Paxil Information
Paxil (Paroxetine) Suicidality And Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Paxil (Paroxetine) CR or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Paxil (Paroxetine) CR is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
Paxil (Paroxetine) Description
Paxil (Paroxetine) CR (paroxetine hydrochloride) is an orally administered psychotropic drug with a chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic, or other available antidepressant or antipanic agents. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)--4(4'-fluorophenyl)-3-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of CHFNO•HCl•1/2HO. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is:
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water.
Each enteric, film-coated, controlled-release tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 12.5 mg–yellow, 25 mg–pink, 37.5 mg–blue. One layer of the tablet consists of a degradable barrier layer and the other contains the active material in a hydrophilic matrix.
Inactive ingredients consist of hypromellose, polyvinylpyrrolidone, lactose monohydrate, magnesium stearate, silicon dioxide, glyceryl behenate, methacrylic acid copolymer type C, sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate, titanium dioxide, polyethylene glycols, and 1 or more of the following colorants: Yellow ferric oxide, red ferric oxide, D&C Red No. 30 aluminum lake, FD&C Yellow No. 6 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake.
Paxil (Paroxetine) Clinical Pharmacology
The efficacy of paroxetine in the treatment of major depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder (PMDD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha-, alpha-, beta-adrenergic-, dopamine (D)-, 5-HT-, 5-HT-, and histamine (H)-receptors; antagonism of muscarinic, histaminergic, and alpha-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.
The efficacy of Paxil (Paroxetine) CR controlled-release tablets as a treatment for major depressive disorder has been established in two 12-week, flexible-dose, placebo-controlled studies of patients with DSM-IV Major Depressive Disorder. One study included patients in the age range 18 to 65 years, and a second study included elderly patients, ranging in age from 60 to 88. In both studies, Paxil (Paroxetine) CR was shown to be significantly more effective than placebo in treating major depressive disorder as measured by the following: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)–Severity of Illness score.
A study of outpatients with major depressive disorder who had responded to immediate-release paroxetine tablets (HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on immediate-release paroxetine tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking immediate-release paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.
The effectiveness of Paxil (Paroxetine) CR in the treatment of panic disorder was evaluated in three 10-week, multicenter, flexible-dose studies (Studies 1, 2, and 3) comparing paroxetine controlled-release (12.5 to 75 mg daily) to placebo in adult outpatients who had panic disorder (DSM-IV), with or without agoraphobia. These trials were assessed on the basis of their outcomes on 3 variables: (1) the proportions of patients free of full panic attacks at endpoint; (2) change from baseline to endpoint in the median number of full panic attacks; and (3) change from baseline to endpoint in the median Clinical Global Impression Severity score. For Studies 1 and 2, Paxil (Paroxetine) CR was consistently superior to placebo on 2 of these 3 variables. Study 3 failed to consistently demonstrate a significant difference between Paxil (Paroxetine) CR and placebo on any of these variables.
For all 3 studies, the mean dose of Paxil (Paroxetine) CR for completers at endpoint was approximately 50 mg/day. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
Long-term maintenance effects of the immediate-release formulation of paroxetine in panic disorder were demonstrated in an extension study. Patients who were responders during a 10-week double-blind phase with immediate-release paroxetine and during a 3-month double-blind extension phase were randomized to either immediate-release paroxetine or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.
The efficacy of Paxil (Paroxetine) CR as a treatment for social anxiety disorder has been established, in part, on the basis of extrapolation from the established effectiveness of the immediate-release formulation of paroxetine. In addition, the effectiveness of Paxil (Paroxetine) CR in the treatment of social anxiety disorder was demonstrated in a 12-week, multicenter, double-blind, flexible-dose, placebo-controlled study of adult outpatients with a primary diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness of Paxil (Paroxetine) CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1) change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and (2) the proportion of responders who scored 1 or 2 (very much improved or much improved) on the Clinical Global Impression (CGI) Global Improvement score.
Paxil (Paroxetine) CR demonstrated statistically significant superiority over placebo on both the LSAS total score and the CGI Improvement responder criterion. For patients who completed the trial, 64% of patients treated with Paxil (Paroxetine) CR compared to 34.7% of patients treated with placebo were CGI Improvement responders.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of gender. Subgroup analyses of studies utilizing the immediate-release formulation of paroxetine generally did not indicate differences in treatment outcomes as a function of age, race, or gender.
The effectiveness of Paxil (Paroxetine) CR for the treatment of PMDD utilizing a continuous dosing regimen has been established in 2 placebo-controlled trials. Patients in these trials met DSM-IV criteria for PMDD. In a pool of 1,030 patients, treated with daily doses of Paxil (Paroxetine) CR 12.5 or 25 mg/day, or placebo the mean duration of the PMDD symptoms was approximately 11 ± 7 years. Patients on systemic hormonal contraceptives were excluded from these trials. Therefore, the efficacy of Paxil (Paroxetine) CR in combination with systemic (including oral) hormonal contraceptives for the continuous daily treatment of PMDD is unknown. In both positive studies, patients (N = 672) were treated with 12.5 mg/day or 25 mg/day of Paxil (Paroxetine) CR or placebo continuously throughout the menstrual cycle for a period of 3 menstrual cycles. The VAS-Total score is a patient-rated instrument that mirrors the diagnostic criteria of PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. 12.5 mg/day and 25 mg/day of Paxil (Paroxetine) CR were significantly more effective than placebo as measured by change from baseline to the endpoint on the luteal phase VAS-Total score.
In a third study employing intermittent dosing, patients (N = 366) were treated for the 2 weeks prior to the onset of menses (luteal phase dosing, also known as intermittent dosing) with 12.5 mg/day or 25 mg/day of Paxil (Paroxetine) CR or placebo for a period of 3 months. 12.5 mg/day and 25 mg/day of Paxil (Paroxetine) CR, as luteal phase dosing, was significantly more effective than placebo as measured by change from baseline luteal phase VAS total score.
There is insufficient information to determine the effect of race or age on outcome in these studies.
Paxil (Paroxetine) Indications And Usage
Paxil (Paroxetine) CR is indicated for the treatment of major depressive disorder.
The efficacy of Paxil (Paroxetine) CR in the treatment of a major depressive episode was established in two 12-week controlled trials of outpatients whose diagnoses corresponded to the DSM-IV category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least 5 of the following 9 symptoms during the same 2-week period: Depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation.
The antidepressant action of paroxetine in hospitalized depressed patients has not been adequately studied.
Paxil (Paroxetine) CR has not been systematically evaluated beyond 12 weeks in controlled clinical trials; however, the effectiveness of immediate-release paroxetine hydrochloride in maintaining a response in major depressive disorder for up to 1 year has been demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). The physician who elects to use Paxil (Paroxetine) CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Paxil (Paroxetine) CR 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 (Paroxetine) CR controlled-release tablets was established in two 10-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
Long-term maintenance of efficacy with the immediate-release formulation of paroxetine was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to immediate-release paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician who prescribes Paxil (Paroxetine) CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Paxil (Paroxetine) CR is indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of Paxil (Paroxetine) CR as a treatment for social anxiety disorder has been established, in part, on the basis of extrapolation from the established effectiveness of the immediate-release formulation of paroxetine. In addition, the efficacy of Paxil (Paroxetine) CR was established in a 12-week trial, in adult outpatients with social anxiety disorder (DSM-IV). Paxil (Paroxetine) CR has not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY—Clinical Trials).
The effectiveness of Paxil (Paroxetine) CR in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to prescribe Paxil (Paroxetine) CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Paxil (Paroxetine) CR is indicated for the treatment of PMDD.
The efficacy of Paxil (Paroxetine) CR in the treatment of PMDD has been established in 3 placebo-controlled trials (see CLINICAL PHARMACOLOGY—Clinical Trials).
The essential features of PMDD, according to DSM-IV, include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following the onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.
The effectiveness of Paxil (Paroxetine) CR in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Paxil (Paroxetine) CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Paxil (Paroxetine) Contraindications
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs), including linezolid, an antibiotic which is a reversible non-selective MAOI, or thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Paxil (Paroxetine) CR is contraindicated in patients with a hypersensitivity to paroxetine or to any of the inactive ingredients in Paxil (Paroxetine) CR.
Paxil (Paroxetine) Warnings
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment With Paxil (Paroxetine) CR, for a description of the risks of discontinuation of Paxil (Paroxetine) CR).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
In patients receiving another serotonin reuptake inhibitor drug in combination with an MAOI, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with paroxetine hydrochloride, 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) CR not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI (see CONTRAINDICATIONS). At least 2 weeks should be allowed after stopping Paxil (Paroxetine) CR before starting an MAOI.
The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including treatment with Paxil (Paroxetine) CR, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of Paxil (Paroxetine) CR with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Paxil (Paroxetine) CR with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of Paxil (Paroxetine) CR with serotonin precursors (such as tryptophan) is not recommended.
Treatment with Paxil (Paroxetine) CR and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be dose related.
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).
Paxil (Paroxetine) Precautions
Paxil (Paroxetine) CR should not be chewed or crushed, and should be swallowed whole.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Paxil (Paroxetine) CR and triptans, tramadol, or other serotonergic agents.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Paxil (Paroxetine) CR and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for Paxil (Paroxetine) CR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Paxil (Paroxetine) CR.
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with Paxil (Paroxetine) , and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Paxil (Paroxetine) CR in a child or adolescent must balance the potential risks with the clinical need.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with immediate-release paroxetine hydrochloride and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.
Events reported upon discontinuation of treatment with immediate-release paroxetine hydrochloride in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received immediate-release paroxetine hydrochloride and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see Discontinuation of Treatment With Paxil (Paroxetine) CR).
SSRIs and SNRIs, including Paxil (Paroxetine) CR, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
In worldwide premarketing clinical trials with immediate-release paroxetine hydrochloride, 17% of paroxetine-treated patients (approximately 700) were 65 years 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).
In a controlled study focusing specifically on elderly patients with major depressive disorder, Paxil (Paroxetine) CR was demonstrated to be safe and effective in the treatment of elderly patients (>60 years) with major depressive disorder. (See CLINICAL PHARMACOLOGY—Clinical Trials and ADVERSE REACTIONS—Table 2.)
Paxil (Paroxetine) Adverse Reactions
The information included under the “Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paxil (Paroxetine) CR” subsection of ADVERSE REACTIONS is based on data from 11 placebo-controlled clinical trials. Three of these studies were conducted in patients with major depressive disorder, 3 studies were done in patients with panic disorder, 1 study was conducted in patients with social anxiety disorder, and 4 studies were done in female patients with PMDD. Two of the studies in major depressive disorder, which enrolled patients in the age range 18 to 65 years, are pooled. Information from a third study of major depressive disorder, which focused on elderly patients (60 to 88 years), is presented separately as is the information from the panic disorder studies and the information from the PMDD studies. Information on additional adverse events associated with Paxil (Paroxetine) CR and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events).
Table 2 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with Paxil (Paroxetine) CR, aged 18 to 65, who participated in 2 short-term (12-week) placebo-controlled trials in major depressive disorder in which patients were dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse events reported at an incidence of 5% or greater among elderly patients (ages 60 to 88) treated with Paxil (Paroxetine) CR who participated in a short-term (12-week) placebo-controlled trial in major depressive disorder in which patients were dosed in a range of 12.5 mg to 50 mg/day. Table 4 enumerates adverse events reported at an incidence of 1% or greater among patients (19 to 72 years) treated with Paxil (Paroxetine) CR who participated in short-term (10-week) placebo-controlled trials in panic disorder in which patients were dosed in a range of 12.5 mg to 75 mg/day. Table 5 enumerates adverse events reported at an incidence of 1% or greater among adult patients treated with Paxil (Paroxetine) CR who participated in a short-term (12-week), double-blind, placebo-controlled trial in social anxiety disorder in which patients were dosed in a range of 12.5 to 37.5 mg/day. Table 6 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with Paxil (Paroxetine) CR who participated in three, 12-week, placebo-controlled trials in PMDD in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses (luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
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The following adverse events were reported during the clinical development of Paxil (Paroxetine) CR and/or the clinical development of the immediate-release formulation of paroxetine.
Adverse events for which frequencies are provided below occurred in clinical trials with the controlled-release formulation of paroxetine. During its premarketing assessment in major depressive disorder, panic disorder, social anxiety disorder, and PMDD, multiple doses of Paxil (Paroxetine) CR were administered to 1,627 patients in phase 3 double-blind, controlled, outpatient studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of the 1,627 patients exposed to Paxil (Paroxetine) CR who experienced an event of the type cited on at least 1 occasion while receiving Paxil (Paroxetine) CR. All reported events are included except those already listed in Tables 2 through 6 and those events where a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was deleted or, when possible, replaced with a more informative term. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.
Adverse events for which frequencies are not provided occurred during the premarketing assessment of immediate-release paroxetine in phase 2 and 3 studies of major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to immediate-release paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. Only those events not previously listed for controlled-release paroxetine are included. The extent to which these events may be associated with Paxil (Paroxetine) CR is unknown.
Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in the PRECAUTIONS section.
Paxil (Paroxetine) Overdosage
Since the introduction of immediate-release paroxetine hydrochloride in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.
Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for paroxetine are known.
A specific caution involves patients taking or recently having taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS—
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 (PDR).
Paxil (Paroxetine) How Supplied
Paxil (Paroxetine) CR is supplied as an enteric film-coated, controlled-release, round tablet, as follows:
12.5-mg yellow tablets, engraved with Paxil (Paroxetine) CR and 12.5
NDC 21695-159-15 Bottles of 15
NDC 21695-159-30 Bottles of 30
25-mg pink tablets, engraved with Paxil (Paroxetine) CR and 25
NDC 21695-160-30 Bottles of 30
GEOMATRIX is a trademark of Jago Pharma, Muttenz, Switzerland.
Paxil (Paroxetine)
Paxil (Paroxetine) Principal Display Panel
NDC 21695-159-30
Paxil (Paroxetine) CR
PAROXETINE HCl
CONTROLLED-RELEASE TABLETS
30 Tablets
R only
Federal Law requires dispensing of Paxil (Paroxetine) CR with the Medication Guide under this label. Store at or below 25C (77F) [see USP].
Each controlled-release tablet contains paroxetine hydrochloride equivalent to 12.5 mg paroxetine.
Dosage: See accompanying prescribing information.
Important: Use safety closures when dispensing this product unless otherwise directed by physician or requested by purchaser.
GlaxoSmithKline
RTP, NC 27709
Made in Ireland
A053835 Rev. 4/08
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
Paxil (Paroxetine) Principal Display Panel
NDC 21695-160-30
Paxil (Paroxetine) CR
PAROXETINE HCl
CONTROLLED-RELEASE TABLETS
25 mg
30 Tablets
R only
Federal Law requires dispensing of Paxil (Paroxetine) CR with the Medication Guide under this label.
Store at or below 25C (77F) [see USP].
Each controlled-release tablet contains paroxetine hydrochloride equivalent to 25 mg paroxetine.
Dosage: See accompanying prescribing information.
Important: Use safety closures when dispensing this product unless otherwise directed by physician or requested by purchaser.
GlaxoSmithKline
RTP, NC 27709
Made in Ireland
A053838 Rev. 4/08
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
