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4-17-01 — PROOF 2 — Paxil PX:L20A — 6/5.9 x 23.6 — PROMO/(8.5x11) — Univers Light, Bold & Italic — Page 1 PRESCRIBING INFORMATION
Improvement Item for Completers in Study 1 PAXIL
paroxetine hydrochloride
tablets and oral suspension
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 respon-
ders 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
DESCRIPTION
studies of adult outpatients (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these Paxil (paroxetine hydrochloride) is an orally administered antidepressant with a chemical structure unrelated to other selective sero- studies, Paxil was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of tonin reuptake inhibitors or to tricyclic, tetracyclic or other available antidepressant agents. It is the hydrochloride salt of a panic attack frequency and on the Clinical Global Impression Severity of Illness score.
phenylpiperidine compound identified chemically as (-)-trans-4R-(4’-fluorophenyl)-3S-[(3’,4’-methylenedioxyphenoxy) methyl] piperi- 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 place- dine hydrochloride hemihydrate and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as bo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxe- tine 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 stan-dardized 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 respon- ders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxe- tine (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.
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/mLin water.
Social Anxiety Disorder
The effectiveness of Paxil in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-con-
trolled studies (Studies 1-3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of Paxil Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 10 mg–yellow (scored); 20 mg–pink compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impressions (scored); 30 mg–blue, 40 mg–green. Inactive ingredients consist of dibasic calcium phosphate dihydrate, hydroxypropyl methylcellu- (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social lose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide and one 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.
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statisti- Suspension for Oral Administration
cally significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale Each 5 mL of orange-colored, orange-flavored liquid contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingre- (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine- treated patients compared to 29% of placebo-treat- dients consist of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methyl paraben, propyl paraben, ed patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and sodium citrate dihydrate, citric acid anhydrate, sodium saccharin, flavorings, FD&C Yellow No. 6 and simethicone emulsion, USP.
placebo-treated patients, respectively.
CLINICAL PHARMACOLOGY
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40 or 60 mg/day with placebo. Paroxetine 20 mg was demon- Pharmacodynamics
strated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were The efficacy of paroxetine in the treatment of depression, social anxiety disorder, obsessive compulsive disorder (OCD), panic dis- trends for superiority over placebo for the 40 and 60 mg/day dose groups. There was no indication in this study of any additional order (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central benefit for doses higher than 20 mg/day.
nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically rele-vant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in Subgroup analyses did not indicate differences in treatment outcomes as a function of age, race, or gender.
animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very Generalized Anxiety Disorder
weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has 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).
1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2- and histamine (H1)-receptors; antago- nism of muscarinic, histaminergic and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative and Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Paxil 20 mg or 40 mg were both cardiovascular effects for other psychotropic drugs.
demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially 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 superi- Pharmacokinetics
ority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible dose comparing paroxe- Paroxetine is equally bioavailable from oral suspension and tablet.
tine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of Paxil over placebo on the Hamilton Rating Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal Scale for Anxiety (HAM-A) total score, the primary outcome. male subjects (n=15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C patients to conduct subgroup analyses on the basis of age.
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 hr. (CV 32%), respectively. The steady- INDICATIONS AND USAGE
state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure Depression
based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess Paxil (paroxetine hydrochloride) is indicated for the treatment of depression. accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable.
The efficacy of Paxil in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 to 40 mg daily for the elderly and diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY). A major 20 to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic path- depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily func- way. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. tioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food.
sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.
The antidepressant action of Paxil in hospitalized depressed patients has not been adequately studied.
Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxida- The efficacy of Paxil in maintaining an antidepressant response for up to 1 year was demonstrated in a placebo-controlled trial (see tion and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use Paxil for extended periods should periodically re-evalu- been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibit- ate the long-term usefulness of the drug for the individual patient.
ing serotonin uptake. The metabolism of paroxetine is accomplished in part by cytochrome P450IID6. Saturation of this enzyme at clin- ical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment.
Obsessive Compulsive Disorder
The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS).
Paxil is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occu- 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.
The efficacy of Paxil was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded Distribution: Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.
most closely to the DSM-IIIR category of obsessive compulsive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
Protein Binding: Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively.
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro pro- ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or tein binding of phenytoin or warfarin.
Renal and Liver Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to paroxetine mean plasma concentrations in patients with creatinine clearance below 30 mL/min. was approximately 4 times greater than seen in showed a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about to use Paxil for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see a 2-fold increase in plasma concentrations (AUC, C The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, Panic Disorder
should be at increased intervals (see DOSAGE AND ADMINISTRATION).
Paxil is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30 and 40 mg, C
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.
min concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION).
The efficacy of Paxil (paroxetine hydrochloride) was established in three 10- to 12-week trials in panic disorder patients whose Clinical Trials
diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
Depression
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in The efficacy of Paxil (paroxetine hydrochloride) as a treatment for depression has been established in 6 placebo-controlled studies of which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, patients with depression (ages 18 to 73). In these studies Paxil was shown to be significantly more effective than placebo in treating or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of chok- depression by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, ing; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization and the Clinical Global Impression (CGI)–Severity of Illness. Paxil (paroxetine hydrochloride) was significantly better than placebo in (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthe- improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor and anxiety factor.
sias (numbness or tingling sensations); (13) chills or hot flushes.
A study of depressed outpatients who had responded to Paxil (HDRS total score <8) during an initial 8-week open-treatment phase Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder and were then randomized to continuation on Paxil or placebo for 1 year demonstrated a significantly lower relapse rate for patients assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY).
taking Paxil (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.
Nevertheless, the physician who prescribes Paxil for extended periods should periodically re-evaluate the long-term usefulness of the Obsessive Compulsive Disorder
The effectiveness of Paxil in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter Social Anxiety Disorder
placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with Paxil is indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose- anxiety disorder is characterized by a marked and persistent fear of one or more social or performance situations in which the per- range finding study where patients were treated with fixed doses of 20, 40 or 60 mg of paroxetine/day demonstrated that daily son is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60 mg paroxetine experi- anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or enced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal the approximate 4 point reduction at 20 mg and a 3 point reduction in the placebo-treated patients. Study 2 was a flexible dose study routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experi- phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
enced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduc- The efficacy of Paxil (paroxetine hydrochloride) was established in three 12-week trials in adult patients with social anxiety disor- tion of approximately 4 points in placebo-treated patients.
der (DSM-IV). Paxil has not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY—Clinical The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impressions (CGI) scale for Study 1.
The effectiveness of Paxil in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systemati- 4-17-01 — PROOF 2 — Paxil PX:L20A — 6/5.9 x 23.6 — PROMO/(8.5x11) — Univers Light, Bold & Italic — Page 2 Paxil (paroxetine hydrochloride) continued
cally evaluated in adequate and well-controlled trials. Therefore, the physician who elects to prescribe Paxil for extended periods
Drugs Metabolized by Cytochrome P450IID6: Many drugs, including most antidepressants (paroxetine, other SSRIs and many tri-
should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMIN- cyclics), are metabolized by the cytochrome P450 isozyme P450IID6. Like other agents that are metabolized by P450IID6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this P450IID6 isozyme is saturated early during Paxil dosing.
Generalized Anxiety Disorder
In one study, daily dosing of Paxil (20 mg q.d.) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC Paxil is indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with and T1/2 by an average of approximately two-, five- and three-fold, respectively. Concomitant use of Paxil with other drugs metabolized the stress of everyday life usually does not require treatment with an anxiolytic.
by cytochrome P450IID6 has not been formally studied but may require lower doses than usually prescribed for either Paxil or the other 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 Therefore, co-administration of Paxil with other drugs that are metabolized by this isozyme, including certain antidepressants (e.g., nortriptyline, amitriptyline, imipramine, desipramine and fluoxetine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persis- flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
tent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, thioridazine, paroxetine and thioridazine should not be co-administered (see CONTRAINDICATIONS and WARNINGS).
irritability, muscle tension, sleep disturbance.
At steady state, when the P450IID6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes The effectiveness of Paxil in the long-term treatment of GAD, that is, for more than 8 weeks, has not been systematically evaluated which, unlike P450IID6, show no evidence of saturation (see PRECAUTIONS–Tricyclic Antidepressants).
in controlled trials. The physician who elects to prescribe Paxil for extended periods should periodically re-evaluate the long-term Drugs Metabolized by Cytochrome P450IIIA4: An in vivo interaction study involving the co-administration under steady-state con-
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
ditions of paroxetine and terfenadine, a substrate for cytochrome P450IIIA4, revealed no effect of paroxetine on terfenadine phar- macokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P CONTRAINDICATIONS
450IIIA4 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, astem- Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or thioridazine is contraindicated (see WARNINGS izole, cisapride, triazolam, and cyclosporin. 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 IIIA Paxil is contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in Paxil.
4 substrates, paroxetine’s extent of inhibition of IIIA4 activity is not likely to be of clinical significance.
WARNINGS
Tricyclic Antidepressants (TCA): Caution is indicated in the co-administration of tricyclic antidepressants (TCAs) with Paxil,
Potential for Interaction with Monoamine Oxidase Inhibitors
because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor
need to be reduced, if a TCA is co-administered with Paxil (see PRECAUTIONS–Drugs Metabolized by Cytochrome P450IID6 ).
(MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus,
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of Paxil to a patient
autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme
taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently dis-
adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.
continued that drug and have been started on a 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
Alcohol: Although Paxil does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised
effects of combined use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate blood
to avoid alcohol while taking Paxil (paroxetine hydrochloride). pressure and evoke behavioral excitation. Therefore, it is recommended that Paxil (paroxetine hydrochloride) not be
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction between Paxil and lithium carbonate. However,
used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI. At least 2 weeks should
since there is little clinical experience, the concurrent administration of paroxetine and lithium should be undertaken with caution.
be allowed after stopping Paxil before starting a MAOI.
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean
Potential Interaction with Thioridazine
digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious
administration of paroxetine and digoxin should be undertaken with caution.
ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on
dose related.
An in vivo study suggests that drugs which inhibit P450IID6, such as paroxetine, will elevate plasma levels of
Procyclidine: Daily oral dosing of Paxil (30 mg q.d.) increased steady-state AUC0-24, Cmax and Cmin values of procyclidine (5 mg oral
thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CON-
q.d.) by 35%, 37% and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose TRAINDICATIONS and PRECAUTIONS).
PRECAUTIONS
Beta-Blockers: In a study where propranolol (80 mg b.i.d.) was dosed orally for 18 days, the established steady-state plasma
concentrations of propranolol were unaltered during co-administration with Paxil (30 mg q.d.) for the final 10 days. The effects of Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 1.0% of Paxil-treat-
propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS–Postmarketing Reports).
ed unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients Theophylline: Reports of elevated theophylline levels associated with Paxil treatment have been reported. While this interaction has
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 not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.
antidepressants, Paxil should be used cautiously in patients with a history of mania.
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and Paxil.
Seizures: During premarketing testing, seizures occurred in 0.1% of Paxil-treated patients, a rate similar to that associated with other
Carcinogenesis, Mutagenesis, Impairment of Fertility
antidepressants. Paxil should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who Carcinogenesis: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day
(mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close super-
dose (MRHD) for depression, social anxiety disorder and GAD on a mg/m2 basis. Because the MRHD for depression is slightly less vision of high-risk patients should accompany initial drug therapy. Prescriptions for Paxil should be written for the smallest quantity of than that for OCD (50 mg vs. 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the tablets consistent with good patient management, in order to reduce the risk of overdose.
MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when Paxil was
0/50, 0/50 and 4/50 for control, low-, middle- and high-dose groups, respectively) and a significantly increased linear trend across discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose- related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The rele- Abnormal Bleeding: There have been several reports of abnormal bleeding (mostly ecchymosis and purpura) associated with parox-
vance of these findings to humans is unknown.
etine treatment, including a report of impaired platelet aggregation. While a causal relationship to paroxetine is unclear, impaired Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following:
platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations Use in Patients with Concomitant Illness: Clinical experience with Paxil in patients with certain concomitant systemic illness is
in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
limited. Caution is advisable in using Paxil in patients with diseases or conditions that could affect metabolism or hemodynamic Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day
which is 2.9 times the MRHD for depression, social anxiety disorder and GAD or 2.4 times the MRHD for OCD on a mg/m2 basis.
Paxil has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions con- heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation sisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes of electrocardiograms of 682 patients who received Paxil in double-blind, placebo-controlled trials, however, did not indicate that Paxil with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for depression, social anxiety disorder and GAD; is associated with the development of significant ECG abnormalities. Similarly, Paxil (paroxetine hydrochloride) does not cause any 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2 basis).
clinically important changes in heart rate or blood pressure.
Pregnancy
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance <30 mL/min.) or Teratogenic Effects–Pregnancy Category C
severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organo-genesis. These doses are equivalent to 9.7 (rat) and 2.2 (rabbit) times the maximum recommended human dose (MRHD) for depres- Information for Patients
sion, social anxiety disorder and GAD (50 mg) and 8.1 (rat) and 1.9 (rabbit) times the MRHD for OCD, on a mg/m2 basis. These stud- Physicians are advised to discuss the following issues with patients for whom they prescribe Paxil: ies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of Interference with Cognitive and Motor Performance: Any psychoactive drug may impair judgment, thinking or motor skills.
lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a Although in controlled studies Paxil has not been shown to impair psychomotor performance, patients should be cautioned about oper- dose of 1 mg/kg/day or 0.19 times (mg/m2) the MRHD for depression, social anxiety disorder and GAD, and at 0.16 times (mg/m2) the ating hazardous machinery, including automobiles, until they are reasonably certain that Paxil therapy does not affect their ability to MRHD for OCD. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human Completing Course of Therapy: While patients may notice improvement with Paxil therapy in 1 to 4 weeks, they should be advised
response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
Concomitant Medication: Patients should be advised to inform their physician if they are taking, or plan to take, any prescription
The effect of paroxetine on labor and delivery in humans is unknown.
or over-the-counter drugs, since there is a potential for interactions.
Nursing Mothers
Alcohol: Although Paxil has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should
Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when Paxil (paroxetine hydrochloride) 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.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS–Nursing Mothers).
Geriatric Use
Laboratory Tests
In worldwide premarketing Paxil clinical trials, 17% of Paxil-treated patients (approximately 700) were 65 years of age or older.
There are no specific laboratory tests recommended.
Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, how- Drug Interactions
ever, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in Tryptophan: As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are
younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
co-administered. Adverse experiences, consisting primarily of headache, nausea, sweating and dizziness, have been reported when ADVERSE REACTIONS
tryptophan was administered to patients taking Paxil (paroxetine hydrochloride). Consequently, concomitant use of Paxil with trypto- Associated with Discontinuation of Treatment
Twenty percent (1,199/6,145) of Paxil patients in worldwide clinical trials in depression and 16.1% (84/522), 11.8% (64/542), 9.4% Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
(44/469) and 10.7% (79/735) of Paxil patients in worldwide trials in social anxiety disorder, OCD, panic disorder, and GAD, respectively, Thioridazine: See CONTRAINDICATIONS and WARNINGS.
discontinued treatment due to an adverse event. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for Paxil compared to placebo) 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 concomi- Social Generalized
tant administration of Paxil and warfarin should be undertaken with caution.
Sumatriptan: There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination fol-
Depression
Disorder
Disorder
Disorder
lowing the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
Paxil
Paxil
Paxil
Paxil
Paxil
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 q.d.) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during co-administration with oral cimetidine (300 mg t.i.d.) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of Paxil (paroxetine hydrochloride) after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimet- idine’s pharmacokinetics was not studied.
intestinal
Phenobarbital–Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30 mg dose of Paxil was admin- istered at phenobarbital steady state (100 mg q.d. 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 stud- ied. 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 Paxil dosage adjustment is considered necessary when co-administered 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 q.d. 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 q.d. for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacoki- netics, the above studies may not address the case where the two drugs are both being chronically dosed. No initial dosage adjust- ments are considered necessary when these drugs are co-administered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS–Postmarketing Reports).
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Where numbers are not provided the incidence of the adverse events in Paxil (paroxetine hydrochloride) patients was not >1% or was not greater than or equal to
Commonly Observed Adverse Events
Depression
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Paxil at least twice that for placebo, derived from Table 1 below) were: asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance and other male genital disorders.
Obsessive Compulsive Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Paxil at least twice that of placebo, derived from Table 2 below) were: nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence and abnormal ejaculation.
Panic Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Paxil at least twice that for placebo, derived from Table 2 below) were: asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders and impotence.
Social Anxiety Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Paxil at least twice that for placebo, derived from Table 2 below) were: sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders and impotence.
Generalized Anxiety Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Paxil at least twice that for placebo, derived from Table 3 below) were: asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.
Incidence in Controlled Clinical Trials
The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical tri- als. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied.
Depression
Table 1 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 to 50 mg/day. Reported adverse events 1. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder Paxil-treated patients are included, except the were classified using a standard COSTART-based Dictionary terminology.
following events which had an incidence on placebo ≥ Paxil: [OCD]: abdominal pain, agitation, anxiety, back pain, cough increased, Table 1. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Depression1
depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis and sinusitis. [panic disorder]:abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syn- Body System
Preferred Term
Paxil
drome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired and vasodilation. [social anxiety disorder]: abdominal pain, depression, headache, infection,respiratory disorder, and sinusitis.
Generalized Anxiety Disorder
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on Paxil who participated in placebo-controlled trials of 8 weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day.
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized
Anxiety Disorder1
Generalized
Anxiety Disorder
Paxil
Body System
Preferred Term
1. Events reported by at least 2% of Paxil-treated patients are included, except the following events which had an incidence on 1. Events reported by at least 1% of patients treated with Paxil (paroxetine hydrochloride) are included, except the following events placebo ≥Paxil: abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis.
which had an incidence on placebo ≥ Paxil: abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”), trauma Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose study comparing Paxil 10, 20, 30 and
40 mg/day with placebo in the treatment of depression revealed a clear dose dependency for some of the more common adverse 2. Includes mostly “lump in throat” and “tightness in throat.” events associated with Paxil use, as shown in the following table: 3. Percentage corrected for gender.
4. Mostly “ejaculatory delay.” Table 4. Treatment-Emergent Adverse Experience Incidence in a Depression Dose-Comparison Trial*
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.”6. Includes mostly “difficulty with micturition” and “urinary hesitancy.” Paxil
7. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” Body System/
Preferred Term
Obsessive Compulsive Disorder, Panic Disorder and Social Anxiety Disorder
Table 2 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on Paxil who participated in place-
bo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 to 60 mg/day or among patients with panic disorder on Paxil who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 to 60 mg/day or among patients with social anxiety disorder on Paxil (paroxetine hydrochloride) who participated in placebo- controlled trials of 12-weeks duration in which patients were dosed in a range of 20 to 50 mg/day.
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive
Compulsive Disorder, Panic Disorder and Social Anxiety Disorder1
Obsessive
Compulsive
Disorder
Disorder
Disorder
Body Preferred
Paxil
Paxil
Paxil
*Rule for including adverse events in table: incidence at least 5% for one of paroxetine groups and ≥ twice the placebo incidence for In a fixed-dose study comparing placebo and Paxil 20, 40 and 60 mg in the treatment of OCD, there was no clear relationship between adverse events and the dose of Paxil (paroxetine hydrochloride) to which patients were assigned. No new adverse events were observed in the Paxil 60 mg dose group compared to any of the other treatment groups. In a fixed-dose study comparing placebo and Paxil 10, 20 and 40 mg in the treatment of panic disorder, there was no clear relation- ship between adverse events and the dose of Paxil to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving Paxil 60 mg compared to any of the other treatment groups.
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In a fixed-dose study comparing placebo and Paxil 20, 40 and 60 mg in the treatment of social anxiety disorder, for most of the
DRUG ABUSE AND DEPENDENCE
adverse events, there was no clear relationship between adverse events and the dose of Paxil (paroxetine hydrochloride) to which Controlled Substance Class: Paxil (paroxetine hydrochloride) is not a controlled substance.
Physical and Psychologic Dependence: Paxil has not been systematically studied in animals or humans for its potential for abuse,
In a fixed-dose study comparing placebo and Paxil 20 mg and 40 mg in the treatment of generalized anxiety disorder, for most of tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations the adverse events, there was no clear relationship between adverse events and the dose of Paxil (paroxetine hydrochloride) to 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 which patients were assigned, except for the following adverse events: asthenia, constipation, and abnormal ejaculation.
misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with
patients should be observed closely for signs of Paxil misuse or abuse (e.g., development of tolerance, incrementations of dose, drug- continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence and asthenia).
Male and Female Sexual Dysfunction with SSRIs: Although changes in sexual desire, sexual performance and sexual satisfac-
OVERDOSAGE
tion often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particu- Human Experience: Since the introduction of Paxil in the U.S., 342 spontaneous cases of deliberate or accidental overdosage dur-
lar, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences.
ing paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combina- Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are tion with other substances. Of these, 48 cases were fatal and, of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the cases which documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence. the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The In placebo-controlled clinical trials involving more than 2,500 patients, the ranges for the reported incidence of sexual side effects largest known ingestion involved 2000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.
in males and females with depression, OCD, panic disorder, social anxiety disorder, and GAD are displayed in Table 5 below.
Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, Table 5. Incidence of Sexual Adverse Events in Controlled Clinical Trials
confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or withother substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), Paxil
hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dys- n (males)
function (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
Overdosage Management: Treatment should consist of those general measures employed in the management of overdosage with
n (females)
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. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfu- There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment.
sion and exchange transfusion are unlikely to be of benefit. No specific antidotes for paroxetine are known.
Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered A specific caution involves patients who are taking or have recently taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire of clinically significant sequelae and extend the time needed for close medical observation (see Drugs Metabolized by Cytochrome Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of treatment with Paxil for some patients
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison but, on average, patients in controlled trials had minimal (about 1 pound) weight loss vs. smaller changes on placebo and active con- control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers trol. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients are listed in the Physicians’ Desk Reference (PDR).
treated with Paxil in controlled clinical trials.
DOSAGE AND ADMINISTRATION
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with Paxil and 415 patients treated with placebo in controlled
Depression
clinical trials, no clinically significant changes were seen in the ECGs of either group.
Usual Initial Dosage: Paxil (paroxetine hydrochloride) should be administered as a single daily dose with or without food, usually in
Liver Function Tests: In placebo-controlled clinical trials, patients treated with Paxil exhibited abnormal values on liver function tests
the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials at no greater rate than that seen in placebo-treated patients. In particular, the Paxil-vs.-placebo comparisons for alkaline phosphatase, demonstrating the antidepressant effectiveness of Paxil. As with all antidepressants, the full antidepressant effect may be delayed.
SGOT, SGPT and bilirubin revealed no differences in the percentage of patients with marked abnormalities.
Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.
Other Events Observed During the Premarketing Evaluation of Paxil (paroxetine hydrochloride)
During its premarketing assessment in depression, multiple doses of Paxil were administered to 6,145 patients in phase 2 and 3 stud-
Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with Paxil
ies. The conditions and duration of exposure to Paxil varied greatly and included (in overlapping categories) open and double-blind should remain on it. It is generally agreed that acute episodes of depression require several months or longer of sustained pharma- studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. During premarket- cologic therapy. Whether the dose of an antidepressant needed to induce remission is identical to the dose needed to maintain and/or ing clinical trials in OCD, panic disorder, social anxiety disorder, and generalized anxiety disorder, 542, 469, 522, and 735 patients, respectively, received multiple doses of Paxil. Untoward events associated with this exposure were recorded by clinical investigators Systematic evaluation of the efficacy of Paxil (paroxetine hydrochloride) has shown that efficacy is maintained for periods of up to using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of indi- 1 year with doses that averaged about 30 mg.
viduals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized Obsessive Compulsive Disorder
Usual Initial Dosage: Paxil (paroxetine hydrochloride) should be administered as a single daily dose with or without food, usually in
In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The the morning. The recommended dose of Paxil in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the frequencies presented, therefore, represent the proportion of the 8,413 patients exposed to multiple doses of Paxil (paroxetine dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a hydrochloride) who experienced an event of the type cited on at least one occasion while receiving Paxil. All reported events are includ- range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of Paxil in the treatment of OCD. The maximum dosage ed except those already listed in Tables 1-3, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial,
patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHAR- Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: MACOLOGY). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the Panic Disorder
Usual Initial Dosage: Paxil should be administered as a single daily dose with or without food, usually in the morning. The target
Body as a Whole: frequent: chills, malaise; infrequent: allergic reaction, face edema, moniliasis, neck pain; rare: adrenergic
dose of Paxil in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in syndrome, cellulitis, neck rigidity, pelvic pain, peritonitis, ulcer.
10 mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials Cardiovascular System: frequent: hypertension, tachycardia; infrequent: bradycardia, hematoma, hypotension, migraine, syncope;
demonstrating the effectiveness of Paxil. The maximum dosage should not exceed 60 mg/day.
rare: angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, conges- Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial,
tive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINI- supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
CAL PHARMACOLOGY). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient.
Digestive System: infrequent: bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased sali-
Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically vation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; rare: aphthous stomatitis, bloody diarrhea, bulimia, reassessed to determine the need for continued treatment.
cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileus, Social Anxiety Disorder
intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, stomach ulcer, stomatitis, tongue Usual Initial Dosage: Paxil should be administered as a single daily dose with or without food, usually in the morning. The rec-
discoloration, tongue edema, tooth caries.
ommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of Paxil was demonstrated in patients dosed in a range Endocrine System: rare: diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis.
of 20 to 60 mg/day. While the safety of Paxil has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day,available information does not suggest any additional benefit for doses above 20 mg/day. (See CLINICAL PHARMACOLOGY).
Hemic and Lymphatic Systems: infrequent: anemia, eosinophilia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare:
Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with Paxil
abnormal erythrocytes, basophilia, bleeding time increased, hypochromic anemia, iron deficiency anemia, lymphedema, abnormal should remain on it. Although the efficacy of Paxil beyond 12 weeks of dosing has not been demonstrated in controlled clinical tri- lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia.
als, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a Metabolic and Nutritional: frequent: weight gain, weight loss; infrequent: alkaline phosphatase increased, edema, peripheral edema,
responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients SGOT increased, SGPT increased, thirst; rare: bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma should be periodically reassessed to determine the need for continued treatment.
globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, Generalized Anxiety Disorder
hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPG) increased.
Usual Initial Dosage: Paxil should be administered as a single daily dose with or without food, usually in the morning. In clini-
Musculoskeletal System: frequent: arthralgia; infrequent: arthritis, arthrosis; rare: bursitis, myositis, osteoporosis, generalized
cal trials the effectiveness of Paxil was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses Nervous System: frequent: emotional lability, vertigo; infrequent: abnormal thinking, alcohol abuse, ataxia, delirium, dystonia, dysk-
higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week. inesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with Paxil
manic reaction, neurosis, paralysis, paranoid reaction, psychosis; rare: abnormal gait, akinesia, antisocial reaction, aphasia, cho- should remain on it. Although the efficacy of Paxil beyond 8 weeks of dosing has not been demonstrated in controlled clinical tri- reoathetosis, circumoral paresthesias, convulsion, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasci- als, generalized anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for culations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients nystagmus, peripheral neuritis, psychotic depression, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal should be periodically reassessed to determine the need for continued treatment.
Dosage for Elderly or Debilitated, and Patients with Severe Renal or Hepatic Impairment: The recommended initial dose is
Respiratory System: infrequent: asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: emphyse-
10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made ma, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, voice alteration.
if indicated. Dosage should not exceed 40 mg/day.
Skin and Appendages: frequent: pruritus; infrequent: acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, furunculosis,
Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of a
herpes simplex, maculopapular rash, photosensitivity, urticaria; rare: angioedema, erythema nodosum, erythema multiforme, exfoliative MAOI and initiation of Paxil therapy. Similarly, at least 14 days should be allowed after stopping Paxil (paroxetine hydrochloride) before dermatitis, fungal dermatitis, herpes zoster, hirsutism, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, NOTE: SHAKE SUSPENSION WELL BEFORE USING.
Special Senses: frequent: tinnitus; infrequent: abnormality of accommodation, conjunctivitis, ear pain, eye pain, mydriasis, otitis
HOW SUPPLIED
media, photophobia; rare: amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye Tablets: Film-coated, modified-oval as follows:
hemorrhage, glaucoma, hyperacusis, keratoconjunctivitis, night blindness, otitis externa, parosmia, ptosis, retinal hemorrhage, taste 10 mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
Urogenital System: infrequent: abortion, amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria,
urinary incontinence, urinary retention, urinary urgency, vaginal moniliasis, vaginitis; rare: breast atrophy, breast enlargement,
20 mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrha- gia, nephritis, oliguria, pyuria, urethritis, uterine spasm, urolith, vaginal hemorrhage.
Postmarketing Reports
NDC 0029-3211-21 SUP 100’s (intended for institutional use only) Voluntary reports of adverse events in patients taking Paxil (paroxetine hydrochloride) that have been received since market introduction 30 mg blue tablets engraved on the front with PAXIL and on the back with 30.
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- 40 mg green tablets engraved on the front with PAXIL and on the back with 40.
Barré syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea, neuroleptic malignant syndrome-like events; extrapyramidal symptoms which have included akathisia, bradykinesia, Store tablets between 15° and 30°C (59° and 86°F).
cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide, tremor and tris- Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.
mus; serotonin syndrome, associated in some cases with concomitant use of serotonergic drugs and with drugs which may have impairedPaxil metabolism (symptoms have included agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachy- cardia and tremor), status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngis- Store suspension at or below 25°C (77°F).
mus, optic neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, and events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocy- tosis). There have been spontaneous reports that discontinuation (particularly when abrupt) may lead to symptoms such as dizziness, SmithKline Beecham Pharmaceuticals
sensory disturbances, agitation or anxiety, nausea and sweating; these events are generally self-limiting. There has been a case reportof an elevated phenytoin level after 4 weeks of Paxil and phenytoin co-administration. There has been a case report of severe hypoten- sion when Paxil was added to chronic metoprolol treatment.

Source: http://www.paxilprogress.org/pdf/us_paxil.pdf