PAXIL ®  (paroxetine hydrochloride)  

Suicidality in Children and Adolescents    Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in  short-term studies in children and adolescents with Major Depressive Disorder (MDD) and  other psychiatric disorders. Anyone considering the use of PAXIL or any other  antidepressant in a child or adolescent must balance this risk with the clinical need.  Patients who are started on therapy should be observed closely for clinical worsening,  suicidality, or unusual changes in behavior. Families and caregivers should be advised of  the need for close observation and communication with the prescriber. PAXIL is not  approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS—Pediatric  Use.)    Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of  9 antidepressant drugs (SSRIs and others) in children and adolescents with major  depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric  disorders (a total of 24 trials involving over 4,400 patients) have revealed a greater risk of  adverse events representing suicidal thinking or behavior (suicidality) during the first few  months of treatment in those receiving antidepressants. The average risk of such events in  patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides  occurred in these trials.  DESCRIPTION    PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the  hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate  and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8  (329.4 as free base). The structural formula of paroxetine hydrochloride is:      Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of  120° to 138°C and a solubility of 5.4 mg/mL in water. Tablets: Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as  follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive  ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate,  polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of  the following: D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 2, FD&C Yellow No. 6.  Suspension for Oral Administration: Each 5 mL of orange-colored, orange-flavored liquid  contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist  of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methyl  paraben, propyl paraben, sodium citrate dihydrate, citric acid anhydrate, sodium saccharin,  flavorings, FD&C Yellow No. 6, and simethicone emulsion, USP.   CLINICAL PHARMACOLOGY  Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive  disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD),  generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) 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 mean elimination half-life is approximately 21 hours  (CV 32%) after oral dosing of 30 mg tablets of PAXIL daily for 30 days. 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).    Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension  and tablet.    Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the  hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets  daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At  steady state, mean values of Cmax, Tmax, Cmin, and T1⁄2 were 61.7 ng/mL (CV 45%), 5.2 hr.  (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax  and Cmin values were about 6 and 14 times what would be predicted from single-dose studies.  Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been  predicted from single-dose data in these subjects. The excess accumulation is a consequence of  the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.    The effects of food on the bioavailability of paroxetine were studied in subjects administered  a single dose with and without food. AUC was only slightly increased (6%) when drug was  administered with food but the Cmax was 29% greater, while the time to reach peak plasma  concentration decreased from 6.4 hours post-dosing to 4.9 hours.    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.     Metabolism and Excretion: The mean elimination half-life is approximately 21 hours  (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose  proportionality studies involving elderly and nonelderly patients, at doses 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).    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: Specific Populations: 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. was 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 paroxetine doses of 20,  30, and 40 mg, 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   Major Depressive Disorder: The efficacy of PAXIL as a treatment for major depressive  disorder has been established in 6 placebo-controlled studies of patients with major depressive  disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective  than placebo in treating major depressive disorder by at least 2 of the following measures:  Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical  Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in  improvement of the HDRS sub-factor scores, including the depressed mood item, sleep  disturbance factor, and anxiety factor.    A study of outpatients with major depressive disorder who had responded to PAXIL (HDRS  total score <8) during an initial 8-week open-treatment phase and were then randomized to  continuation on PAXIL or placebo for 1 year demonstrated a significantly lower relapse rate for  patients taking PAXIL (15%) compared to those on placebo (39%). Effectiveness was similar for  male and female patients.  Obsessive Compulsive Disorder: The effectiveness of PAXIL in the treatment of obsessive  compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled  studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD  (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale  (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients  were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily  doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses  of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points,  respectively, on the YBOCS total score which was significantly greater than the approximate 4point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a  flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of  approximately 7 points on the YBOCS total score, which was significantly greater than the mean  reduction of approximately 4 points in placebo-treated patients.    The following table provides the outcome classification by treatment group on Global  Improvement items of the Clinical Global Impression (CGI) scale for Study 1.    Outcome Classification (%) on CGI-Global Improvement Item  for Completers in Study 1  Outcome   Classification  Placebo  (n = 74)  PAXIL 20 mg  (n = 75)  PAXIL 40 mg (n = 66)  PAXIL 60 mg  (n = 66)  Worse 14% 7% 7% 3%  No Change 44% 35% 22% 19%  Minimally Improved 24% 33% 29% 34%  Much Improved 11% 18% 22% 24%  Very Much Improved  7%  7%  20%  20%      Subgroup analyses did not indicate that there were any differences in treatment outcomes as a  function of age or gender.    The long-term maintenance effects of PAXIL in OCD were demonstrated in a long-term  extension to Study 1. Patients who were responders on paroxetine during the 3-month  double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were  randomized to either paroxetine or placebo in a 6-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.  Panic Disorder: The effectiveness of PAXIL in the treatment of panic disorder was  demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients  (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia.  In these studies, PAXIL was shown to be significantly more effective than placebo in treating  panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical  Global Impression Severity of Illness score.    Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine  doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed  only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were  free of panic attacks, compared to 44% of placebo-treated patients.    Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and  placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of  placebo-treated patients.    Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to  placebo in patients concurrently receiving standardized cognitive behavioral therapy. At  endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks  compared to 14% of placebo patients. In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was  approximately 40 mg/day of paroxetine.    Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an  extension to Study 1. Patients who were responders during the 10-week double-blind phase and  during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or  40 mg/day) 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.    Subgroup analyses did not indicate that there were any differences in treatment outcomes as a  function of age or gender.  Social Anxiety Disorder: The effectiveness of PAXIL in the treatment of social anxiety  disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1,  2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the  effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of  responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very  much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social  Anxiety Scale (LSAS).    Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and  placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the  CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In  Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to  29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI  Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients,  respectively.    Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with  placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the  LSAS Total Score and the CGI Improvement responder criterion; there were trends for  superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in  this study of any additional benefit for doses higher than 20 mg/day.    Subgroup analyses generally did not indicate differences in treatment outcomes as a function  of age, race, or gender.  Generalized Anxiety Disorder: The effectiveness of PAXIL in the treatment of Generalized  Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled  studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).     Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with  placebo. Doses of 20 mg or 40 mg of PAXIL were both demonstrated to be significantly superior  to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not  sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to  the 20 mg/day dose. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo.  PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating  Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine  (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of PAXIL over  placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.     Subgroup analyses did not indicate differences in treatment outcomes as a function of race or  gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.    In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety  Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to  50 mg/day of PAXIL, were randomized to continuation of PAXIL at their same dose, or to  placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase  was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of  Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase  of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or  withdrawal due to lack of efficacy. Patients receiving continued PAXIL experienced a  significantly lower relapse rate over the subsequent 24 weeks compared to those receiving  placebo.   Posttraumatic Stress Disorder: The effectiveness of PAXIL in the treatment of  Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebocontrolled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The  mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year  to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD  anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out  of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered  PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement  Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the  following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal.  The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2  total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were  defined as patients having a score of 1 (very much improved) or 2 (much improved).    Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to  placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to  placebo on change from baseline for the CAPS-2 total score and on proportion of responders on  the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the  40 mg/day dose compared to the 20 mg/day dose.    Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to  placebo. PAXIL was demonstrated to be significantly superior to placebo on change from  baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,  demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS2 total score, but not on proportion of responders on the CGI-I.    The majority of patients in these trials were women (68% women: 377 out of 551 subjects in  Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not  indicate differences in treatment outcomes as a function of gender. There were an insufficient  number of patients who were 65 years and older or were non-Caucasian to conduct subgroup  analyses on the basis of age or race, respectively.  INDICATIONS AND USAGE  Major Depressive Disorder: PAXIL is indicated for the treatment of major depressive  disorder.    The efficacy of PAXIL in the treatment of a major depressive episode was established in  6-week controlled trials of outpatients whose diagnoses corresponded most closely to the  DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical  Trials). A major depressive episode implies a prominent and relatively persistent depressed or  dysphoric mood that usually interferes with daily functioning (nearly every day for at least  2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in  sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in  sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired  concentration, and a suicide attempt or suicidal ideation.    The effects of PAXIL in hospitalized depressed patients have not been adequately studied.    The efficacy of PAXIL in maintaining a response in major depressive disorder for up to 1 year  was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical  Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should  periodically re-evaluate the long-term usefulness of the drug for the individual patient.  Obsessive Compulsive Disorder: PAXIL is indicated for the treatment of obsessions and  compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV.  The obsessions or compulsions cause marked distress, are time-consuming, or significantly  interfere with social or occupational functioning.    The efficacy of PAXIL was established in two 12-week trials with obsessive compulsive  outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive  compulsive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).    Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts,  impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and  intentional behaviors (compulsions) that are recognized by the person as excessive or  unreasonable.    Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In  this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on  placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should periodically re-evaluate the long-term  usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).  Panic Disorder: PAXIL is indicated for the treatment of panic disorder, with or without  agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of  unexpected panic attacks and associated concern about having additional attacks, worry about  the implications or consequences of the attacks, and/or a significant change in behavior related to  the attacks.    The efficacy of PAXIL was established in three 10- to 12-week trials in panic disorder  patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see  CLINICAL PHARMACOLOGY—Clinical Trials).    Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a  discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms  develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or  accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of  breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or  abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings  of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;  (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.    Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In  this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate  compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials).  Nevertheless, the physician who prescribes PAXIL for extended periods should periodically  re-evaluate the long-term usefulness of the drug for the individual patient.  Social Anxiety Disorder: PAXIL is indicated for the treatment of social anxiety disorder,  also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is  characterized by a marked and persistent fear of 1 or more social or performance situations in  which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to  the feared situation almost invariably provokes anxiety, which may approach the intensity of a  panic attack. The feared situations are avoided or endured with intense anxiety or distress. The  avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with  the person's normal routine, occupational or academic functioning, or social activities or  relationships, or there is marked distress about having the phobias. Lesser degrees of  performance anxiety or shyness generally do not require psychopharmacological treatment.    The efficacy of PAXIL was established in three 12-week trials in adult patients with social  anxiety disorder (DSM-IV). PAXIL has not been studied in children or adolescents with social  phobia (see CLINICAL PHARMACOLOGY—Clinical Trials).    The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more  than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.  Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND  ADMINISTRATION).  Generalized Anxiety Disorder: PAXIL is indicated for the treatment of Generalized Anxiety  Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of  everyday life usually does not require treatment with an anxiolytic.    The efficacy of PAXIL in the treatment of GAD was established in two 8-week  placebo-controlled trials in adults with GAD. PAXIL has not been studied in children or  adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY—Clinical  Trials).     Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry  (apprehensive expectation) that is persistent for at least 6 months and which the person finds  difficult to control. It must be associated with at least 3 of the following 6 symptoms:  Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or  mind going blank, irritability, muscle tension, sleep disturbance.    The efficacy of PAXIL in maintaining a response in patients with Generalized Anxiety  Disorder, who responded during an 8-week acute treatment phase while taking PAXIL and were  then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebocontrolled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the  physician who elects to use PAXIL for extended periods should periodically re-evaluate the  long-term usefulness of the drug for the individual patient (see DOSAGE AND  ADMINISTRATION).  Posttraumatic Stress Disorder: PAXIL is indicated for the treatment of Posttraumatic  Stress Disorder (PTSD).    The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebocontrolled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY—Clinical  Trials).    PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or  threatened death or serious injury, or threat to the physical integrity of self or others, and a  response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of  exposure to the traumatic event include reexperiencing of the event in the form of intrusive  thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity  on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,  inability to recall details of the event, and/or numbing of general responsiveness manifested as  diminished interest in significant activities, estrangement from others, restricted range of affect,  or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,  exaggerated startle response, sleep disturbance, impaired concentration, and irritability or  outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month  and that they cause clinically significant distress or impairment in social, occupational, or other  important areas of functioning. The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has  not been systematically evaluated in placebo-controlled trials. Therefore, the physician who  elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term  usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).  CONTRAINDICATIONS    Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or  thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).     Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).    PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the  inactive ingredients in PAXIL.  WARNINGS  Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),  both adult and pediatric, may experience worsening of their depression and/or the emergence of  suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they  are taking antidepressant medications, and this risk may persist until significant remission  occurs. There has been a long-standing concern that antidepressants may have a role in inducing  worsening of depression and the emergence of suicidality in certain patients. Antidepressants  increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children  and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.    Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and  others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of  24 trials involving over 4,400 patients) have revealed a greater risk of adverse events  representing suicidal behavior or thinking (suicidality) during the first few months of treatment  in those receiving antidepressants. The average risk of such events in patients receiving  antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk  among drugs, but a tendency toward an increase for almost all drugs studied. The risk of  suicidality was most consistently observed in the MDD trials, but there were signals of risk  arising from some trials in other psychiatric indications (obsessive compulsive disorder and  social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown  whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several  months. It is also unknown whether the suicidality risk extends to adults.     All pediatric patients being treated with antidepressants for any indication should be  observed closely for clinical worsening, suicidality, and unusual changes in behavior,  especially during the initial few months of a course of drug therapy, or at times of dose  changes, either increases or decreases. Such observation would generally include at least  weekly face-to-face contact with patients or their family members or caregivers during the  first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at  12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may  be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness  being treated with antidepressants should be observed similarly for clinical worsening and  suicidality, especially during the initial few months of a course of drug therapy, or at times  of dose changes, either increases or decreases.    In addition, patients with a history of suicidal behavior or thoughts, those patients  exhibiting a significant degree of suicidal ideation prior to commencement of treatment,  and young adults, are at an increased risk of suicidal thoughts or suidcide attempts, and  should receive careful monitoring during treatment.     The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,  aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have  been reported in adult and pediatric patients being treated with antidepressants for major  depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.  Although a causal link between the emergence of such symptoms and either the worsening of  depression and/or the emergence of suicidal impulses has not been established, there is concern  that such symptoms may represent precursors to emerging suicidality.    Consideration should be given to changing the therapeutic regimen, including possibly  discontinuing the medication, in patients whose depression is persistently worse, or who are  experiencing emergent suicidality or symptoms that might be precursors to worsening depression  or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the  patient’s presenting symptoms.    If the decision has been made to discontinue treatment, medication should be tapered, as  rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with  certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION— Discontinuation of Treatment With PAXIL, for a description of the risks of discontinuation of  PAXIL).    Families and caregivers of pediatric patients being treated with antidepressants for  major depressive disorder or other indications, both psychiatric and nonpsychiatric,  should be alerted about the need to monitor patients for the emergence of agitation,  irritability, unusual changes in behavior, and the other symptoms described above, as well  as the emergence of suicidality, and to report such symptoms immediately to health care  providers. Such monitoring should include daily observation by families and caregivers.  Prescriptions for PAXIL should be written for the smallest quantity of tablets consistent with  good patient management, in order to reduce the risk of overdose. Families and caregivers of  adults being treated for depression should be similarly advised.  Screening Patients for Bipolar Disorder: A major depressive episode may be the initial  presentation of bipolar disorder. It is generally believed (though not established in controlled  trials) that treating such an episode with an antidepressant alone may increase the likelihood of  precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the  symptoms described above represent such a conversion is unknown. However, prior to initiating  treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a  detailed psychiatric history, including a family history of suicide, bipolar disorder, and  depression. It should be noted that PAXIL is not approved for use in treating bipolar depression.   Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving  another serotonin reuptake inhibitor drug in combination with a monoamine oxidase  inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including  hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of  vital signs, and mental status changes that include extreme agitation progressing to  delirium and coma. These reactions have also been reported in patients who have recently  discontinued that drug and have been started on an MAOI. Some cases presented with  features resembling neuroleptic malignant syndrome. While there are no human data  showing such an interaction with PAXIL, limited animal data on the effects of combined  use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate  blood pressure and evoke behavioral excitation. Therefore, it is recommended that PAXIL  not be used in combination with an MAOI, or within 14 days of discontinuing treatment  with an MAOI. At least 2 weeks should be allowed after stopping PAXIL before starting an  MAOI.  Potential Interaction With Thioridazine: Thioridazine administration alone produces  prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,  such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be  dose related.    An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will  elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be  used in combination with thioridazine (see CONTRAINDICATIONS and  PRECAUTIONS).   Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that  infants born to women who had first trimester paroxetine exposure had an increased risk of  cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs).  In general, septal defects range from those that are symptomatic and may require surgery to those  that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while  taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of  paroxetine to the mother justify continuing treatment, consideration should be given to either  discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS— Discontinuation of Treatment with PAXIL). For women who intend to become pregnant or are in  their first trimester of pregnancy, paroxetine should only be initiated after consideration of the  other available treatment options.    A study based on Swedish national registry data evaluated infants of 6,896 women exposed to  antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for  paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of  cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations  following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population.  Among the same paroxetine exposed infants, an examination of the data showed no increase in  the overall risk for congenital malformations.    A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants  of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815 for  paroxetine). This study showed a trend towards an increased risk for cardiovascular  malformations for paroxetine compared to other antidepressants (OR 1.5; 95% confidence  interval 0.8-2.9). The prevalence of cardiovascular malformations following first trimester  dispensing was 1.5% for paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with  cardiovascular malformations whose mothers were dispensed paroxetine in the first trimester had  VSDs. This study also suggested an increased risk of overall major congenital malformations  (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR  1.8; 95% confidence interval 1.2-2.8). The prevalence of all congenital malformations following  first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants.    Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats  and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately  8 (rat) and 2 (rabbit) times the MRHD on an mg/m 2 basis. These studies have revealed no  evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the  first 4 days of lactation when dosing occurred during the last trimester of gestation and continued  throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of  the MRHD on an mg/m 2 basis. The no-effect dose for rat pup mortality was not determined. The  cause of these deaths is not known.    Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs or serotonin and  norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed  complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such  complications can arise immediately upon delivery. Reported clinical findings have included  respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,  vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and  constant crying. These features are consistent with either a direct toxic effect of SSRIs and  SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the  clinical picture is consistent with serotonin syndrome (see WARNINGS—Potential for  Interaction With Monoamine Oxidase Inhibitors).     There have also been postmarketing reports of premature births in pregnant women exposed  to paroxetine or other SSRIs.    When treating a pregnant woman with paroxetine during the third trimester, the physician  should carefully consider the potential risks and benefits of treatment (see DOSAGE AND  ADMINISTRATION). PRECAUTIONS  General: Activation of Mania/Hypomania: During premarketing testing, hypomania or  mania occurred in approximately 1.0% of unipolar patients treated with PAXIL compared to  1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients  classified as bipolar, the rate of manic episodes was 2.2% for PAXIL and 11.6% for the  combined active-control groups. As with all drugs effective in the treatment of major depressive  disorder, PAXIL should be used cautiously in patients with a history of mania.    Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with  PAXIL, a rate similar to that associated with other drugs effective in the treatment of major  depressive disorder. PAXIL should be used cautiously in patients with a history of seizures. It  should be discontinued in any patient who develops seizures.    Discontinuation of Treatment With PAXIL: Recent clinical trials supporting the various  approved indications for PAXIL employed a taper-phase regimen, rather than an abrupt  discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials  involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a  daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before  treatment was stopped.     With this regimen in those studies, the following adverse events were reported at an incidence  of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams,  paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and  were self-limiting and did not require medical intervention.     During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports  of adverse events occurring, upon the discontinuation of these drugs (particularly when abrupt),  including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances  (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache,  lethargy, emotional lability, insomnia, and hypomania. While these events are generally selflimiting, there have been reports of serious discontinuation symptoms.     Patients should be monitored for these symptoms when discontinuing treatment with PAXIL.  A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.  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  physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND  ADMINISTRATION).    See also PRECAUTIONS—Pediatric Use, for adverse events reported upon discontinuation  of treatment with PAXIL in pediatric patients.   Akathisia: 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. Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia  appeared to be reversible when PAXIL was discontinued. The majority of these occurrences  have been in elderly individuals, some in patients taking diuretics or who were otherwise volume  depleted.    Serotonin Syndrome: The development of a serotonin syndrome may occur in association  with treatment with paroxetine, particularly with concomitant use of serotonergic drugs and with  drugs which may have impaired metabolism of paroxetine. Symptoms have included agitation,  confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia, and  tremor. The concomitant use of PAXIL with serotonin precursors (such as tryptophan) is not  recommended (see WARNINGS—Potential for Interaction with Monoamine Oxidase Inhibitors  and PRECAUTIONS—Drug Interactions).    Abnormal Bleeding: Published case reports have documented the occurrence of bleeding  episodes in patients treated with psychotropic agents that interfere with serotonin reuptake.  Subsequent epidemiological studies, both of the case-control and cohort design, have  demonstrated an association between use of psychotropic drugs that interfere with serotonin  reuptake and the occurrence of upper gastrointestinal bleeding. In 2 studies, concurrent use of a  nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see  Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is  reason to believe that bleeding at other sites may be similarly potentiated. Patients should be  cautioned regarding the risk of bleeding associated with the concomitant use of paroxetine with  NSAIDs, aspirin, or other drugs that affect coagulation.    Use in Patients With Concomitant Illness: Clinical experience with PAXIL in patients  with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in  patients with diseases or conditions that could affect metabolism or hemodynamic responses.     As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with  PAXIL. A few cases of acute angle closure glaucoma associated with paroxetine therapy have  been reported in the literature. As mydriasis can cause acute angle closure in patients with  narrow angle glaucoma, caution should be used when PAXIL is prescribed for patients with  narrow angle glaucoma.    PAXIL has not been evaluated or used to any appreciable extent in patients with a recent  history of myocardial infarction or unstable heart disease. Patients with these diagnoses were  excluded from clinical studies during the product’s premarket testing. Evaluation of  electrocardiograms of 682 patients who received PAXIL in double-blind, placebo-controlled  trials, however, did not indicate that PAXIL is associated with the development of significant  ECG abnormalities. Similarly, PAXIL does not cause any clinically important changes in heart  rate or blood pressure.    Increased plasma concentrations of paroxetine occur in patients with severe renal impairment  (creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should  be used in such patients (see DOSAGE AND ADMINISTRATION). Information for Patients: Prescribers or other health professionals should inform patients,  their families, and their caregivers about the benefits and risks associated with treatment with  PAXIL and should counsel them in its appropriate use. A patient Medication Guide About Using  Antidepressants in Children and Teenagers is available for PAXIL. The prescriber or health  professional should instruct patients, their families, and their caregivers to read the Medication  Guide and should assist them in understanding its contents. Patients should be given the  opportunity to discuss the contents of the Medication Guide and to obtain answers to any  questions they may have. The complete text of the Medication Guide is reprinted at the end of  this document.     Patients should be advised of the following issues and asked to alert their prescriber if these  occur while taking PAXIL.  Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should  be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,  irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),  hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal  ideation, especially early during antidepressant treatment and when the dose is adjusted up or  down. Families and caregivers of patients should be advised to observe for the emergence of  such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be  reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in  onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be  associated with an increased risk for suicidal thinking and behavior and indicate a need for very  close monitoring and possibly changes in the medication.    Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Patients  should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs  that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin  reuptake and these agents has been associated with an increased risk of bleeding.    Interference With Cognitive and Motor Performance: Any psychoactive drug may  impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been  shown to impair psychomotor performance, patients should be cautioned about operating  hazardous machinery, including automobiles, until they are reasonably certain that therapy with  PAXIL does not affect their ability to engage in such activities.    Completing Course of Therapy: While patients may notice improvement with treatment  with PAXIL in 1 to 4 weeks, they should be advised to continue therapy as directed.    Concomitant Medication: Patients should be advised to inform their physician if they are  taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for  interactions.    Alcohol: Although PAXIL has not been shown to increase the impairment of mental and  motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL. Pregnancy: Patients should be advised to notify their physician if they become pregnant or  intend to become pregnant during therapy. (See WARNINGS—Usage in Pregnancy:  Teratogenic and Nonteratogenic Effects).    Nursing: Patients should be advised to notify their physician if they are breast-feeding an  infant (see PRECAUTIONS—Nursing Mothers).   Laboratory Tests: There are no specific laboratory tests recommended.  Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction  between paroxetine and tryptophan may occur when they are coadministered. Adverse  experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been  reported when tryptophan was administered to patients taking PAXIL. Consequently,  concomitant use of PAXIL with tryptophan is not recommended (see Serotonin Syndrome).    Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.   Pimozide: In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg  daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in  pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. Due to the  narrow therapeutic index of pimozide and its known ability to prolong the QT interval,  concomitant use of pimozide and PAXIL is contraindicated (see CONTRAINDICATIONS).    Serotonergic Drugs: Based on the mechanism of action of paroxetine and the potential for  serotonin syndrome, caution is advised when PAXIL is coadministered with other drugs or  agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans,  serotonin reuptake inhibitors, linezolid (an antibiotic which is a reversible non-selective MAOI),  lithium, tramadol, or St. John's Wort (see Serotonin Syndrome).    Thioridazine: See CONTRAINDICATIONS and WARNINGS.     Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that  causes an increased bleeding diathesis in the face of unaltered prothrombin time) between  paroxetine and warfarin. Since there is little clinical experience, the concomitant administration  of PAXIL and warfarin should be undertaken with caution (see Drugs That Interfere With  Hemostasis).     Triptans: There have been rare postmarketing reports describing patients with weakness,  hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor  (SSRI) and sumatriptan. If concomitant treatment with a triptan and an SSRI (e.g., fluoxetine,  fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient  is advised (see Serotonin Syndrome).    Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of  paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.    Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study  where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma  concentrations of paroxetine were increased by approximately 50% during coadministration with  oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are  administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not  studied.    Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a  single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once  daily for 14 days), paroxetine AUC and T1⁄2 were reduced (by an average of 25% and 38%,  respectively) compared to paroxetine administered alone. The effect of paroxetine on  phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear  pharmacokinetics, the results of this study may not address the case where the 2 drugs are both  being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when  coadministered with phenobarbital; any subsequent adjustment should be guided by clinical  effect.    Phenytoin: When a single oral 30-mg dose of PAXIL was administered at phenytoin steady  state (300 mg once daily for 14 days), paroxetine AUC and T1⁄2 were reduced (by an average of  50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a  single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once  daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to  phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above  studies may not address the case where the 2 drugs are both being chronically dosed. No initial  dosage adjustments are considered necessary when these drugs are coadministered; any  subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS— Postmarketing Reports).    Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the  treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are  metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized  byCYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients  (>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily  dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose  desipramine (100 mg) Cmax, AUC, and T1⁄2 by an average of approximately 2-, 5-, and 3-fold,  respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been  evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to  8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased  9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the  active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The  effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs  were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,  paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This  resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in  atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.  Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be  initiated at a reduced dose when it is given with paroxetine. Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not been  formally studied but may require lower doses than usually prescribed for either PAXIL or the  other drug.    Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme,  including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,  amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type  1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme  (e.g., quinidine), should be approached with caution.     However, due to the risk of serious ventricular arrhythmias and sudden death potentially  associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be  coadministered (see CONTRAINDICATIONS and WARNINGS).    At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is  governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see  PRECAUTIONS—Tricyclic Antidepressants).    Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving  the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for  cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In  addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be  at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several  substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and  cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and  its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4  substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical  significance.    Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of  tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism.  Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be  reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS—Drugs Metabolized by  Cytochrome CYP2D6).    Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma  protein, administration of PAXIL to a patient taking another drug that is highly protein bound  may cause increased free concentrations of the other drug, potentially resulting in adverse events.  Conversely, adverse effects could result from displacement of paroxetine by other highly bound  drugs.    Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.):  Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of  the case-control and cohort design that have demonstrated an association between use of  psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper  gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently  with paroxetine.    Alcohol: Although PAXIL does not increase the impairment of mental and motor skills  caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.    Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction  between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome,  caution is advised when PAXIL is coadministered with lithium.    Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered  with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the  presence of paroxetine. Since there is little clinical experience, the concurrent administration of  paroxetine and digoxin should be undertaken with caution.    Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine  kinetics. The effects of paroxetine on diazepam were not evaluated.    Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC024, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%,  respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen,  the dose of procyclidine should be reduced.    Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for  18 days, the established steady-state plasma concentrations of propranolol were unaltered during  coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of  propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS— Postmarketing Reports).     Theophylline: Reports of elevated theophylline levels associated with treatment with  PAXIL have been reported. While this interaction has not been formally studied, it is  recommended that theophylline levels be monitored when these drugs are concurrently  administered.    Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine  significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by  clinical effect (tolerability and efficacy).     Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of  ECT and PAXIL. 

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