PAROXETINE HCL
DESCRIPTION
PAROXETINE HCL (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 -4 R -(4'-fluorophenyl)-3 S -[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of C 19 H 20 FNO 3 Β·HClΒ·1/2H 2 O. The molecular weight is 374.8 (329.4 as free base).
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120Β° to 138Β° C and a solubility of 5.4 mg/mL in water.
Tablets
CLINICAL PHARMACOLOGY
Pharmacodynamics
The antidepressant action of paroxetine and its efficacy in the treatment of social anxiety disorder, 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, alpha 1 -, alpha 2 -, beta-adrenergic-, dopamine (D 2 )-, 5-HT 1 -, 5-HT 2 - and histamine (H 1 )-receptors; antagonism of muscarinic, histaminergic and alpha 1 -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 is equally bioavailable from oral suspension and tablet.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n=15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C max , T max , C min and T 1/2 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-state C max and C min values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC 0-24 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.
The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the C max was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.
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 450 IID 6 . Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS ).
Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.
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 had about a 2-fold increase in plasma concentrations (AUC, C max ).
The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION ).
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30 and 40 mg, C min concentrations were about 70% to 80% greater than the respective C min concentrations in non elderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION ).
Clinical Trials
Depression
The efficacy of PAROXETINE HCL (paroxetine hydrochloride) as a treatment for depression has been established in 6 placebo-controlled studies of patients with depression (ages 18 to 73). In these studies PAROXETINE HCL 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. PAROXETINE HCL (paroxetine hydrochloride) 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 had responded to PAROXETINE HCL (HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on PAROXETINE HCL or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking PAROXETINE HCL (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.
Obsessive Compulsive Disorder
The effectiveness of PAROXETINE HCL 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 a 3 point reduction in the placebo-treated patients. Study 2 was a flexible dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients.
The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impressions (CGI) scale for Study 1.
Outcome Classification (%) on CGI-Global
Improvement Item for Completers in Study 1 Outcome
Classification Placebo PAROXETINE HCL 20 mg PAROXETINE HCL 40 mg PAROXETINE HCL 60 mg
(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 PAROXETINE HCL in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.
Panic Disorder
The effectiveness of PAROXETINE HCL (paroxetine hydrochloride) 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, PAROXETINE HCL was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score.
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients.
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients.
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients.
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine.
Long-term maintenance effects of PAROXETINE HCL in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
Social Anxiety Disorder
The effectiveness of PAROXETINE HCL in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1-3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of PAROXETINE HCL compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impressions (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS).
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively.
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40 or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day.
Subgroup analyses did not indicate differences in treatment outcomes as a function of age, race, or gender.
INDICATIONS AND USAGE
Depression
PAROXETINE HCL (paroxetine hydrochloride) is indicated for the treatment of depression.
The efficacy of PAROXETINE HCL 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 PAROXETINE HCL in hospitalized depressed patients has not been adequately studied.
The efficacy of PAROXETINE HCL in maintaining an antidepressant response for up to 1 year was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY ). Nevertheless, the physician who elects to use PAROXETINE HCL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Obsessive Compulsive Disorder
PAROXETINE HCL 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 PAROXETINE HCL was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see CLINICAL PHARMACOLOGY -- Clinical Trials ).
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY ). Nevertheless, the physician who elects to use PAROXETINE HCL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).
Panic Disorder
PAROXETINE HCL 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 PAROXETINE HCL (paroxetine hydrochloride) 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) 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 PAROXETINE HCL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Social Anxiety Disorder
PAROXETINE HCL is indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of PAROXETINE HCL (paroxetine hydrochloride) was established in three 12-week trials in adult patients with social anxiety disorder (DSM-IV). PAROXETINE HCL has not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY -- Clinical Trials ).
The effectiveness of PAROXETINE HCL in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to prescribe PAROXETINE HCL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).
CONTRAINDICATIONS
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS and PRECAUTIONS ).
PAROXETINE HCL is contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in PAROXETINE HCL .
WARNINGS
Potential for Interaction with Monoamine Oxidase Inhibitors
In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with PAROXETINE HCL , 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 PAROXETINE HCL (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 PAROXETINE HCL before starting a MAOI.
PRECAUTIONS
General
Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 1.0% of PAROXETINE HCL -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 PAROXETINE HCL and 11.6% for the combined active-control groups. As with all antidepressants, PAROXETINE HCL should be used cautiously in patients with a history of mania.
Seizures: During premarketing testing, seizures occurred in 0.1% of PAROXETINE HCL -treated patients, a rate similar to that associated with other antidepressants. PAROXETINE HCL 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 and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for PAROXETINE HCL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Hyponatremia Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when PAROXETINE HCL 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. While a causal relationship to paroxetine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.
Use in Patients with Concomitant Illness: Clinical experience with PAROXETINE HCL in patients with certain concomitant systemic illness is limited. Caution is advisable in using PAROXETINE HCL in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
PAROXETINE HCL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product' premarket testing. Evaluation of electrocardiograms of 682 patients who received PAROXETINE HCL in double-blind, placebo-controlled trials, however, did not indicate that PAROXETINE HCL is associated with the development of significant ECG abnormalities. Similarly, PAROXETINE HCL (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 PAROXETINE HCL:
Interference with Cognitive and Motor Performance: Any psychoactive drug may impair judgment, thinking or motor skills. Although in controlled studies PAROXETINE HCL has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that PAROXETINE HCL therapy does not affect their ability to engage in such activities.
Completing Course of Therapy: While patients may notice improvement with PAROXETINE HCL 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 PAROXETINE HCL 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 PAROXETINE HCL .
Pregnancy Patients should be advised 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 tests recommended.
Drug Interactions
Tryptophan As with other serotonin reuptake 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 PAROXETINE HCL (paroxetine hydrochloride). Consequently, concomitant use of PAROXETINE HCL 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 PAROXETINE HCL and warfarin should be undertaken with caution.
Sumatriptan: There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
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 P 450 (oxidative) enzymes. In a study where PAROXETINE HCL (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 PAROXETINE HCL (paroxetine hydrochloride) after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine' pharmacokinetics was not studied.
Phenobarbital-Phenobarbital induces many cytochrome P 450 (oxidative) enzymes. When a single oral 30 mg dose of PAROXETINE HCL was administered at phenobarbital steady state (100 mg q.d. for 14 days), paroxetine AUC and T 1/2 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 PAROXETINE HCL exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial PAROXETINE HCL 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 PAROXETINE HCL was administered at phenytoin steady state (300 mg q.d. for 14 days), paroxetine AUC and T 1/2 were reduced (by an average of 50% and 35%, respectively) compared to PAROXETINE HCL 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 two 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 P 450 IID 6 : Many drugs, including most antidepressants (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P 450 isozyme P 450 IID 6 . Like other agents that are metabolized by P 450 IID 6 , paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this P 450 IID 6 isozyme is saturated early during PAROXETINE HCL dosing. In one study, daily dosing of PAROXETINE HCL (20 mg q.d.) under steady-state conditions increased single dose desipramine (100 mg) C max , AUC and T 1/2 by an average of approximately two-, five- and three-fold, respectively. Concomitant use of PAROXETINE HCL with other drugs metabolized by cytochrome P 450 IID 6 has not been formally studied but may require lower doses than usually prescribed for either PAROXETINE HCL or the other drug.
Therefore, co-administration of PAROXETINE HCL 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), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
At steady state, when the P 450 IID 6 pathway is essentially saturated, paroxetine clearance is governed by alternative P 450 isozymes which, unlike P 450 IID 6 , show no evidence of saturation (see PRECAUTIONS -- Tricyclic Antidepressants ).
Drugs Metabolized by Cytochrome P 450 IIIA 4 : An in vivo interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome P 450 IIIA 4 , revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P 450 IIIA 4 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' in vivo clearance predicts its effect on other IIIA 4 substrates, paroxetine's extent of inhibition of IIIA 4 activity is not likely to be of clinical significance.
Tricyclic Antidepressants (TCA): Caution is indicated in the co-administration of tricyclic antidepressants (TCAs) with PAROXETINE HCL , 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 PAROXETINE HCL (see PRECAUTIONS -- Drugs Metabolized by Cytochrome P 450 IID 6 ).
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of PAROXETINE HCL 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 PAROXETINE HCL does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAROXETINE HCL (paroxetine hydrochloride).
Lithium A multiple-dose study has shown that there is no pharmacokinetic interaction between PAROXETINE HCL and lithium carbonate. However, since there is little clinical experience, the concurrent administration of paroxetine 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 PAROXETINE HCL (30 mg q.d.) increased steady-state AUC 0-24 , C max and C min 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 PAROXETINE HCL (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 PAROXETINE HCL 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 PAROXETINE HCL .
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 and social anxiety disorder on a mg/m 2 basis. Because the MRHD for depression is slightly less 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 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 and social anxiety disorder or 2.4 times the MRHD for OCD on a mg/m 2 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 seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for depression and social anxiety disorder; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m 2 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 and social anxiety disorder (50 mg) and 8.1 (rat) and 1.9 (rabbit) times the MRHD for OCD, on a mg/m 2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or 0.19 times (mg/m 2 ) the MRHD for depression and social anxiety disorder and at 0.16 times (mg/m 2 ) 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 PAROXETINE HCL (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 PAROXETINE HCL clinical trials, 17% of PAROXETINE HCL -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 ).
ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Twenty percent (1,199/6,145) of PAROXETINE HCL patients in worldwide clinical trials in depression and 16.1% (84/522), 11.8% (64/542) and 9.4% (44/469) of PAROXETINE HCL patients in worldwide trials in social anxiety disorder, 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 PAROXETINE HCL compared to placebo) included the following:
Depression OCD Panic
Disorder Social
Anxiety
Disorder
PAROXETINE Placebo PAROXETINE Placebo PAROXETINE Placebo PAROXETINE Placebo
HCL HCL HCL HCL
CNS
Somnolence 2.3% 0.7% -- 1.9% 0.3% 3. 4% 0.3%
Insomnia- -- -- 1.7% 0% 1.3% 0.3% 3.1% 0%
Agitation 1.1% 0.5% -- -- -- -- -- --
Tremor 1.1% 0.3% -- -- -- -- 1.7% 0%
Anxiety -- -- -- -- -- -- 1.1% 0%
Dizziness -- -- 1.5% 0% -- -- 1.9% 0%
Gastrointestinal
Constipation -- -- -- -- -- -- 1.1% 0%
Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 4.0% 0.3%
Diarrhea 1.0% 0.3% -- -- -- -- -- --
Dry mouth 1.0% 0.3% -- -- -- -- -- --
Vomiting 1.0% 0.3% -- -- -- -- 1.0% 0%
Flatulence -- -- -- -- -- -- 1.0% 0.3%
Other
Asthenia 1.6% 0.4% 1.9% 0.4% -- -- 2.5% 0.6%
Abnormal
ejaculation 1 1.6% 0% 2.1% 0% -- -- 4.9% 0.6%
Sweating 1.0% 0.3% -- -- -- -- 1.1% 0%
Impotence 1% -- -- -- -- -- 1.5% 0%
Libido
Decreased -- -- -- -- -- -- 1.0% 0%
Where numbers are not provided the incidence of the adverse events in PAROXETINE HCL (paroxetine hydrochloride) patients was not >1% or was not greater than or equal to two times the incidence of placebo.
1. Incidence corrected for gender.