(brand of paroxetine hydrochloride)
Tablets
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DRUG ABUSE AND DEPENDENCE
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
Paxil (paroxetine hydrochloride) is an orally administered antidepressant with a chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic or other available antidepressant agents. 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 is:
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120o to 138oC and a solubility of 5.4 mg/mL in water.
Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as follows:
10 mg-Yellow; 20 mg-pink (scored); 30 mg-blue, 40 mg-green. Inactive ingredients consist of dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, 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.
Pharmacodynamics
The antidepressant action of paroxetine and its efficacy in the treatment of obsessive compulsive disorder (OCD) and panic disorder (PD) 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 week effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that the antidepressant action of paroxetine and its efficacy in the treatment of obsessive compulsive disorder (OCD) and panic disorder (PD) 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 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 C max, Tmax, Cmin and T1/2 were 61.7 ng/mL (CV 45%) and 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%) and 21.0 hr (CV 32%), respectively. The steady-state Cmax and C min 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 one of the enzymes that metabolizes paroxetine is readily saturable.
In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 to 40 mg daily for the elderly and 20 to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to C min 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 cytochrome P 450IID6. Saturation of this enzyme at clinical doses appears to account for the nonlinarity of paroxetine kinetics with increasing dose and increasing duration of treatment. The rolse of this enzyme is 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.
Distribution: Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.
Protein Binding: 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.
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 has 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).
Elderely 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 nonelderely subjects. Therefore the initial dosage in the elderly should be reduced. (see DOSAGE AND ADMINISTRATION.)
Clinical Trials
Depression
The efficacy of Paxil as a treatment of depression has been established in 6 placebo-controlled studies of patients with depression (ages 18 to 73). In these studies Paxil was shown to be significantly more effective than placebo in treating depression 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 depressed outpatients who has 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 4 point reduction at 20 mg and 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 Impressions (CGI) scale for Study 1.
Outcome Classification (%) on CGI-Global
Improvement item for Completers in Study 1
Paxil Paxil Paxil
Outcome placebo 20 mg 40 mg 60 mg
Classification (n= 74) (n=75) (n=66) (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 (20-60 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 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.
Depression
Paxil (paroxetine hydrochloride) is indicated for the treatment of depression.
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). 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 antidepressant action of Paxil in hospitalized depressed patients has not been adequately studied.
The efficacy of Paxil in maintaining an antidepressant response for up to 1 year was demonstrated in placebo-controlled trial (see CLINICAL PHARMACOLOGY). 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 egodystonic 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). Nevertheless, the physician who elects to use Paxil for extended periods should periodically reevaluate 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 four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: [1 [(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). Nevertheless, the physician who prescribes Paxil for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS and PRECAUTIONS).
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 fluctuation of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reaction have also been reported in patients who have recently discontinued 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 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 (paroxetine hydrochloride) not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI. At least 2 weeks should be allowed after stopping Paxil before starting a MAOI.
General
Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 1.0% of Paxil-treated unipolar patients 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 antidepressants, Paxil should be used cautiously in patients with a history of mania.
Seizures: During premarketing testing, seizures occurred in 0.1% of Paxil-treated patients, a rate similar to that associated with other antidepressants. Paxil should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
Suicide: The possibility of a suicide attempt is inherent in depression any may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for Paxil should be written for the smallest quantity of tablets consistent with good patients management, in order to reduce the risk of overdose.
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.
Abnormal Bleeding: There have been several reports of abnormal bleeding (mostly ecchymosis and purpura) associated with paroxetine treatment, including a report of impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.
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 disease or conditions that could affect metabolism or hemodynamic responses.
Paxil has not been evaluated or used to any appreciable extend 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 (paroxetine hydrochloride) 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
Physicians are advised to discuss the following issues with patients for whom they prescribe Paxil:
Interference with Cognitive and Motor Performances: 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 Paxil therapy does not affect their ability to engage in such activities.
Completing Course of Therapy: While patients may notice improvement with Paxil therapy 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 devised to notify their physician if they become pregnant or intend to become pregnant during therapy.
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 test recommended.
Drug Interactions
Tryptophan: As with other serotonin reuptke inhibitors, an interaction between paroxetine and tryptophan may occur when they are co-administered. Adverse experiences, consisting primarily of headache, nausea, sweating and dizziness, have been reported when tryptophan was administered to patients taking Paxil (paroxetine hydrochloride). Consequently, concomitant use of Paxil with tryptophan is not recommended.
Monoamine Oxidase Inhibitors: 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.
Drugs Affecting Hepatic Metabolism: The metabolism and phamacokinetics 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 after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine of 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 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 studied. Since Paxil exhibits nonlinear pharmacokinetics, 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 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 co-administered; any subsequent adjustments should be guided by clinical effect. (see ADVERSE REACTIONS Postmarketing Reports).
Drugs Metabolized by cytochrome P450IID6:
Many drugs, including most antidepressants (paroxetine, other SSRIs and many tricyclics), 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 is saturated early during Paxil dosing. In one study, daily dosing of Paxil (20 mg q.d.) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC an
T1/2 by an average of approximately two-, five-, and three-fold, respectively. Concomitant use of Paxil with other drugs metabolized by cytochrome P450IID6 has not been formally studied but may require lower doses than usually prescribed for either Paxil or the other drug.
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 (e.g., thioridazine) and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), should be approached with caution.
At steady state, when the P450IID6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes which unlike P450IID6 show no evidence of saturation. (see PRECAUTIONS-Tricyclic Antidepressants).
Drugs Metabolized by Cytochrome P450IIIA4:
An in vivo interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome P450IIIA4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P450IIIA4, 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 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 IIIA4 substrates, paroxetine’s extent of inhibition of IIIA4 activity is not likely to be of clinical significance.
Tricyclin Antidepressants (TCA): Caution is indicated in the co-administration 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 co-administered with Paxil (see PRECAUTIONS-Drugs Metabolized by Cytochrome P450IID6).
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.
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 (paroxetine hydrochloride).
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction between Paxil and lithium carbonate. However, since there is little clinical experience, the concurrent administration of proxetine and lithium should be undertaken with caution.
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 q.d.) increased steady-state AUC0-24 , Cmax and Cmin values of procyclidine (5 mg oral q.d.) 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 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 propranolol on paroxetine have not been evaluated. (See ADVERSE REACTIONS Postmarketing Reports).
Theophylline: Reports of elevated theophylline levels associated with Paxil treatment 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.
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and Paxil.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 dose (MRHD) for depression on a mg/m2 basis. Because the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50 and 4/50 for control, low-, middle- and high-dose groups, respectively) and a significantly increased linear trend across 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 relevance of these findings to humans is unknown.
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
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 or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the somniferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for depression; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2 basis).
Pregnancy
Teratogenic Effects-Pregnancy Category C
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 equivalent to 9.7 (rat) and 2.2 (rabbit) times the maximum recommended human dose (MRHD) for depression (50 mg) and 8.1 (rat) and 1.9 (rabbit) times the MRHD for OCD, on a mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pupdeaths 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 0.19 times (mg/m2) the MRHD for depression and at 0.16 times (mg/m2) the 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 response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of paroxetine on labor and delivery in humans is unknown.
Nursing Mothers
Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when Paxil (paroxetine hydrochloride) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
Geriatric Use
In worldwide premarketing Paxil clinical trials, 17% of Paxil-treated patients (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients. (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Associated with Discontinuation of
Treatment
Twenty percent of (1,199/6,145) of Paxil patients in worldwide clinical trials in depression and 11.8% (64/542) and 9.4% (44/469) of Paxil patients in worldwide trials in OCD and panic disorder, respectively, 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)
included the following:
Depression OCD Panic Disorder
Paxil Placebo Paxil Placebo Paxil Placebo
CNS
Somnolence 2.3% 0.7% -- 1.9% 0.3%
Insomnia -- -- 1.7% 0% 1.3% 0.3%
Agitation 1.1% 0.5% --
Tremor 1.1% 0.3% --
Anxiety -- -- --
Dizziness -- -- 1.5% 0%
Gastrointestinal
Constipation -- 1.1% 0%
Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2%
Diarrhea 1.0% 0.3% --
Dry mouth 1.0% 0.3% --
Vomiting 1.0% 0.3% --
Other
Asthenia 1.6% 0.4% 1.9% 0.4%
Abnormal 1.6% 0% 2.1% 0%
ejaculation1
Sweating 1.0% 0.3% --
Impotence1 -- 1.5% 0%
Where numbers are not provided the incidence of the adverse events in Paxil patients was not >1% or was greater than or equal to two times the incidence of placebo.
1. Incidence corrected for gender.
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, insomnea, 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 of Paxil at least twice that of placebo, derived from Table 2 below) were : nausea, drymouth, 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 of 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.
Incidence in controlled Clinical Trials
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 were classified using a standard COSTART-based Dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
Experience Incidence in Placebo-Controlled
Clinical Trials for Depression1
Body System Preferred Term Paxil Placebo
(n=421) (n=421)
Body as a Whole Headache 18% 17%
Asthenia 15% 6%
Cardiovascular Palpitation 3% 1%
Vasodilation 3% 1%
Dermatologic Sweating 11% 2%
Rash 2% 1%
Gastrointestinal Nausea 26% 9%
Dry Mouth 18% 12%
Constipation 14% 9%
Diarrhea 12% 8%
Decreased Appetite 6% 2%
Flatulence 4% 2%
Oropharynx Disorder2 2% 0%
Dyspepsia 2% 0%
Musculoskeletal Myopathy 2% 1%
Myalgia 2% 1%
Myasthenia 1% 0%
Nervous System Somnolence 23% 9%
Dizziness 13% 6%
Insomnia 13% 6%
Tremor 8% 2%
Nervousness 5% 3%
Anxiety 5% 3%
Paresthesia 4% 2%
Libido Decreased 3% 0%
Drugged Feeling 2% 1%
Confusion 1% 0%
Respiration Yawn 4% 0%
Special Senses Blurred Vision 4% 0%
Taste Perversion 2% 0%
Urogenital Ejaculatory 13% 0%
System Disturbance3.4
Other Male Genital 10% 0%
Disorders3.5
Urinary Frequency 3% 1%
Urination Disorder6 3% 0%
Female Genital 2% 0%
Disorders3.7
1. Events reported by at least 1% of patients treated with Paxil (paroxetine hydrochloride) are included, except the following: events 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 and vomiting.
2. Includes mostly “lump in throat” and “tightness in throat.”
3. Percentage corrected for gender.
4. Mostly “ejaculatory delay.”
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/Orgasm,” and “sexual dysfunction,” and “impotence”.
6. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7. Includes mostly “anorgasmia” and “difficulty reaching climax, orgasm.”
Obsessive Compulsive Disorder and Panic Disorder
Table 2 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on Paxil who participated in placebo-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.
Obsessive Panic
Compulsive Disorder Disorder
Paxil Placebo Paxil Placebo
Body System Preferred Term (n=542) (n=295) (n=499) (n=324)
Body as a Asthenia 22% 14% 14% 5%
Whole Abdominal Pain 4% 3%
Chest Pain 3% 2% -- --
Back Pain -- -- 3% 2%
Chills 2% 1% 2% 1%
Cardiovascular Vasodilation 4% 1% -- --
Palpitation 2% 0% -- --
Dermatologic Sweating 9% 3% 14% 6%
Rash 3% 2% -- --
Gastrointestinal Nausea 23% 10% 23% 17%
Drymouth 18% 9% 18% 11%
Constipation 16% 6% 8% 5%
Diarrhea 10% 10% 12% 7%
Decreased 9% 3% 7% 3%
Appetite
Increased 4% 3% 2% 1%
Appetite
Nervous System Insomnia 24% 13% 18% 10%
Somnolence 24% 7% 19% 11%
Dizziness 12% 6% 14% 10%
Tremor 11% 1% 9% 1%
Nervousness 9% 8% -- --
Libido Decreased 7% 4% 9% 1%
Agitation -- -- 5% 4%
Anxiety -- -- 5% 4%
Abnormal Dreams 4% 1% -- --
Concentration 3% 2% -- --
Impaired
Depersonalization 3% 0% -- --
Myoclonus 3% 0% 3% 2%
Amnesia 2% 1% -- --
Respiratory Rhinitis -- -- 3% 0%
System
Special Senses Abnormal Vision 4% 2% -- --
Taste Perversion 2% 0% -- --
Urogenital Abnormal 23% 1% 21% 1%
System Ejaculation2
Female Genital 3% 0% 9% 1%
Disorder
Impotence2 8% 1% 5% 0%
Urinary 3% 1% 2% 0%
Frequency
Urination 3% 0% -- --
Impaired
Urinary Tract 2% 1% 2% 1%
Infection
1. Events reported by at least 2% of OCD or panic disorder Paxil-treated patients are included, except the following events which had an incidence on placebo >/= Paxil: [OCD]: abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis and sinusitis.[panic disorder]: abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depressions, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired and vasodilation.
2. Percentage corrected for gender.
Dose Dependeney of Adverse Events: A comparison of adverse events 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 events associated with Paxil use, as shown in the following table:
Placebo Paxil Body System/ 10 mg 20 mg 30 mg 40 mg Preferred Term n=51 n=102 n=104 n=101 n=102
Body as a Whole Asthenia 0.0% 2.9% 10.6% 13.9% 12.7% Dermatology Sweating 2.0% 1.0% 6.7% 8.9% 11.8% Gastrointestinal Constipation 5.9% 4.9% 7.7% 9.9% 12.7% Decreased 2.0% 2.0% 5.8% 4.0% 4.9% Appetite Diarrhea 7.8% 9.8% 19.2% 7.9% 14.7% Dry Mouth 2.0% 10.8% 18.3% 15.8% 20.6% Nausea 13.7% 14.7% 26.9% 34.7% 36.3% Nervous System Anxiety 0.0% 2.0% 5.8% 5.9% 5.9% Dizziness 3.9% 6.9% 6.7% 8.9% 12.7% Nervousness 0.0% 5.9% 5.8% 4.0% 2.9% Paresthesia 0.0% 2.9% 1.0% 5.0% 5.9% Somnolence 7.8% 12.7% 18.3% 20.8% 21.6% Tremor 0.0% 0.0% 7.7% 7.9% 14.7% Special Senses Blurred Vision 2.0% 2.9% 2.9% 2.0% 7.8% Urogenital System Abnormal Ejaculation 0.0% 5.8% 6.5% 10.6% 13.0% Impotence 0.0% 1.9% 4.3% 6.4% 1.9% Male Genital Disorders 0.0% 3.8% 8.7% 6.4% 3.7%
* Rule for including adverse events in table: incidence at least 5% for one of paroxetine groups and >/= twice the placebo incidence for at least one paroxetine group.
In a fixed dose study comparing placebo and Paxil 20, 40, and 60mg in the treatment of OCD, there was no clear relationship between adverse events and the dose of Paxil 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 40mg in the treatment of panic disorder, there was no clear relationship 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.
Adaption to certain adverse events: Over a 4 to 6 week period, there was evidence of adaptation to some adverse events with continued therapy (e.g nausea and dizziness), but less to other effects (e.g dry mouth, somnolence and asthenia).
Weight and vital sign changes: Significant weight loss may be an undesirable result of treatment with Paxil for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss vs. smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with Paxil in controlled clinical trials.
ECG changes: In an analysis of ECGs obtained in 682 patients treated with Paxil and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group.
Liver Function Tests: In placebo-controlled clinical trials, patients treated with Paxil exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the Paxil-vs-placebo comparisons for alkaline phosphatase, SGOT, SGPT and bilirubin revealed no differences in the percentage of patients with marked abnormalities.
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 studies. The conditions and duration of exposure to Paxil varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed dose and titration studies. During premarketing clinical trials in OCD and panic disorder, 542 and 469 patients, respectively, received multiple doses of Paxil. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 7156 patients exposed to multiple doses of Paxil (paroxetine hydrochloride) who experienced an event of the type cited on at least one occasion while receiving Paxil. All reported events are included except those already listed in Tables 1 and 2 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 not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section.
Body as a Whole: frequent: chills, malaise; infrequent: allergic reaction, carcinoma, face edema, moniliasis, neck pain; rare; abscess, adrenergic syndrome, celulitis, neck rigidity, pelvic pain, peritonitis, ulcer.
Cardiovascular System: frequent: hypertension, syncope, tachycardia; infrequent; bradycardia, conduction abnormalities, electrocardiogram abnormal, hematoma, hypotension, migraine, peripheral vascular disorder; rare: angina pectoris, arrhythmia, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, suprabentricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
Digestive System: infrequent: bruxism, colitis, dysphagia, eructation, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, mouth ulceration, rectal hemorrhage, ulcerative stomatitis; rare; aphthous stomatitis, bloody diarrhea, bulimia, choleithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gastritis, gum hemorrhage, hematemesis, hepatitis, ileus, intestinal obstruction, jaundice, melena, peptic ulcer, salivary gland enlargement, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries, tooth malformation.
Endocrine System: rare: diabetes mellitus, hyperthyroidism, hypothyroidism, thyroiditis.
Hemic and Lymphatic Systems: infrequent: anemia, leukopenia, lymphadenopathy, purpura; rare: abnormal erythrocytes, basophilia, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcyic anemia, monocytosis, normocytic anemia, thrombocythemia.
Metabolic and Nutritional: frequent: edema, weight gain, weight loss; infrequent; hyperglycemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare: alkaline phosphatase increased, bilirubinemia, BUN increased creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperkalemia, hypoglycemia, hyperphosphatemia, hyponatremia, ketosis, lactic dehydrogenase increased.
Musculoskeletal System: frequent: arthralgia; infrequent: arthritis; rare; arthrosis, bursitis, myositis osteoporosis, generalized spasm, tenosynovitis, tetany.
Nervous System: frequent: amnesia, CNS stimulation, concentration impaired, depression, emotional liability, vertigo; infrequent: abnormal thinking, akinesia, alcohol abuse, ataxia, convulsion, depersonalization, dystonia, hallucinations, incoordination, lack of emotion, manic reaction, neurosis, paralysis, paranoid reaction; rare: abnormal electroencephalogram, abnormal gait, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, delirum, delusions, diplopia, drug dependence, dysarthria, dyskinesia, euphoria, extrapyramidal syndrome, fasciculations, grand mal conclusion, hyperalgesia, hyperalgesia, hypokinesia, hysteria, libido increased, manic-depressive reaction, meningitis, myelitis, neuralgia, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus, withdrawal syndrome.
Respiratory System: frequent: cough increased, rhinitis; infrequent: asthma, bronchitis, dyspnea, epistaxis hyperventilation, pneumonia, respiratory flu, sinusitis, vice alteration; rare: emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased.
Skin and Appendages: frequent: prupritus; infrequent: acne, alopecia, dry skin, ecchymosis, eczema, furunculosis, urticaria; rare: angioedema, contact dermatitis, kerythema nodosum, erythema, multiforme, fugal dermatitis, herpes simplex, herpes zoster, hirsutism, maculopapular rash, photosensitivity, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, vesiculobullous rash.
Special Senses: Frequent: tinnitus; infrequent: abnormality of accommodation, conjunctivitis, ear pain, eye pain, mydriasis, otitis media, taste loss, visual field defect; rare, amblyopia, anisocroia, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, keratoconjunctivitis, night blindness, otitis external, parosmia, photophobia, ptosis, retinal hemorrhage.
Urogenital System: infrequent: abortion, amenorrhea, breast pain, cystitis, dysmenorrhea, dysuria, hematuria, menorrhagia, nocuria, polyuria, urethritis, urinary incontinence, urinary retention, urinary urgency, vaginiitis; rare: breast atrophy, breast carcinoma, breast enlargement, breast neoplasm, epididymitis, female lactation, fibrosystic breast, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, prostatic carcinoma, pyuria, urethritis, uterine spasm, urolith, vaginal monilasis, vaginal hemorrhage.
Postmarketing Reports
Voluntary reports of adverse events in patients taking Paxil that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancratitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Gullain-Barre syndrome, toxic epidermal necrolysis, priapism, thrombocytopenia, syndrome of inapropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea, neuroleptic maligant syndrome-like events; extrapyramidal symptoms which have included akathisia, bradyinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide, tremor and trismus; and serotonin syndrome, associated in some cases with concomitant use of serotonergic drugs and with drugs which may have impaired Paxil metabolism (symptoms have included agitation, confusion, deaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor.) There have been spontaneous reports that abrupt discontinuation may lead to symptoms such as dizziness, sensory disturbances, agitation or anxiety, nausea and sweating; these events are generally self-limiting. There has been a case report of an elevated
phenytoin level after 4 weeks Paxil and phenytoin co-administration. There has been a case report of severe hypotension when Paxil was added to chronic metroprolol treatment.
Controlled Substances 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, tolerance or physical dependence. While the clinical trials did not reveal any tendencey for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/ or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of Paxil misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behabior).
Human Experience: No deaths were reported following acute overdose with Paxil alone or in combination with other drugs and/or alcohol (18 cases, with doses up to 850 mg) during premarketing clinical trials in depression, OCD, and panic disorder . Signs and symptoms of overdose with Paxil included; nausea, vomiting, drowsiness, sinus tachycardia, and dialated pupils. There were no reports of ECG abnormalities, coma or convulsions following overdosage with Paxil alone.
Overdosage Management: Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. There are no specific antidotes for Paxil. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Gasrtic evacuation either by the induction of emesis or lavage or both should be performed. In most cases, following evacuation, 20 to 30 grams of activated charcoal may be administered every 4 to 6 hours during the first 24 to 48 hours after ingestion. An ECG should be taken and monitoring of cardiac function instituted if there is any evidence of abnormality. Supportive care with frequent, monitoring of vital signs and careful observation is indicated. Due to the large volume of distribution of Paxil, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
A specific caution involves patients taking or recently having taking or recently having taken paroxetine who might ingest by accident or intent excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation.
In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
Depression
Usual Initial Dosage: Paxil (paroxetine hydrochloride) should be administered as a single daily dose, usually in 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 demonstrating the antidepressant effectiveness of Paxil. As with all antidepressants, the full antidepressant effect may be delayed. 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.
Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with Paxil should remain on it. It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission as identical to the dose needed to maintain and/or sustain euthymia is unknown.
Systematic evaluation of the efficacy of Paxil (paroxetine hydrochloride) has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.
Obsessive Compulsive Disorder
Usual Initial Dosage: Paxil should be administered as a single daily dose, usually in 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 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 range of 20 to 60 mg day in the clinical trials demonstrating the effectiveness of Paxilin the treatment of OCD. The maximum dosage should not exceed 60 mg/day.
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 Pharmacology). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Panic Disorder
Usual Initial Dosage: Paxil should be administered as a single daily dose, usually in the morning. The target 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 10 mg/week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of Paxil. The maximum dosage should not exceed 60 mg/day.
Maintenance Therapy: 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). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.
Dosage for Elderly or Debilitated, and Patients with Severe Renal of Hepatic Impairment: The recommended initial dose is 10 mg/day and or for elderly patients, debilitated patients, and or patients with severe renal or hepatic impairment. Increases may be made if indicated.
Dosage should not exceed 40 mg/day.
Swithching Patients to or from a Monoamine Oxidase Inhibitor: At lease 14 days should elapse between discontinuation of MAOI and initiation of Paxil therapy. Similarly, at least 14 days should be allowed after stopping Paxil before starting a MAOI.
Paxil is supplied as film-coated, modified-oval tablets as as follows:
10 mg yellow tablets engraved on the front with PAXIL and on the back with 10.
NDC 0029-3210-13 bottles of 30
20 mg pink scored tablets engraved on the front with PAXIL and on the back with 20.
NDC 0029-3211-13 Bottles of 30
NDC 0029-3211-20 Bottles of 100
NDC 0029-3211-21 SUP 100’s (intended for institutional use only).
30 mg blue tablets engraved on the front with PAXIL and on the back with 30.
NDC 0029-3212-13 Bottles of 30
40 mg green tablets engraved on the front with PAXIL and on the back with 40.
NDC 0029-3213-13 Bottles of 30
Store between (15o and 30oC; 59o and 86oF)
DATE OF ISSUANCE MAY 1996
© SmithKline Beecham, 1996
SmithKline Beecham Pharmaceuticals
Philadelphia, PA 19101
PX;L10
Printed in U.S.A.