotonergic agents (e.g., serotonin syndrome), or possibly a drug discontinuation syndrome. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) have been 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. Other potential adverse events have also been reported, including a potential association between maternal use of SSRIs in the third trimester and the development of persistent pulmonary hypertension of the newborn (PPHN). Some retrospective studies have not shown an increased risk of PPHN with SSRI exposure. The FDA has stated that an increased risk of PPHN from SSRI exposure cannot be determined due to conflicting data.

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 in children and adolescents 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.

Paroxetine is contraindicated in those patients with a hypersensitivity to paroxetine or any of the formulation components.

Avoid abrupt discontinuation of any SSRI if possible. Gradual tapering is recommended during discontinuation of paroxetine to decrease or prevent the occurrence of potential discontinuation symptoms. Such symptoms have been reported with abrupt discontinuation of paroxetine, and in some cases, even with a gradual tapering schedule. The most frequent SSRI discontinuation symptoms include dizziness, vertigo, nausea, vomiting, flu-like symptoms, sensory disturbances (e.g., paresthesias, electric shock sensation), sleep disturbances, irritability, anxiety, and/or agitation. Discontinuation symptoms are more likely to occur after withdrawal of SSRIs with a short half-life and no active metabolites such as paroxetine.

The risks or benefits of using paroxetine during electroconvulsive therapy (ECT) have not been established in clinical studies.

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 and adolescents in short-term studies. If used in pediatric patients, 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. 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. 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.

Mania or hypomania can be precipitated in predisposed individuals during treatment with an antidepressant, including paroxetine. Children with a family history of bipolar disorder, those who have a diagnosis of bipolar disorder, and those with subthreshold manic symptoms may be at increased risk for developing mania during treatment. In addition, patients with pre-existing bipolar disorder type I, compared to those with subsyndromal or type II bipolar disorder, and those with psychiatric comorbidities may be at increased risk for antidepressant-induced mania. Younger patients may be more likely to experience antidepressant-induced mania. Suicidal ideation appears to be more prevalent in children with or at high risk for bipolar disorder on antidepressants. In a study of 52 patients (mean age of 15 years, ranging from 7 to 22 years) with bipolar disorder or subthreshold manic symptoms, 25.5% had new-onset suicidal ideation within the first 3 months of antidepressant use. Progressive evaluation of youth at risk for bipolar disorder who were exposed to antidepressants (n = 21; age range of 9 to 20 years) suggested psychiatric adverse events such as irritability, aggression, impulsivity, and hyperactivity were more common in younger patients. A major depressive episode may be the initial presentation of bipolar disorder. Patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder prior to initiating treatment. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. The response of patients with a previously established history of bipolar disorder should be closely monitored if therapy with an antidepressant is indicated.

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 should be used with caution in patients with severe renal impairment or renal failure because clearance can be reduced. Specific dosage adjustments are recommended in adult patients with severe renal impairment; however, quantitative guidelines are not available for pediatric patients.

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 ECGs of 682 adult 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.

Adult patients with severe hepatic impairment have about a 2-fold increase in plasma concentrations of paroxetine compared to patients without hepatic impairment. Therefore, paroxetine should be used cautiously in patients with hepatic disease. Specific dosage adjustments are recommended in adult patients with severe hepatic impairment; however, quantitative guidelines are not available for pediatric patients.

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. Patients 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.

Decreased appetite and weight loss have been observed during administration of SSRIs. Therefore, caution is advisable when administering paroxetine to patients with anorexia nervosa or other conditions where weight loss is undesirable. Growth and weight should be monitored in pediatric patients receiving paroxetine.

Because paroxetine may impair judgment, thinking, or motor skills, patients should use caution when engaging in activities requiring coordination and concentration (such as riding bicycles, driving, or operating machinery) until they are aware of the effects of paroxetine on their cognition. 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.

Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. Paroxetine and other SSRIs may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulant therapy may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients and practitioners should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, anticoagulants, or other drugs that affect coagulation, such as thrombolytic therapy. Monitor patients for signs and symptoms of bleeding.

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.

Paroxetine is contraindicated with concurrent use or use within 14 days of monoamine oxidase inhibitor therapy (MAOI therapy) because of an increased risk of serotonin syndrome. 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 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. 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.

In utero exposure to paroxetine in the first trimester may increase the risk for congenital malformations, particularly cardiac malformations. Neonates with in utero exposure to SSRIs late in the third trimester have developed 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 either a direct toxic effect of SSRIs, a drug discontinuation syndrome, or serotonin syndrome. In addition, although available data are conflicting, some epidemiologic reports suggest an association between maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension of the newborn (PPHN). Because PPHN is associated with significant morbidity and mortality, it is important that practitioners are aware of antidepressant exposure to avoid delays in diagnosis and treatment. In a meta-analysis of 7 studies, there was a small but significant association between SSRI exposure in late pregnancy and PPHN; effects were not significant for other variables examined (e.g., study design, congenital malformations, meconium aspiration). Effects of caesarian delivery, maternal body mass index, and preterm delivery were not assessed. PPHN occurs in approximately 1.9 of 1000 live births in the general population and is a relatively uncommon event; based on this analysis it is estimated that an average of 1 associated case of PPHN would result from 286 to 351 women being treated with an SSRI during late gestation. There have also been postmarketing reports of premature births in pregnant patients exposed to paroxetine; however, causality has not been established. A prospective, cohort study evaluated outcomes 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, and stillbirth; mean birth weight and gestational age at birth were also similar.

The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy. Monitor height and weight periodically while the patient is receiving paroxetine. 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. 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.

Description: Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is not approved for any indication in children or adolescents; however, the drug has been used off-label in children as young as 7 years for certain childhood anxiety disorders. Although clinical guidelines describe a role for many SSRIs in treating childhood depression, studies evaluating paroxetine have generally indicated a lack of efficacy for depression in pediatric patients. In addition, clinically significant drug interactions may result from potent CYP2D6 inhibition by paroxetine. SSRIs are considered first-line therapy for childhood anxiety disorders requiring pharmacologic treatment. Paroxetine has been used in children and adolescents for the treatment of panic disorder, obsessive-compulsive disorder, and social anxiety disorder. Product labels for all antidepressants contain a warning related to an increased risk of suicidality in children and adolescents during initial treatment; therefore, the necessity of pharmacologic therapy versus the potential risks should be carefully considered in these populations.

For the treatment of obsessive-compulsive disorder (OCD)*:
Oral dosage (immediate-release products; e.g. Paxil, Pexeva):
Children and Adolescents 7 to 17 years: 10 mg PO once daily for 1 week initially; may titrate at intervals of at least 7 days if needed based upon response and tolerability. Max: 50 mg/day PO. Periodically reassess the need for continued treatment. This regimen was studied in a large randomized, placebo-controlled trial (n = 207); the mean dose in children was 30.1 mg/day and the mean dose in adolescents was 36.5 mg/day. The change in the primary efficacy measure (the Children's Yale-Brown Obsessive-Compulsive Scale) and 3 of 6 secondary efficacy measures were statistically significant in favor of paroxetine. Global assessments showed no change between the groups. Evaluation of the long-term safety and efficacy of paroxetine in the treatment of childhood OCD is needed.

For the treatment of panic disorder*:
Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva):
Children and Adolescents 7 to 17 years: Initially, 10 mg/day PO. 10 to 40 mg/day PO has been studied. To minimize the frequency and severity of adverse effects, slowly titrate at weekly intervals based on response and tolerability. Periodically reassess the need for continued treatment. Further study is needed to establish the safety and efficacy of SSRIs in the treatment of childhood panic disorder. Results from 1 naturalistic study (n = 18) used a mean initial dose of 8.9 mg/day PO followed by titration up to 40 mg/day PO depending on response and tolerability. Improvement began after a mean duration of 3 weeks treatment. The final mean dose was 24 mg/day (range: 10 to 40 mg/day). At study end, 83.3% of patients were considered responders, with 55.5% showing marked improvement on the CGI-Improvement scale score and 27.8% with moderate improvement.

For the treatment of social phobia (social anxiety disorder)*:
Oral dosage:
Children and Adolescents 8 to 17 years: 10 mg/day PO initially, then may titrate by 10 mg/day at intervals of at least 7 days based on response and tolerability. Max: 50 mg/day PO. Periodically reassess the need for continued treatment. Further study is needed to evaluate the safety and efficacy of SSRIs in the treatment of childhood anxiety disorders. The suggested regimen was used in a multicenter, placebo-controlled clinical trial (n = 322), at the study end (16 weeks) the mean dose for children was 26.5 mg/day and for adolescents was 35 mg/day. Overall, responders on the primary efficacy measure (CGI-I score) were statistically significant in favor of paroxetine vs. placebo (77.6% vs. 38.3%). The remission rate for paroxetine was also greater vs. placebo (47.8% vs. 14.9%).

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 6 years: Safety and efficacy have not been established.
7 to 12 years: Safety and efficacy have not been established; however, doses up to 50 mg/day PO have been used off-label for anxiety disorders.
-Adolescents
Safety and efficacy have not been established; however, doses up to 50 mg/day PO have been used off-label for anxiety disorders.

Patients with Hepatic Impairment Dosing
Immediate-release dosage forms: Initially, 10 mg/day PO in adults; final adult dosage should not exceed 40 mg/day PO. There are no guidelines available for pediatric patients.
Controlled-release tablets: The initial dose is 12.5 mg/day PO in adults, with final adult dosage not to exceed 50 mg/day PO, regardless of indication. There are no guidelines available for pediatric patients.

Patients with Renal Impairment Dosing
CrCl 30-60 ml/min: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Lower doses may be needed.
CrCl < 30 ml/min: Immediate-release dosage forms: Initially, 10 mg/day PO in adults; final adult dosage should not exceed 40 mg/day PO. Controlled-release tablets: The initial dose is 12.5 mg/day PO in adults, with final adult dosage not to exceed 50 mg/day PO, regardless of indication. There are no guidelines available for pediatric patients.

Intermittent hemodialysis
See dosage for patients with CrCl < 30 ml/min. Paroxetine is unlikely to be significantly removed by hemodialysis given its large volume of distribution.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The precise antidepressant effect of the selective serotonin reuptake inhibitors (SSRIs) is not fully understood, but involves selective serotonin reuptake blockade at the neuronal membrane, which enhances the actions of serotonin (5-HT). Initially, SSRIs increase availability of serotonin in the somatodendritic area through serotonin reuptake blockade at the serotonin transport pump. During long-term administration of SSRIs, serotonin autoreceptors are down-regulated and desensitized, allowing the neuron to increase serotonin release in the axon terminal synapses and increase its neuronal impulses. Because of the delay in therapeutic response to SSRIs, it is theorized that the change in the balance of serotonin receptors over time is an important mechanism of effect. The therapeutic action of SSRIs in treating anxiety disorders is thought to occur from potent central serotonin reuptake blockade although the exact mechanism is unknown. SSRIs exhibit less sedative, anticholinergic, and cardiovascular effects than do tricyclic antidepressants due to decreased binding to histaminergic, muscarinic, and alpha-adrenergic receptors. However, paroxetine is noted to have the most anticholinergic activity of all the SSRIs.

Pharmacokinetics: Paroxetine is administered orally. The drug is widely distributed, including within the CNS. Only 1% of paroxetine remains in the plasma, and it is 93% to 95% bound to plasma protein; however, the drug does not displace other highly protein-bound drugs. Based on pharmacokinetic studies, the steady-state paroxetine exposure based on AUC is several-fold higher than with a single dose. The excess accumulation is a consequence of a saturable metabolic pathway. Paroxetine is extensively metabolized via oxidation, methylation and conjugation to several metabolites, none of which shows any appreciable pharmacological activity. Conjugates with glucuronic acid and sulfate predominate. Metabolism is achieved predominantly by CYP2D6. Due to saturation of CYP2D6 by paroxetine, the relationship between pharmacokinetics and dosage or duration of treatment is nonlinear. At steady-state, when the CYP2D6 is essentially saturated, paroxetine clearance becomes governed by CYP3A4, which, unlike CYP2D6, does not show evidence of saturation. In adults, the mean elimination half-life of the immediate-release paroxetine is approximately 21 hours while the elimination half-life for the controlled-release product is 15 to 20 hours. Excretion is mainly renal (about 62%), mostly as metabolites and about 2% as unchanged drug. Roughly 36% is excreted in the feces, mainly via the bile as metabolites.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6
Paroxetine is a substrate and potent inhibitor of CYP2D6. In more than 90% of patients, CYP2D6 is saturated early in dosing with paroxetine (in roughly 10 to 14 days). Subsequently, paroxetine clearance is governed by CYP3A4 that, unlike CYP2D6, shows no evidence of saturation. Paroxetine does not appear to inhibit other CYP isoenzymes, including CYP3A4, to any clinically significant degree.


-Route-Specific Pharmacokinetics
Oral Route
Paroxetine is absorbed completely after oral administration. Paroxetine immediate-release tablets and oral suspension are bioequivalent. Paxil CR controlled-release tablets are enteric coated to delay the start of drug release until the tablets have left the stomach; they are also designed via the Geomatrix polymeric matrix to allow for a 4 to 5-hour dissolution rate, with a Tmax occurring roughly 6 to 10 hours after dosing. The bioavailability of paroxetine, regardless of dosage form, is not affected by food. There appears to be individual patient variation in response, but steady-state concentrations are achieved in about 10 to 14 days with either the immediate-release or controlled-release formulations. The onset of action, however, typically requires 1 to 4 weeks of therapy.


-Special Populations
Pediatrics
Children and Adolescents
More individual variability in pharmacokinetics occurs with lower doses than higher doses in children. In a 6-week multiple dose pharmacokinetic study in children (n = 27) and adolescents (n = 35), the Cmax and AUC were higher in children than adolescents at all doses studied (10 mg, 20 mg, 30 mg); however, the geometric mean values in children were about 100% higher than in adolescents at 10 mg/day, but less than 30% higher at 30mg/day. These differences are primarily attributable to differences in weight between the groups. Oral clearance and volume of distribution were highly dependent on paroxetine dose, CYP2D6 genotype, and weight, but not age or gender. Side effects, such as gastrointestinal complaints and behavioral events, occurred more frequently in younger children than adolescents. Saturability of CYP2D6 suggests that modest increases in dose may be associated with disproportionate increases in plasma concentrations. Therefore, a more conservative approach to dosing in children, such as lower initial doses or slower titration, is advisable.

Hepatic Impairment
Paroxetine is extensively metabolized in the liver. Plasma concentrations of paroxetine are about 2-fold higher in adult patients with severe hepatic impairment. A similar effect can be expected in pediatric patients. Lower initial and maximum daily doses are recommended in adult patients with severe hepatic impairment. Quantitative guidelines are not available for pediatric patients.

Renal Impairment
Increased plasma concentrations of paroxetine occur in adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute). Mean plasma concentrations were about 4 times higher in those with a creatinine clearance less than 30 mL/minute than in healthy volunteers. Adult patients with a creatinine clearance of 30 to 60 mL/minute had an approximate 2-fold increase in plasma concentrations. A similar effect can be expected in pediatric patients. Lower initial and maximum daily doses are recommended in adult patients with severe renal impairment. Quantitative guidelines are not available for pediatric patients.