Paroxetine Hydrochloride

The information included under the “Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With PAXIL CR” subsection of ADVERSE REACTIONS is based on data from 11 placebo-controlled clinical trials. Three of these studies were conducted in patients with major depressive disorder, 3 studies were done in patients with panic disorder, 1 study was conducted in patients with social anxiety disorder, and 4 studies were done in female patients with PMDD. Two of the studies in major depressive disorder, which enrolled patients in the age range 18 to 65 years, are pooled. Information from a third study of major depressive disorder, which focused on elderly patients (60 to 88 years), is presented separately as is the information from the panic disorder studies and the information from the PMDD studies. Information on additional adverse events associated with PAXIL CR and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During the Clinical Development of Paroxetine).

Adverse Findings Observed In Short-Term, Placebo-Controlled Trials With PAXIL CR

Ten percent (21/212) of patients treated with PAXIL CR discontinued treatment due to an adverse event in a pool of 2 studies of patients with major depressive disorder. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for PAXIL CR compared to placebo) included the following:

In a placebo-controlled study of elderly patients with major depressive disorder, 13% (13/104) of patients treated with PAXIL CR discontinued due to an adverse event. Events meeting the above criteria included the following:

Eleven percent (50/444) of patients treated with PAXIL CR in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

Three percent (5/186) of patients treated with PAXIL CR in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

Spontaneously reported adverse events were monitored in studies of both continuous and intermittent dosing of PAXIL CR in the treatment of PMDD. Generally, there were few differences in the adverse event profiles of the 2 dosing regimens. Thirteen percent (88/681) of patients treated with PAXIL CR in PMDD studies of continuous dosing discontinued treatment due to an adverse event.

The most common events ( ≥ 1%) associated with discontinuation in either group treated with PAXIL CR with an incidence rate that is at least twice that of placebo in PMDD trials that employed a continuous dosing regimen are shown in the following table. This table also shows those events that were dose dependent (indicated with an asterisk) as defined as events having an incidence rate with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the placebo group).

Commonly Observed Adverse Events

The most commonly observed adverse events associated with the use of PAXIL CR in a pool of 2 trials (incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo, derived from Table 2) were: Abnormal ejaculation, abnormal vision, constipation, decreased libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma, tremor, and yawning.

Using the same criteria, the adverse events associated with the use of PAXIL CR in a study of elderly patients with major depressive disorder were: Abnormal ejaculation, constipation, decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.

In the pool of panic disorder studies, the adverse events meeting these criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating, and female genital disorders (generally anorgasmia or difficulty achieving orgasm).

In the social anxiety disorder study, the adverse events meeting these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence, insomnia, and libido decreased.

The most commonly observed adverse events associated with the use of PAXIL CR either during continuous dosing or luteal phase dosing (incidence of 5% or greater and incidence for PAXIL CR at least twice that for placebo, derived from Table 6) were: Nausea, asthenia, libido decreased, somnolence, insomnia, female genital disorders, sweating, dizziness, diarrhea, and constipation.

In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day of PAXIL CR limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the 3 off-drug phases were combined, the following adverse events were reported at an incidence of 2% or greater for PAXIL CR and were at least twice the rate of that reported for placebo: Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%), sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).

Incidence In Controlled Clinical Trials

Table 2 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with PAXIL CR, aged 18 to 65, who participated in 2 short-term (12-week) placebo-controlled trials in major depressive disorder in which patients were dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse events reported at an incidence of 5% or greater among elderly patients (ages 60 to 88) treated with PAXIL CR who participated in a short-term (12-week) placebo-controlled trial in major depressive disorder in which patients were dosed in a range of 12.5 mg to 50 mg/day. Table 4 enumerates adverse events reported at an incidence of 1% or greater among patients (19 to 72 years) treated with PAXIL CR who participated in short-term (10-week) placebo-controlled trials in panic disorder in which patients were dosed in a range of 12.5 mg to 75 mg/day. Table 5 enumerates adverse events reported at an incidence of 1% or greater among adult patients treated with PAXIL CR who participated in a short-term (12-week), double-blind, placebo-controlled trial in social anxiety disorder in which patients were dosed in a range of 12.5 to 37.5 mg/day. Table 6 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with PAXIL CR who participated in three, 12-week, placebo-controlled trials in PMDD in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses (luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

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

Table 2: Treatment-Emergent Adverse Events Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Pool of 2 Studies in Major Depressive Disordera,b

Table 3: Treatment-Emergent Adverse Events Occurring in ≥ 5% of Patients Treated With PAXIL CR in a Study of Elderly Patients With Major Depressive Disordera,b

Table 4: Treatment-Emergent Adverse Events Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Pool of 3 Panic Disorder Studiesa,b

Table 5: Treatment-Emergent Adverse Effects Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Social Anxiety Disorder Studya,b

Table 6: Treatment-Emergent Adverse Events Occurring in ≥ 1% of Patients Treated With PAXIL CR in a Pool of 3 Premenstrual Dysphoric Disorder Studies With Continuous Dosing or in 1 Premenstrual Dysphoric Disorder Study With Luteal Phase Dosinga,b,c

Table 7 shows results in PMDD trials of common adverse events, defined as events with an incidence of ≥ 1% with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR and with placebo.

Table 7: Incidence of Common Adverse Events in Placebo, 12.5 mg, and 25 mg of PAXIL CR in a Pool of 3 Fixed-Dose PMDD Trials

A comparison of adverse event rates in a fixed-dose study comparing immediate-release paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with the use of immediate-release paroxetine.

Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain; however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.

The percentage of patients reporting symptoms of sexual dysfunction in the pool of 2 placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of 3 placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients with social anxiety disorder, and in the intermittent dosing and the pool of 3 placebo-controlled continuous dosing trials in female patients with PMDD are as follows:

There are no adequate, controlled studies examining sexual dysfunction with paroxetine treatment.

Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae.

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

Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials with PAXIL CR or the immediate-release formulation, had minimal weight loss (about 1 pound). No significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature) were observed in patients treated with PAXIL CR, or immediate-release paroxetine hydrochloride, in controlled clinical trials.

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

In a pool of 2 placebo-controlled clinical trials, patients treated with PAXIL CR or placebo exhibited abnormal values on liver function tests at comparable rates. In particular, the controlled-release paroxetine-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities.

In a study of elderly patients with major depressive disorder, 3 of 104 patients treated with PAXIL CR and none of 109 placebo patients experienced liver transaminase elevations of potential clinical concern.

Two of the patients treated with PAXIL CR dropped out of the study due to abnormal liver function tests; the third patient experienced normalization of transaminase levels with continued treatment. Also, in the pool of 3 studies of patients with panic disorder, 4 of 444 patients treated with PAXIL CR and none of 445 placebo patients experienced liver transaminase elevations of potential clinical concern. Elevations in all 4 patients decreased substantially after discontinuation of PAXIL CR. The clinical significance of these findings is unknown.

In placebo-controlled clinical trials with the immediate-release formulation of paroxetine, patients exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients.

In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving drug and in 4 of 3,187 patients receiving placebo.

Other Events Observed During The Clinical Development Of Paroxetine

The following adverse events were reported during the clinical development of PAXIL CR and/or the clinical development of the immediate-release formulation of paroxetine.

Adverse events for which frequencies are provided below occurred in clinical trials with the controlled-release formulation of paroxetine. During its premarketing assessment in major depressive disorder, panic disorder, social anxiety disorder, and PMDD, multiple doses of PAXIL CR were administered to 1,627 patients in phase 3 double-blind, controlled, outpatient studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of the 1,627 patients exposed to PAXIL CR who experienced an event of the type cited on at least 1 occasion while receiving PAXIL CR. All reported events are included except those already listed in Tables 2 through 7 and those events where a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was deleted or, when possible, replaced with a more informative term. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.

Adverse events for which frequencies are not provided occurred during the premarketing assessment of immediate-release paroxetine in phase 2 and 3 studies of major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to immediate-release paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. Only those events not previously listed for controlled-release paroxetine are included. The extent to which these events may be associated with PAXIL CR is unknown.

Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in the PRECAUTIONS section.

Body as a Whole: Infrequent were chills, face edema, fever, flu syndrome, malaise; rare were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed were adrenergic syndrome, neck rigidity, sepsis.

Cardiovascular System: Infrequent were angina pectoris, bradycardia, hematoma, hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia, syncope; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation, cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.

Digestive System: Infrequent were bruxism, dysphagia, eructation, gastritis, gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function test abnormal, melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis, glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction, peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue edema.

Endocrine System: Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus, hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis.

Hemic and Lymphatic System: Infrequent were anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis, lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.

Metabolic and Nutritional Disorders: Infrequent were generalized edema, hyperglycemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare were bilirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperphosphatemia, hypocalcemia, hypoglycemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.

Musculoskeletal System: Infrequent were arthritis, bursitis, tendonitis; rare were myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis, tenosynovitis, tetany.

Nervous System: Frequent were depression; infrequent were amnesia, convulsion, depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis, vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis, withdrawal syndrome; also observed were abnormal gait, akathisia, akinesia, aphasia, choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction, manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus.

Respiratory System: Frequent were pharyngitis; infrequent were asthma, dyspnea, epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema, hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum increased.

Skin and Appendages: Frequent were rash; infrequent were acne, alopecia, dry skin, eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash, seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.

Special Senses: Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis, photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss.

Urogenital System: Frequent were dysmenorrhea*; infrequent were albuminuria, amenorrhea*, breast pain*, cystitis, dysuria, prostatitis*, urinary retention; rare were breast enlargement*, breast neoplasm*, female lactation, hematuria, kidney calculus, metrorrhagia* , nephritis, nocturia, pregnancy and puerperal disorders*, salpingitis, urinary incontinence, uterine fibroids enlarged*; also observed were breast atrophy, ejaculatory disturbance, endometrial disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria, urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage.

*Based on the number of men and women as appropriate.

Postmarketing Reports

Voluntary reports of adverse events in patients taking immediate-release paroxetine hydrochloride that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura) and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when immediate-release paroxetine was added to chronic metoprolol treatment.

Drug Abuse And Dependence

PAXIL CR is not a controlled substance.

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

Human Experience

Since the introduction of immediate-release paroxetine hydrochloride in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.

Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.

Overdosage Management

No specific antidotes for paroxetine are known. Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, or exchange perfusion are unlikely to be of benefit.

A specific caution involves patients taking or recently having taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6).

In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

Pharmacodynamics

The efficacy of paroxetine in the treatment of major depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder (PMDD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs.

Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent compound, they are essentially inactive.

Pharmacokinetics

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The elimination half-life is approximately 15 to 20 hours after a single dose of PAXIL CR. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

Tablets of PAXIL CR contain a degradable polymeric matrix designed to control the dissolution rate of paroxetine over a period of approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until tablets of PAXIL CR have left the stomach.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male and female subjects (n = 23) received single oral doses of PAXIL CR at 4 dosage strengths (12.5 mg, 25 mg, 37.5 mg, and 50 mg), paroxetine Cmax and AUC0-inf increased disproportionately with dose (as seen also with immediate-release formulations). Mean Cmax and AUC0-inf values at these doses were 2.0, 5.5, 9.0, and 12.5 ng/mL, and 121, 261, 338, and 540 ng•hr./mL, respectively. Tmax was observed typically between 6 and 10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release formulations. The bioavailability of 25 mg PAXIL CR is not affected by food.

Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.

Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

The mean elimination half-life of paroxetine was 15 to 20 hours throughout a range of single doses of PAXIL CR (12.5 mg, 25 mg, 37.5 mg, and 50 mg). During repeated administration of PAXIL CR (25 mg once daily), steady state was reached within 2 weeks (i.e., comparable to immediate-release formulations). In a repeat-dose study in which normal male and female subjects (n = 23) received PAXIL CR (25 mg daily), mean steady state Cmax, Cmin, and AUC0-24 values were 30 ng/mL, 20 ng/mL, and 550 ng•hr./mL, respectively.

Based on studies using immediate-release formulations, steady-state drug exposure based on AUC0-24 was several-fold greater than would have been predicted from single-dose data. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.

In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of the immediate-release formulation of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6).

Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.

Other Clinical Pharmacology Information

Renal and Liver Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, Cmax).

The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION).

Elderly Patients: In a multiple-dose study in the elderly at daily doses of 20, 30, and 40 mg of the immediate-release formulation, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see PRECAUTIONS: DRUG INTERACTIONS).

Clinical Trials

The efficacy of PAXIL CR controlled-release tablets as a treatment for major depressive disorder has been established in two 12-week, flexible-dose, placebo-controlled studies of patients with DSM-IV Major Depressive Disorder. One study included patients in the age range 18 to 65 years, and a second study included elderly patients, ranging in age from 60 to 88. In both studies, PAXIL CR was shown to be significantly more effective than placebo in treating major depressive disorder as measured by the following: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)–Severity of Illness score.

A study of outpatients with major depressive disorder who had responded to immediate-release paroxetine tablets (HDRS total score < 8) during an initial 8-week open-treatment phase and were then randomized to continuation on immediate-release paroxetine tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking immediate-release paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.

The effectiveness of PAXIL CR in the treatment of panic disorder was evaluated in three 10-week, multicenter, flexible-dose studies (Studies 1, 2, and 3) comparing paroxetine controlled-release (12.5 to 75 mg daily) to placebo in adult outpatients who had panic disorder (DSM-IV), with or without agoraphobia. These trials were assessed on the basis of their outcomes on 3 variables: (1) the proportions of patients free of full panic attacks at endpoint; (2) change from baseline to endpoint in the median number of full panic attacks; and (3) change from baseline to endpoint in the median Clinical Global Impression Severity score. For Studies 1 and 2, PAXIL CR was consistently superior to placebo on 2 of these 3 variables. Study 3 failed to consistently demonstrate a significant difference between PAXIL CR and placebo on any of these variables.

For all 3 studies, the mean dose of PAXIL CR for completers at endpoint was approximately 50 mg/day. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

Long-term maintenance effects of the immediate-release formulation of paroxetine in panic disorder were demonstrated in an extension study. Patients who were responders during a 10-week double-blind phase with immediate-release paroxetine and during a 3-month double-blind extension phase were randomized to either immediate-release paroxetine or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.

The efficacy of PAXIL CR as a treatment for social anxiety disorder has been established, in part, on the basis of extrapolation from the established effectiveness of the immediate-release formulation of paroxetine. In addition, the effectiveness of PAXIL CR in the treatment of social anxiety disorder was demonstrated in a 12-week, multicenter, double-blind, flexible-dose, placebo-controlled study of adult outpatients with a primary diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness of PAXIL CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1) change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and (2) the proportion of responders who scored 1 or 2 (very much improved or much improved) on the Clinical Global Impression (CGI) Global Improvement score.

PAXIL CR demonstrated statistically significant superiority over placebo on both the LSAS total score and the CGI Improvement responder criterion. For patients who completed the trial, 64% of patients treated with PAXIL CR compared to 34.7% of patients treated with placebo were CGI Improvement responders.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of gender. Subgroup analyses of studies utilizing the immediate-release formulation of paroxetine generally did not indicate differences in treatment outcomes as a function of age, race, or gender.

The effectiveness of PAXIL CR for the treatment of PMDD utilizing a continuous dosing regimen has been established in 2 placebo-controlled trials. Patients in these trials met DSM-IV criteria for PMDD. In a pool of 1,030 patients, treated with daily doses of PAXIL CR 12.5 or 25 mg/day, or placebo the mean duration of the PMDD symptoms was approximately 11 ± 7 years. Patients on systemic hormonal contraceptives were excluded from these trials. Therefore, the efficacy of PAXIL CR in combination with systemic (including oral) hormonal contraceptives for the continuous daily treatment of PMDD is unknown. In both positive studies, patients (N = 672) were treated with 12.5 mg/day or 25 mg/day of PAXIL CR or placebo continuously throughout the menstrual cycle for a period of 3 menstrual cycles. The VAS-Total score is a patient-rated instrument that mirrors the diagnostic criteria of PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. 12.5 mg/day and 25 mg/day of PAXIL CR were significantly more effective than placebo as measured by change from baseline to the endpoint on the luteal phase VAS-Total score.

In a third study employing intermittent dosing, patients (N = 366) were treated for the 2 weeks prior to the onset of menses (luteal phase dosing, also known as intermittent dosing) with 12.5 mg/day or 25 mg/day of PAXIL CR or placebo for a period of 3 months. 12.5 mg/day and 25 mg/day of PAXIL CR, as luteal phase dosing, was significantly more effective than placebo as measured by change from baseline luteal phase VAS total score.

There is insufficient information to determine the effect of race or age on outcome in these studies.

PAXIL CR®
(PAX-il)
(paroxetine hydrochloride) Controlled-Release Tablets

Read the Medication Guide that comes with PAXIL CR before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

What is the most important information I should know about PAXIL CR?

PAXIL CR and other antidepressant medicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

• PAXIL CR and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment or when the dose is changed.
• Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions.
• Watch for these changes, and call your healthcare provider right away if you notice:
• New or sudden changes, in mood, behavior, actions, thoughts, or feelings, especially if severe.
• Pay particular attention to such changes when PAXIL CR is started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic attacks
• feeling agitated, restless, angry, or irritable
• trouble sleeping
• an increase in activity and talking more than what is normal for you
• other unusual changes in behavior or mood

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. PAXIL CR may be associated with these serious side effects:

2. Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This condition can be life-threatening and may include:

• agitation, hallucinations, coma, or other changes in mental status
• coordination problems or muscle twitching (overactive reflexes)
• racing heartbeat, high or low blood pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity

3. Visual problems

• eye pain
• changes in vision
• swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

4. Severe allergic reactions:

• trouble breathing
• swelling of the face, tongue, eyes, or mouth
• rash, itchy welts (hives), or blisters, alone or with fever or joint pain

5. Abnormal bleeding: PAXIL CR and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin® , Jantoven®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

6. Seizures or convulsions

7. Manic episodes:

• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual

8. Changes in appetite or weight.

Children and adolescents should have height and weight monitored during treatment.

9. Low salt (sodium) levels in the blood.

Elderly people may be at greater risk for this. Symptoms may include:

• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking, or memory problems

Do not stop PAXIL CR without first talking to your healthcare provider. Stopping PAXIL CR too quickly may cause serious symptoms including:

• anxiety, irritability, high or low mood, feeling restless, or changes in sleep habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking, confusion

What is PAXIL CR?

PAXIL CR is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. PAXIL CR is also used to treat:

• Major Depressive Disorder (MDD)
• Panic Disorder
• Social Anxiety Disorder
• Premenstrual Dysphoric Disorder (PMDD)

Talk to your healthcare provider if you do not think that your condition is getting better with treatment using PAXIL CR.

Who should not take PAXIL CR?

Do not take PAXIL CR if you:

• are allergic to paroxetine or any of the ingredients in PAXIL CR. See the end of this Medication Guide for a complete list of ingredients in PAXIL CR.
• take a monoamine oxidase inhibitor (MAOI) . Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
  • Do not take an MAOI within 2 weeks of stopping PAXIL CR unless directed to do so by your physician.
  • Do not start PAXIL CR if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
  • People who take PAXIL CR close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:
    • high fever
    • uncontrolled muscle spasms
    • stiff muscles
    • rapid changes in heart rate or blood pressure
    • confusion
    • loss of consciousness (pass out)
• take MELLARIL® (thioridazine). Do not take MELLARIL® together with PAXIL CR because this can cause serious heart rhythm problems or sudden death.
• take the antipsychotic medicine pimozide (ORAP®) because this can cause serious heart problems.

What should I tell my healthcare provider before taking PAXIL CR? Ask if you are not sure.

Before starting PAXIL CR, tell your healthcare provider if you:

• are pregnant, may be pregnant, or plan to become pregnant. There is a possibility that PAXIL CR may harm your unborn baby, including an increased risk of birth defects, particularly heart defects. Other risks may include a serious condition in which there is not enough oxygen in the baby's blood. Your baby may also have certain other symptoms shortly after birth. Premature births have also been reported in some women who used PAXIL CR during pregnancy.
• are breastfeeding. PAXIL CR passes into your milk. Talk to your healthcare provider about the best way to feed your baby while taking PAXIL CR.
• are taking certain drugs such as:
  • triptans used to treat migraine headache
  • other antidepressants (SSRIs, SNRIs, tricyclics, or lithium) or antipsychotics
  • drugs that affect serotonin, such as lithium, tramadol, tryptophan, St. John's wort
  • certain drugs used to treat irregular heart beats
  • certain drugs used to treat schizophrenia
  • certain drugs used to treat HIV infection
  • certain drugs that affect the blood, such as warfarin, aspirin, and ibuprofen
  • certain drugs used to treat epilepsy
  • atomoxetine
  • cimetidine
  • fentanyl
  • metoprolol
  • pimozide
  • procyclidine
  • tamoxifen
• have liver problems
• have kidney problems
• have heart problems
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have a history of a stroke
• have high blood pressure
• have or had bleeding problems
• have glaucoma (high pressure in the eye)

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. PAXIL CR and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take PAXIL CR with your other medicines. Do not start or stop any medicine while taking PAXIL CR without talking to your healthcare provider first.

If you take PAXIL CR, you should not take any other medicines that contain paroxetine, including PAXIL and PEXEVA® (paroxetine mesylate).

How should I take PAXIL CR?

• Take PAXIL CR exactly as prescribed. Your healthcare provider may need to change the dose of PAXIL CR until it is the right dose for you.
• PAXIL CR may be taken with or without food.
• PAXIL CR controlled-release tablets should not be chewed or crushed and should be swallowed whole.
• If you miss a dose of PAXIL CR, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of PAXIL CR at the same time.
• If you take too much PAXIL CR, call your healthcare provider or poison control center right away, or get emergency treatment.
• Do not stop taking PAXIL CR suddenly without talking to your doctor (unless you have symptoms of a severe allergic reaction). If you need to stop taking PAXIL CR, your healthcare provider can tell you how to safely stop taking it.

What should I avoid while taking PAXIL CR?

PAXIL CR can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how PAXIL CR affects you. Do not drink alcohol while using PAXIL CR.

What are possible side effects of PAXIL CR?

PAXIL CR may cause serious side effects, including all of those described in the section entitled “What is the most important information I should know about PAXIL CR?”

Common possible side effects in people who take PAXIL CR include:

• nausea
• sleepiness
• feeling anxious or trouble sleeping
• sexual problems
• sweating
• shaking
• constipation
• yawning
• blurred vision
• diarrhea
• dry mouth
• decreased appetite
• weakness

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of PAXIL CR. For more information, ask your healthcare provider or pharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088 or 1-800-332-1088.

How should I store PAXIL CR?

• Store PAXIL CR at or below room temperature (77°F or 25°C).
• Keep PAXIL CR away from light.
• Keep bottle of PAXIL CR closed tightly.

Keep PAXIL CR and all medicines out of the reach of children.

General information about PAXIL CR

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PAXIL CR for a condition for which it was not prescribed. Do not give PAXIL CR to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about PAXIL CR. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about PAXIL CR that is written for healthcare professionals.

For more information about PAXIL CR call 1-800-706-5575.

What are the ingredients in PAXIL CR?

Active ingredient: paroxetine hydrochloride

Inactive ingredients in tablets: hypromellose, polyvinylpyrrolidone, lactose monohydrate, magnesium stearate, silicon dioxide, glyceryl behenate, methacrylic acid copolymer type C, sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate, titanium dioxide, polyethylene glycols, and 1 or more of the following colorants: Yellow ferric oxide, red ferric oxide, D&C Red No. 30 aluminum lake, FD&C Yellow No. 6 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake.

Paroxetine is an antidepressant in a group of drugs called selective serotonin reuptake inhibitors (SSRIs). Paroxetine affects chemicals in the brain that may become unbalanced.

Paroxetine is used to treat depression, obsessive-compulsive disorder, anxiety disorders, post-traumatic stress disorder (PTSD), and premenstrual dysphoric disorder (PMDD).

Paroxetine may also be used for purposes not listed in this medication guide.

Do not take paroxetine together with pimozide (Orap), thioridazine (Mellaril), linezolid (Zyvox), methylene blue (Urolene Blue), or a monoamine oxidase inhibitor (MAOI) such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate). A dangerous drug interaction could occur, leading to serious side effects.

You must wait at least 14 days after stopping an MAO inhibitor before you can take paroxetine. After you stop taking paroxetine, you must wait at least 14 days before you start taking an MAOI.

Tell your doctor about all other antidepressants you take, especially Celexa, Cymbalta, Desyrel, Effexor, Lexapro, Luvox, Oleptro, Prozac, Sarafem, Symbyax, Viibryd, or Zoloft.

To make sure you can safely take paroxetine, tell your doctor if you have any of these other conditions:

• liver or kidney disease;
• a bleeding or blood clotting disorder;
• seizures or epilepsy;
• narrrow-angle glaucoma; or
• bipolar disorder (manic depression), or a history of drug abuse or suicidal thoughts.

You may have thoughts about suicide while taking an antidepressant, especially if you are younger than 24 years old. Tell your doctor if you have worsening depression or suicidal thoughts during the first several weeks of treatment, or whenever your dose is changed.

Your family or other caregivers should also be alert to changes in your mood or symptoms. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.

FDA pregnancy category D. Paroxetine may cause heart defects or serious lung problems in a newborn if you take the medication during pregnancy. However, you may have a relapse of depression if you stop taking your antidepressant during pregnancy. Tell your doctor right away if you become pregnant while taking paroxetine.

Do not start or stop taking paroxetine during pregnancy without your doctor's advice.

Paroxetine can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not take paroxetine together with pimozide (Orap), thioridazine (Mellaril), linezolid (Zyvox), methylene blue (Urolene Blue), or a monoamine oxidase inhibitor (MAOI) such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate). A dangerous drug interaction could occur, leading to serious side effects.

Before you take paroxetine, tell your doctor if you have liver or kidney disease, a bleeding or blood clotting disorder, seizures, glaucoma, bipolar disorder, or a history of drug abuse or suicidal thoughts.

There are many other drugs that can interact with paroxetine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products.

Paroxetine may cause harm to an unborn baby. Tell your doctor right away if you become pregnant while taking paroxetine.

Paroxetine may cause heart defects or serious lung problems in a newborn if you take the medication during pregnancy. However, you may have a relapse of depression if you stop taking your antidepressant during pregnancy.

Do not start or stop taking paroxetine during pregnancy without your doctor's advice.

You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

• Anxiety
• Depression
• Obsessive Compulsive Disorder (OCD)
• Panic Attacks
• Posttraumatic Stress Disorder
• Prescription Anxiety Medications
• Prescription Migraine Medications
• Seasonal Affective Disorder (SAD)

Metabolized partially by CYP2D6.1 Inhibits the activity of CYP2D6 and to a lesser extent CYP3A4.1 91

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6 or CYP3A4: possible increased plasma concentrations of the substrates.1 91 277

Use with caution and consider reducing dosage of concomitantly administered CYP2D6 substrate, particularly those with a narrow therapeutic index, such as TCAs, class IC antiarrhythmics, and some phenothiazines.1 91 277

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzymes (e.g., CYP2D6): potential pharmacokinetic interaction (altered paroxetine metabolism and plasma concentrations).a

Drugs Associated with Serotonin Syndrome

Potentially life-threatening serotonin syndrome with other serotonergic drugs.611 If concomitant use of other serotonergic drugs with paroxetine is clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases.611

If serotonin syndrome occurs, immediately discontinue paroxetine and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment.611 (See Serotonin Syndrome under Cautions.)

Drugs Affecting Hemostasis

Potential pharmacologic interaction (increased risk of bleeding) with concomitant use of drugs that affect hemostasis.1 6 147 323 312 324 325 Use with caution.1

Specific Drugs

Absorption

Bioavailability

Completely absorbed following oral administration.1

Oral bioavailability in humans not fully elucidated to date.1

Equally bioavailable from commercially available conventional tablets and suspension.a

Food

Food does not substantially affect the absorption of paroxetine.19 92

Special Populations

In geriatric patients, trough paroxetine concentrations are 70–80% greater than in younger patients.1

In patients with renal impairment (Clcr <30 mL/minute), mean plasma paroxetine concentrations are approximately 4 times greater than those seen in healthy individuals.1

Hepatic impairment may increase plasma concentrations twofold.1

Distribution

Extent

Widely distributed in the body, including the CNS and breast milk.1

Plasma Protein Binding

≥93%1

Elimination

Metabolism

Extensively metabolized, 1 94 partially by CYP2D6.1 Metabolites are essentially inactive.1 6 84 Inhibits activity of CYP2D6.1 91

Elimination Route

Eliminated principally in urine and feces (probably via bile).1 94

Half-life

Averages approximately 21–24 hours.1 3 4 5 6 19 83 89

Special Populations

In geriatric individuals, elimination half-life may be increased (e.g., to about 36 hours).3 83