Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3204
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Paroxetine Hydrochloride (Tablet, Film Coated, Extended Release)
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Major Depressive Disorder:<br/>Usual Initial Dosage: Paroxetine hydrochloride extended-release tablets should be administered as a single daily dose, usually in the morning, with or without food. The recommended initial dose is 25 mg/day. Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials demonstrating the effectiveness of paroxetine hydrochloride extended-release tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 25 mg dose may benefit from dose increases, in 12.5 mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at intervals of at least one week. Patients should be cautioned that paroxetine hydrochloride extended-release tablets should not be chewed or crushed, and should be swallowed whole.<br/>Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with paroxetine hydrochloride extended-release tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of the efficacy of immediate-release paroxetine hydrochloride has shown that efficacy is maintained for periods of up to one year with doses that averaged about 30 mg, which corresponds to a 37.5 mg dose of paroxetine hydrochloride extended-release tablets, based on relative bioavailability considerations .<br/>Panic Disorder:<br/>Usual Initial Dosage: Paroxetine hydrochloride extended-release tablets should be administered as a single daily dose, usually in the morning. Patients should be started on 12.5 mg/day. Dose changes should occur in 12.5 mg/day increments and at intervals of at least one week. Patients were dosed in a range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of paroxetine hydrochloride extended-release tablets. The maximum dosage should not exceed 75 mg/day. Patients should be cautioned that paroxetine hydrochloride extended-release tablets should not be chewed or crushed, and should be swallowed whole.<br/>Maintenance Therapy: 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. 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.<br/>Social Anxiety Disorder:<br/>Usual Initial Dosage: Paroxetine hydrochloride extended-release tablets should be administered as a single daily dose, usually in the morning, with or without food. The recommended initial dose is 12.5 mg/day. Patients were dosed in a range of 12.5 mg to 37.5 mg/day in the clinical trial demonstrating the effectiveness of paroxetine hydrochloride extended-release tablets in the treatment of social anxiety disorder. If the dose is increased, this should occur at intervals of at least one week, in increments of 12.5 mg/day, up to a maximum of 37.5 mg/day. Patients should be cautioned that paroxetine hydrochloride extended-release tablets should not be chewed or crushed, and should be swallowed whole.<br/>Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with paroxetine hydrochloride extended-release tablets should remain on it. Although the efficacy of paroxetine hydrochloride extended-release tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment 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.<br/>Special Populations:<br/>Treatment of Pregnant Women During the Third Trimester: Neonates exposed to paroxetine hydrochloride extended-release tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding . When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering paroxetine in the third trimester.<br/>Dosage for Elderly or Debilitated Patients, and Patients with Severe Renal or Hepatic Impairment: The recommended initial dose of paroxetine hydrochloride extended-release tablets is 12.5 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 50 mg/day.<br/>Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with paroxetine hydrochloride extended-release tablets. Similarly, at least 14 days should be allowed after stopping paroxetine hydrochloride extended-release tablets before starting an MAOI.<br/>Discontinuation of Treatment with Paroxetine Hydrochloride Extended-Release Tablets: Symptoms associated with discontinuation of immediate-release paroxetine hydrochloride or paroxetine hydrochloride extended-release tablets have been reported . Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine hydrochloride extended-release tablets are being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
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Paroxetine hydrochloride extended-release tablets are 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 (3S-trans)-3-[(1,3-benzodioxol-5-yloxy)methyl)]4-(4-fluorophenyl)-piperidine hydrochloride hemihydrate and has the molecular formula of CHFNO���HCl�����HO. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is: Paroxetine hydrochloride (hemihydrate) is an odorless, white to almost white crystalline 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, extended-release tablet contains paroxetine hydrochloride hemihydrate equivalent to 12.5 mg or 25 mg paroxetine. Inactive ingredients consist of colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, microcrystalline cellulose, polydextrose, polyethylene glycol, polysorbate 80, sodium hydroxide, talc, titanium dioxide, triacetin and triethyl citrate. In addition, the 25 mg product contains the following coloring agents: D&C Red No. 30 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake. In addition, paroxetine hydrochloride extended-release tablets may also contain imprinting ink consisting of either black pigment and natural resin or black iron oxide and propylene glycol. Paroxetine hydrochloride complies with USP Chromatographic Purity Test 1.
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Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive disorder, panic disorder, and social anxiety disorder 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 andhighly 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.<br/>Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The elimination half-life is approximately 15 to 20 hours after a single-dose of paroxetine hydrochloride extended-release tablets. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism ismediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).<br/>Absorption and Distribution: Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male and female subjects (n = 23) received single oral doses of paroxetine hydrochloride extended-release tablets at 4 dosage strengths (12.5 mg, 25 mg, 37.5 mg, and 50 mg), paroxetine Cand AUCincreased disproportionately with dose (as seen also with immediate-release formulations). Mean Cand AUCvalues at these doses were 2, 5.5, 9, and 12.5 ng/mL, and 121, 261, 338, and 540 ng���hr./mL, respectively. Twas observed typically between 6 and 10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release formulations. The bioavailability of 25 mg paroxetine hydrochloride extended-release tablets is not affected by food. Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.<br/>Metabolism and Excretion: The mean elimination half-life of paroxetine was 15 to 20 hours throughout a range of single doses of paroxetine hydrochloride extended-release tablets (12.5 mg, 25 mg, 37.5 mg, and 50 mg). During repeated administration of paroxetine hydrochloride extended-release tablets (25 mg once daily), steady-state was reached within 2 weeks (i.e., comparableto immediate-release formulations). In a repeat dose study in which normal male and female subjects (n = 23) received paroxetine hydrochloride extended-release tablets (25 mg daily), mean steady-state C, C, and AUCvalues were 30 ng/mL, 20 ng/mL, and 550 ng���hr./mL, respectively. Based on studies using immediate-release formulations, steady-state drug exposure based on AUCwas several-fold greater than would have been predicted from single-dose data. 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 the immediate-release formulation of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cvalues after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions . 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.<br/>Other Clinical Pharmacology Information:<br/>Specific Populations:<br/>Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine .<br/>Clinical Trials:<br/>Major Depressive Disorder: The efficacy of paroxetine hydrochloride extended-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, paroxetine hydrochloride extended-release tablets were 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 one 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.<br/>Panic Disorder: The effectiveness of paroxetine hydrochloride extended-release tablets in the treatment of panic disorder was evaluated in three 10 week, multicenter, flexible dose studies (Studies 1, 2, and 3) comparing paroxetine extended-release tablets (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, paroxetine hydrochloride extended-release tablets were consistently superior to placebo on 2 of these 3variables. Study 3 failed to consistently demonstrate a significant difference between paroxetine hydrochloride extended-release tablets and placebo on any of these variables. For all three studies, the mean dose of paroxetine hydrochloride extended-release tablets 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 randomizedto placebo.<br/>Social Anxiety Disorder: The efficacy of paroxetine hydrochloride extended-release tablets 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 paroxetine hydrochloride extended-release tablets 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 paroxetine hydrochloride extended-release tablets (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. Paroxetine hydrochloride extended-release tablets 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 paroxetine hydrochloride extended-release tablets 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.
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Paroxetine Hydrochloride Extended-release Tablets are available as 12.5 mg and 25 mg tablets. The 12.5 mg tablet is a white film-coated, round, unscored tablet with M over P3 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-2003-93bottles of 30 tablets NDC 0378-2003-01bottles of 100 tablets NDC 0378-2003-05bottles of 500 tablets The 25 mg tablet is a lavender film-coated, round, unscored tablet with M over P4 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-2004-93bottles of 30 tablets NDC 0378-2004-01bottles of 100 tablets NDC 0378-2004-05bottles of 500 tablets Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
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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 paroxetine 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 toplacebo 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. Paroxetine is not approved for use in pediatric patients.
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dailymed-ingredient:black_iron_oxide,
dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:hydroxypropyl_cellulose,
dailymed-ingredient:hypromellose,
dailymed-ingredient:lactose_monohydrate,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:methacrylic_acid_copolymer_type_C,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polydextrose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polysorbate_80,
dailymed-ingredient:propylene_glycol,
dailymed-ingredient:sodium_hydroxide,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:triacetin,
dailymed-ingredient:triethyl_citrate
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Human Experience: 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 nonfatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2000 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.<br/>Overdosage Management: 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 .). 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).
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Paroxetine Hydrochloride
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Paroxetine Hydrochloride (Tablet, Film Coated, Extended Release)
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The information included under the "Adverse Findings Observed in Short-Term, Placebo-Controlled Trials with Paroxetine Hydrochloride Extended-Release Tablets" subsection of ADVERSE REACTIONS is based on data from eleven placebo-controlled clinical trials. Three of these studies were conducted in patients with major depressive disorder, three studies were done in patients with panic disorder and one study was conducted in patients with social anxiety disorder. 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. Information on additional adverse events associated with paroxetine hydrochloride extended-release tablet and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During the Clinical Development of Paroxetine).<br/>Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paroxetine Hydrochloride Extended-Release Tablets:<br/>Adverse Events Associated With Discontinuation of Treatment:<br/>Commonly Observed Adverse Events:<br/>Incidence in Controlled Clinical Trials: Table 2 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with paroxetine hydrochloride extended-release tablets, aged 18 to 65, who participated in two 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 paroxetine hydrochloride extended-release tablets who participated in a short-term (12 week) placebo-controlled trial in major depressive disorder in which patients were dosed in arange 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 paroxetine hydrochloride extended-release tablets 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 paroxetine hydrochloride extended-release tabletswho 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. 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 figuresobtained 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. A comparison of adverse event rates in a fixed dose study comparing immediate-release paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with the use of immediate-release paroxetine.<br/>Male and Female Sexual Dysfunction with SSRIs: Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain; however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence. The percentage of patients reporting symptoms of sexual dysfunction in the pool of two placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of three placebo-controlled trials in patients with panic disorder, and in the placebo-controlled trial in patients with social anxiety disorder, are as follows: There are no adequate, controlled studies examining sexual dysfunction with paroxetine treatment. Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.<br/>Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials with paroxetine hydrochloride extended-release tablet or the immediate-release formulation, had minimal weight loss (about 1 pound). No significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature) were observed in patients treated with paroxetine hydrochloride extended-release tablets, or immediate-release paroxetine hydrochloride, in controlled clinical trials.<br/>ECG Changes: In an analysis of ECGs obtained in 682 patients treated with immediate-release paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group.<br/>Liver Function Tests: In a pool of two placebo-controlled clinical trials, patients treated with paroxetine hydrochloride extended-release tablets or placebo exhibited abnormal values on liver function tests at comparable rates. In particular, the extended-release paroxetine versus placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities. In a study of elderly patients with major depressive disorder, 3 of 104 patients treated with paroxetine hydrochloride extended-release tablets and none of 109 placebo patients experienced liver transaminase elevations of potential clinical concern. Two of the patients treated with paroxetine hydrochloride extended-release tablets dropped out of the study due to abnormal liver function tests; the third patient experienced normalization of transaminase levels with continued treatment. Also, in the pool of three studies of patients with panic disorder, 4 of 444 patients treated with paroxetine hydrochloride extended-release tablets and none of 445 placebo patients experienced liver transaminase elevations of potential clinical concern. Elevations in all four patients decreased substantially after discontinuation of paroxetine hydrochloride extended-release tablets. The clinical significance of these findings is unknown. In placebo-controlled clinical trials with the immediate-release formulation of paroxetine, patients exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients.<br/>Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving drug and in 4 of 3,187 patients receiving placebo.<br/>Other Events Observed During the Clinical Development of Paroxetine: The following adverse events were reported during the clinical development of paroxetine hydrochloride extended-release tablet 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 extended-release formulation of paroxetine. During its premarketing assessment in major depressive disorder, panic disorder and social anxiety disorder, multiple doses of paroxetine hydrochloride extended-release tablets were administered to 1,627 patients in phase three 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 paroxetine hydrochloride extended-release tablets who experienced an event of the type cited on at least one occasion while receiving paroxetine hydrochloride extended-release tablets. All reported events are included except those already listed in Tablesone through four 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 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 1/1,000 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 two and three 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 extended-releaseparoxetine are included. The extent to which these events may be associated with paroxetine hydrochloride extended-release tablets is unknown. Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in the PRECAUTIONS section. Body as a Whole: Infrequent were chills, face edema, fever, flu syndrome, malaise; rare were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed were adrenergic syndrome, neck rigidity, sepsis. Cardiovascular System: Infrequent were angina pectoris, bradycardia, hematoma, hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia, syncope; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation, cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricularextrasystoles, thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles. Digestive System: Infrequent were bruxism, dysphagia, eructation, gastritis, gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function test abnormal, melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis, glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction, peptic ulcer, stomach ulcer, throattightness; also observed were aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue edema. Endocrine System: Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus, hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis. Hemic and Lymphatic System: Infrequent were anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis, lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia. Metabolic and Nutritional Disorders: Infrequent were generalized edema, hyperglycemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare were bilirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperphosphatemia, hypocalcemia, hypoglycemia, hyponatremia, ketosis, lactic dehydrogenase increased, nonprotein nitrogen (NPN) increased. Musculoskeletal System: Infrequent were arthritis, bursitis, tendonitis; rare were myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis, tenosynovitis, tetany. Nervous System: Frequent were depression; infrequent were amnesia, convulsion, depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis, vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis, withdrawal syndrome; also observed were abnormal gait, akathisia, akinesia, aphasia, choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction, manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus. Respiratory System: Frequent were pharyngitis; infrequent were asthma, dyspnea, epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema, hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum increased. Skin and Appendages: Frequent were rash; infrequent were acne, alopecia, dry skin, eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash, seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses: Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis, photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss. Urogenital System: Frequent were dysmenorrhea; infrequent were albuminuria, amenorrhea, breast pain, cystitis, dysuria, prostatitis, urinary retention; rare were breast enlargement, breast neoplasm, female lactation, hematuria, kidney calculus, metrorrhagia, nephritis, nocturia, pregnancy and puerperal disorders, salpingitis, urinary incontinence, uterine fibroids enlarged; also observed were breast atrophy, ejaculatory disturbance, endometrial disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria, urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage.<br/>Post-Marketing Reports: Voluntary reports of adverse events in patients taking immediate-release paroxetine hydrochloride that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barr��syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea, neuroleptic malignant syndrome like events, serotonin syndrome; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including Torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic syndromes (such as Henoch-Sch��nlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when immediate-release paroxetine was added to chronic metoprolol treatment.
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Major Depressive Disorder: Paroxetine hydrochloride extended-release tablets are indicated for the treatment of major depressive disorder. The efficacy of paroxetine hydrochloride extended-release tablets 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 . 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. Paroxetine hydrochloride extended-release tablets have 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 one year has been demonstrated in a placebo-controlled trial . The physician who elects to use paroxetine hydrochloride extended-release tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.<br/>Panic Disorder: Paroxetine hydrochloride extended-release tablets are 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 hydrochloride extended-release tablets was established in two 10 week trials in panic disorder patients whose diagnoses corresponded to the DSM-IV category of panic disorder . 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 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 . Nevertheless, the physician who prescribes paroxetine hydrochloride extended-release tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.<br/>Social Anxiety Disorder: Paroxetine hydrochloride extended-release tablets are 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 hydrochloride extended-release tablets 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 paroxetine hydrochloride extended-release tablets was established in a 12 week trial, in adult outpatients with social anxiety disorder (DSM-IV). Paroxetine hydrochloride extended-release tablets have not been studied in children or adolescents with social phobia . The effectiveness of paroxetine hydrochloride extended-release tablets 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 hydrochloride extended-release tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient .
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Paroxetine Hydrochloride
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