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Paroxetine Hydrochloride
Overview
What is Paroxetine Hydrochloride?
Paroxetine Extended-Release Tablets, USP 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 C
H
FNO
•HCl•1/2H
O. 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, extended-release tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 12.5 mg–white, 25 mg–pink and 37.5 mg–blue.
Inactive ingredients consist of hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid and ethyl acrylate copolymer dispersion, polyethylene glycols, polyvinyl alcohol, povidone, silicon dioxide, talc, titanium dioxide, triethyl citrate. In addition, the 25 mg and 37.5 mg colorant contains FD&C Blue No. 2 aluminum lake. In addition, the 25 mg colorant also contains carmine.
USP Dissolution Test is pending.
What does Paroxetine Hydrochloride look like?
What are the available doses of Paroxetine Hydrochloride?
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What should I talk to my health care provider before I take Paroxetine Hydrochloride?
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How should I use Paroxetine Hydrochloride?
Major Depressive Disorder
Paroxetine is indicated for the treatment of major depressive disorder.
The efficacy of Paroxetine 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.
Paroxetine 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 Paroxetine 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 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 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 (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 Paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder
Paroxetine 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 Paroxetine 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 was established in a 12-week trial, in adult outpatients with social anxiety disorder (DSM-IV). Paroxetine has not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY: Clinical Trials).
The effectiveness of Paroxetine 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 for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder
Paroxetine is indicated for the treatment of PMDD.
The efficacy of Paroxetine 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 Paroxetine 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 Paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Major Depressive Disorder
Usual Initial Dosage
Paroxetine 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 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 1 week.
Patients should be cautioned that Paroxetine should not be chewed or crushed, and should be swallowed whole.
Maintenance Therapy
There is no body of evidence available to answer the question of how long the patient treated with Paroxetine 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 1 year with doses that averaged about 30 mg, which corresponds to a 37.5 mg dose of Paroxetine, based on relative bioavailability considerations (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Panic Disorder
Usual Initial Dosage
Paroxetine 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 1 week. Patients were dosed in a range of 12.5 mg to 75 mg/day in the clinical trials demonstrating the effectiveness of Paroxetine. The maximum dosage should not exceed 75 mg/day.
Patients should be cautioned that Paroxetine should not be chewed or crushed, and should be swallowed whole.
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.
Social Anxiety Disorder
Usual Initial Dosage
Paroxetine 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 in the treatment of social anxiety disorder. If the dose is increased, this should occur at intervals of at least 1 week, in increments of 12.5 mg/day, up to a maximum of 37.5 mg/day.
Patients should be cautioned that Paroxetine should not be chewed or crushed, and should be swallowed whole.
Maintenance Therapy
There is no body of evidence available to answer the question of how long the patient treated with Paroxetine should remain on it. Although the efficacy of Paroxetine 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.
Premenstrual Dysphoric Disorder
Usual Initial Dosage
Paroxetine should be administered as a single daily dose, usually in the morning, with or without food. Paroxetine may be administered either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment. The recommended initial dose is 12.5 mg/day. In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective. Dose changes should occur at intervals of at least 1 week.
Patients should be cautioned that Paroxetine should not be chewed or crushed, and should be swallowed whole.
Maintenance/Continuation Therapy
The effectiveness of Paroxetine for a period exceeding 3 menstrual cycles has not been systematically evaluated in controlled trials. However, women commonly report that symptoms worsen with age until relieved by the onset of menopause. Therefore, it is reasonable to consider continuation of a responding patient. Patients should be periodically reassessed to determine the need for continued treatment.
Special Populations
Treatment of Pregnant Women During the Third Trimester
Neonates exposed to Paroxetine and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic Impairment
The recommended initial dose of Paroxetine 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.
Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Paroxetine. Conversely, at least 14 days should be allowed after stopping Paroxetine before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
Use of Paroxetine With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Paroxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving therapy with Paroxetine may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Paroxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Paroxetine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Paroxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Discontinuation of Treatment With Paroxetine
Symptoms associated with discontinuation of immediate-release paroxetine hydrochloride or Paroxetine have been reported (see PRECAUTIONS:
). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which Paroxetine is 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.
What interacts with Paroxetine Hydrochloride?
The use of MAOIs intended to treat psychiatric disorders with Paroxetine or within 14 days of stopping treatment with Paroxetine is contraindicated because of an increased risk of serotonin syndrome. The use of Paroxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION).
Starting Paroxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Concomitant use with thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Paroxetine is contraindicated in patients with a hypersensitivity to paroxetine or to any of the inactive ingredients in Paroxetine.
What are the warnings of Paroxetine Hydrochloride?
Clinical Worsening and Suicide Risk
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.
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:
, for a description of the risks of discontinuation of Paroxetine).
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.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Paroxetine is not approved for use in treating bipolar depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Paroxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of Paroxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Paroxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Paroxetine. Paroxetine should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Paroxetine with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Paroxetine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including Paroxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Potential Interaction With Thioridazine
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).
Usage in Pregnancy
Teratogenic Effects
Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below:
Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations.
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS:
). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options.
Animal Findings
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 approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m
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 approximately one-sixth of the MRHD on an mg/m
basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
Nonteratogenic Effects
Neonates exposed to Paroxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Paroxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with Paroxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS, Postmarketing Reports).
What are the precautions of Paroxetine Hydrochloride?
General
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During premarketing testing of immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately 1.0% of paroxetine-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 immediate-release paroxetine and 11.6% for the combined active-control groups. Among 1,627 patients with major depressive disorder, panic disorder, social anxiety disorder, or PMDD treated with Paroxetine in controlled clinical studies, there were no reports of mania or hypomania. As with all drugs effective in the treatment of major depressive disorder, Paroxetine should be used cautiously in patients with a history of mania.
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During premarketing testing of immediate-release paroxetine hydrochloride, seizures occurred in 0.1% of paroxetine-treated patients, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Among 1,627 patients who received Paroxetine in controlled clinical trials in major depressive disorder, panic disorder, social anxiety disorder, or PMDD, 1 patient (0.1%) experienced a seizure. Paroxetine should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
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Adverse events while discontinuing therapy with Paroxetine were not systematically evaluated in most clinical trials; however, in recent placebo-controlled clinical trials utilizing daily doses of Paroxetine up to 37.5 mg/day, spontaneously reported adverse events while discontinuing therapy with Paroxetine were evaluated. Patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in dose. With this regimen in those studies, the following adverse events were reported for Paroxetine, at an incidence of 2% or greater for Paroxetine and were at least twice that reported for placebo: Dizziness, nausea, nervousness, and additional symptoms described by the investigator as associated with tapering or discontinuing Paroxetine (e.g., emotional lability, headache, agitation, electric shock sensations, fatigue, and sleep disturbances). These events were reported as serious in 0.3% of patients who discontinued therapy with Paroxetine.
During marketing of Paroxetine and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Paroxetine. 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 (see DOSAGE AND ADMINISTRATION).
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients.
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Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of co-administration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
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The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.
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Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Paroxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of Paroxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
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SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
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Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising.
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Clinical experience with immediate-release paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using Paroxetinein patients with diseases or conditions that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with therapy with immediate-release paroxetine have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when Paroxetineis prescribed for patients with narrow angle glaucoma.
Paroxetine or the immediate-release formulation 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 premarket testing. Evaluation of electrocardiograms of 682 patients who received immediate-release paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Similarly, 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
Paroxetine 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 Paroxetine and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking Paroxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Paroxetine and should counsel them in its appropriate use. A patient Medication Guide is available for Paroxetine. 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 Paroxetine.
Array
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Array
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Array
Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies immediate-release paroxetine hydrochloride has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Paroxetine does not affect their ability to engage in such activities.
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While patients may notice improvement with use of Paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed.
Array
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.
Array
Although immediate-release paroxetine hydrochloride 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.
Array
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy:
nd
).
Array
Patients should be advised to notify their physician if they are breastfeeding an infant (see PRECAUTIONS: Nursing Mothers).
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
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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 immediate-release paroxetine. Consequently, concomitant use of Paroxetine with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome).
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See CONTRAINDICATIONS and WARNINGS.
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In a controlled study of healthy volunteers, after immediate-release paroxetine hydrochloride was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C
of 62%, compared to pimozide administered alone. The increase in pimozide AUC and C
is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and Paroxetine is contraindicated (see CONTRAINDICATIONS).
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Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when Paroxetine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS: Serotonin Syndrome).
The concomitant use of Paroxetine with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS). The concomitant use of Paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions,
).
Array
See CONTRAINDICATIONS and WARNINGS.
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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 and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere With Hemostasis).
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There have been rare post-marketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of Paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome).
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The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
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Cimetidine inhibits many cytochrome P
(oxidative) enzymes. In a study where immediate-release paroxetine (30 mg once daily) 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 three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of Paroxetine after the starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied.
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Phenobarbital induces many cytochrome P
(oxidative) enzymes. When a single oral 30-mg dose of immediate-release paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T
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 exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment with Paroxetine is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
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When a single oral 30-mg dose of immediate-release paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T
were reduced (by an average of 50% and 35%, respectively) compared to immediate-release paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when Paroxetine is co-administered with phenytoin; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports).
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Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs, and many tricyclics), are metabolized by the cytochrome P
isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In 1 study, daily dosing of immediate-release paroxetine (20 mg once daily) under steady-state conditions increased single-dose desipramine (100 mg) C
, AUC, and T
by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine C
values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when given with paroxetine.
Concomitant use of Paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either Paroxetine or the other drug.
Therefore, co-administration of Paroxetine with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be co-administered (see CONTRAINDICATIONS and WARNINGS).
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS).
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P
isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS:
).
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An in vivo interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 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 cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro K
and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
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Caution is indicated in the co-administration of TCAs with Paroxetine, 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 (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6).
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Because paroxetine is highly bound to plasma protein, administration of Paroxetine 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.
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Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
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Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Paroxetine.
Array
A multiple-dose study with immediate-release paroxetine hydrochloride has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when immediate-release paroxetine hydrochloride is co-administered with lithium.
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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.
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Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.
Array
Daily oral dosing of immediate-release paroxetine (30 mg once daily) increased steady-state AUC
, C
, and C
values of procyclidine (5 mg oral once daily) 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.
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In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during co-administration with immediate-release paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing Reports).
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Reports of elevated theophylline levels associated with immediate-release paroxetine 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.
Array
Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
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There are no clinical studies of the combined use of ECT and Paroxetine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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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 approximately 2 (mouse) and 3 (rat) times the MRHD on a mg/m
basis. 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.
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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.
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Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men.
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is approximately twice the MRHD on a mg/m
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 (approximately 8 and 4 times the MRHD on a mg/m
basis).
Pregnancy
Pregnancy Category D. See WARNINGS: Usage in Pregnancy:
and
.
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 is administered to a nursing woman.
Pediatric Use
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 immediate-release Paroxetine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Paroxetine in a child or adolescent must balance the potential risks with the clinical need. Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as Paroxetine.
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 DOSAGE AND ADMINISTRATION:
).
Geriatric Use
SSRIs and SNRIs, including Paroxetine, 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, Paroxetine 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 3.)
What are the side effects of Paroxetine Hydrochloride?
The information included under the “Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paroxetine Hydrochloride Controlled-Release Tablets” 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 Paroxetine Hydrochloride Controlled-Release Tablets and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During the Clinical Development of Paroxetine).
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paroxetine Hydrochloride Controlled-Release Tablets:
Adverse Events Associated With Discontinuation of Treatment
Major Depressive Disorder
| Nausea | 3.7% | 0.5% |
| Asthenia | 1.9% | 0.5% |
| Dizziness | 1.4% | 0.0% |
| Somnolence | 1.4% | 0.0% |
| Nausea | 2.9% | 0.0% |
| Headache | 1.9% | 0.9% |
| Depression | 1.9% | 0.0% |
| LFT’s abnormal | 1.9% | 0.0% |
Panic Disorder
Eleven percent (50/444) of patients treated with Paroxetine Hydrochloride Controlled-Release Tablets in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following:
| Nausea | 2.9% | 0.4% |
| Insomnia | 1.8% | 0.0% |
| Headache | 1.4% | 0.2% |
| Asthenia | 1.1% | 0.0% |
Social Anxiety Disorder
Three percent (5/186) of patients treated with Paroxetine Hydrochloride Controlled-Release Tablets in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following:
| Nausea | 2.2% | 0.5% |
| Headache | 1.6% | 0.5% |
| Diarrhea | 1.1% | 0.5% |
Premenstrual Dysphoric Disorder
| 15% | 9.9% | 6.3% | |
| Nausea | 6.0% | 2.4% | 0.9% |
| Asthenia | 4.9% | 3.0% | 1.4% |
| Somnolence | 4.3% | 1.8% | 0.3% |
| Insomnia | 2.3% | 1.5% | 0.0% |
| Concentration Impaired | 2.0% | 0.6% | 0.3% |
| Dry mouth | 2.0% | 0.6% | 0.3% |
| Dizziness | 1.7% | 0.6% | 0.6% |
| Decreased Appetite | 1.4% | 0.6% | 0.0% |
| Sweating | 1.4% | 0.0% | 0.3% |
| Tremor | 1.4% | 0.3% | 0.0% |
| Yawn | 1.1% | 0.0% | 0.0% |
| Diarrhea | 0.9% | 1.2% | 0.0% |
Commonly Observed Adverse Events
Major Depressive Disorder
Panic Disorder
In the pool of panic disorder studies, the adverse events meeting these criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating, and female genital disorders (generally anorgasmia or difficulty achieving orgasm).
Social Anxiety Disorder
In the social anxiety disorder study, the adverse events meeting these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence, insomnia, and libido decreased.
Premenstrual Dysphoric Disorder
Incidence in Controlled Clinical Trials
T
T
| Body System/Adverse Event | % Reporting Event | |||
| Body as a Whole | ||||
| Headache | 27% | 20% | ||
| Asthenia | 14% | 9% | ||
| Infection | 8% | 5% | ||
| Abdominal Pain | 7% | 4% | ||
| Back Pain | 5% | 3% | ||
| Trauma | 5% | 1% | ||
| Pain | 3% | 1% | ||
| Allergic Reaction | 2% | 1% | ||
| Cardiovascular System | ||||
| Tachycardia | 1% | 0% | ||
| Vasodilatation | 2% | 0% | ||
| Digestive System | ||||
| Nausea | 22% | 10% | ||
| Diarrhea | 18% | 7% | ||
| Dry Mouth | 15% | 8% | ||
| Constipation | 10% | 4% | ||
| Flatulence | 6% | 4% | ||
| Decreased Appetite | 4% | 2% | ||
| Vomiting | 2% | 1% | ||
| Nervous System | ||||
| Somnolence | 22% | 8% | ||
| Insomnia | 17% | 9% | ||
| Dizziness | 14% | 4% | ||
| Libido Decreased | 7% | 3% | ||
| Tremor | 7% | 1% | ||
| Hypertonia | 3% | 1% | ||
| Paresthesia | 3% | 1% | ||
| Agitation | 2% | 1% | ||
| Confusion | 1% | 0% | ||
| Respiratory System | ||||
| Yawn | 5% | 0% | ||
| Rhinitis | 4% | 1% | ||
| Cough Increased | 2% | 1% | ||
| Bronchitis | 1% | 0% | ||
| Skin and Appendages | ||||
| Sweating | 6% | 2% | ||
| Photosensitivity | 2% | 0% | ||
| Special Senses | ||||
| Abnormal Vision | 5% | 1% | ||
| Taste Perversion | 2% | 0% | ||
| Urogenital System | ||||
| Abnormal Ejaculation | 26% | 1% | ||
| Female Genital Disorder | 10% | <1% | ||
| Impotence | 5% | 3% | ||
| Urinary Tract Infection | 3% | 1% | ||
| Menstrual Disorder | 2% | <1% | ||
| Vaginitis | 2% | 0% | ||
| Body System/Adverse Event | % Reporting Event | |||
| Body as a Whole | ||||
| Headache | 17% | 13% | ||
| Asthenia | 15% | 14% | ||
| Trauma | 8% | 5% | ||
| Infection | 6% | 2% | ||
| Digestive System | ||||
| Dry Mouth | 18% | 7% | ||
| Diarrhea | 15% | 9% | ||
| Constipation | 13% | 5% | ||
| Dyspepsia | 13% | 10% | ||
| Decreased Appetite | 12% | 5% | ||
| Flatulence | 8% | 7% | ||
| Nervous System | ||||
| Somnolence | 21% | 12% | ||
| Insomnia | 10% | 8% | ||
| Dizziness | 9% | 5% | ||
| Libido Decreased | 8% | <1% | ||
| Tremor | 7% | 0% | ||
| Skin and Appendages | ||||
| Sweating | 10% | <1% | ||
| Urogenital System | ||||
| Abnormal Ejaculation | 17% | 3% | ||
| Impotence | 9% | 3% | ||
| Body System/Adverse Event | % Reporting Event | |||
| Body as a Whole | ||||
| Asthenia | 15% | 10% | ||
| Abdominal Pain | 6% | 4% | ||
| Trauma | 5% | 4% | ||
| Cardiovascular System | ||||
| Vasodilation | 3% | 2% | ||
| Digestive System | ||||
| Nausea | 23% | 17% | ||
| Dry Mouth | 13% | 9% | ||
| Diarrhea | 12% | 9% | ||
| Constipation | 9% | 6% | ||
| Decreased Appetite | 8% | 6% | ||
| Metabolic/Nutritional Disorders | ||||
| Weight Loss | 1% | 0% | ||
| Musculoskeletal System | ||||
| Myalgia | 5% | 3% | ||
| Nervous System | ||||
| Insomnia | 20% | 11% | ||
| Somnolence | 20% | 9% | ||
| Libido Decreased | 9% | 4% | ||
| Nervousness | 8% | 7% | ||
| Tremor | 8% | 2% | ||
| Anxiety | 5% | 4% | ||
| Agitation | 3% | 2% | ||
| Hypertonia | 2% | <1% | ||
| Myoclonus | 2% | <1% | ||
| Respiratory System | ||||
| Sinusitis | 8% | 5% | ||
| Yawn | 3% | 0% | ||
| Skin and Appendages | ||||
| Sweating | 7% | 2% | ||
| Special Senses | ||||
| Abnormal Vision | 3% | <1% | ||
| Urogenital System | ||||
| Abnormal Ejaculation | 27% | 3% | ||
| Impotence | 10% | 1% | ||
| Female Genital Disorders | 7% | 1% | ||
| Urinary Frequency | 2% | <1% | ||
| Urination Impaired | 2% | <1% | ||
| Vaginitis | 1% | <1% | ||
| Body System/Adverse Event | % Reporting Event | |||
| Body as a Whole | ||||
| Headache | 23% | 17% | ||
| Asthenia | 18% | 7% | ||
| Abdominal Pain | 5% | 4% | ||
| Back Pain | 4% | 1% | ||
| Trauma | 3% | <1% | ||
| Allergic Reaction | 2% | <1% | ||
| Chest Pain | 1% | <1% | ||
| Cardiovascular System | ||||
| Hypertension | 2% | 0% | ||
| Migraine | 2% | 1% | ||
| Tachycardia | 2% | 1% | ||
| Digestive System | ||||
| Nausea | 22% | 6% | ||
| Diarrhea | 9% | 8% | ||
| Constipation | 5% | 2% | ||
| Dry Mouth | 3% | 2% | ||
| Dyspepsia | 2% | <1% | ||
| Decreased Appetite | 1% | <1% | ||
| Tooth Disorder | 1% | 0% | ||
| Metabolic/Nutritional Disorders | ||||
| Weight Gain | 3% | 1% | ||
| Weight Loss | 1% | 0% | ||
| Nervous System | ||||
| Insomnia | 9% | 4% | ||
| Somnolence | 9% | 4% | ||
| Libido Decreased | 8% | 1% | ||
| Dizziness | 7% | 4% | ||
| Tremor | 4% | 2% | ||
| Anxiety | 2% | 1% | ||
| Concentration Impaired | 2% | 0% | ||
| Depression | 2% | 1% | ||
| Myoclonus | 1% | <1% | ||
| Paresthesia | 1% | <1% | ||
| Respiratory System | ||||
| Yawn | 2% | 0% | ||
| Skin and Appendages | ||||
| Sweating | 14% | 3% | ||
| Eczema | 1% | 0% | ||
| Special Senses | ||||
| Abnormal Vision | 2% | 0% | ||
| Abnormality of Accommodation | 2% | 0% | ||
| Urogenital System | ||||
| Abnormal Ejaculation | 15% | 1% | ||
| Impotence | 9% | 0% | ||
| Female Genital Disorders | 3% | 0% | ||
| Body System/Adverse Event | % Reporting Event | |||
| Continuous Dosing | Luteal Phase Dosing | |||
| Body as a Whole | ||||
| Asthenia | 17% | 6% | 15% | 4% |
| Headache | 15% | 12% | - | - |
| Infection | 6% | 4% | - | - |
| Abdominal pain | - | - | 3% | 0% |
| Cardiovascular System | ||||
| Migraine | 1% | <1% | - | - |
| Digestive System | ||||
| Nausea | 17% | 7% | 18% | 2% |
| Diarrhea | 6% | 2% | 6% | 0% |
| Constipation | 5% | 1% | 2% | <1% |
| Dry Mouth | 4% | 2% | 2% | <1% |
| Increased Appetite | 3% | <1% | - | - |
| Decreased Appetite | 2% | <1% | 2% | 0% |
| Dyspepsia | 2% | 1% | 2% | 2% |
| Gingivitis | - | - | 1% | 0% |
| Metabolic and Nutritional Disorders | ||||
| Generalized Edema | - | - | 1% | <1% |
| Weight Gain | - | - | 1% | <1% |
| Musculoskeletal System | ||||
| Arthralgia | 2% | 1% | - | - |
| Nervous System | ||||
| Libido Decreased | 12% | 5% | 9% | 6% |
| Somnolence | 9% | 2% | 3% | <1% |
| Insomnia | 8% | 2% | 7% | 3% |
| Dizziness | 7% | 3% | 6% | 3% |
| Tremor | 4% | <1% | 5% | 0% |
| Concentration Impaired | 3% | <1% | 1% | 0% |
| Nervousness | 2% | <1% | 3% | 2% |
| Anxiety | 2% | 1% | - | - |
| Lack of Emotion | 2% | <1% | - | - |
| Depression | - | - | 2% | <1% |
| Vertigo | - | - | 2% | <1% |
| Abnormal Dreams | 1% | <1% | - | - |
| Amnesia | - | - | 1% | 0% |
| Respiratory System | ||||
| Sinusitis | - | - | 4% | 2% |
| Yawn | 2% | <1% | - | - |
| Bronchitis | - | - | 2% | 0% |
| Cough Increased | 1% | <1% | - | - |
| Skin and Appendages | ||||
| Sweating | 7% | <1% | 6% | <1% |
| Special Senses | ||||
| Abnormal Vision | - | - | 1% | 0% |
| Urogenital System | ||||
| Female Genital Disorders | 8% | 1% | 2% | 0% |
| Menorrhagia | 1% | <1% | - | - |
| Vaginal Moniliasis | 1% | <1% | - | - |
| Menstrual Disorder | - | - | 1% | 0% |
Dose Dependency of Adverse Events
Array
| Sweating | 8.9% | 4.2% | 0.9% |
| Tremor | 6.0% | 1.5% | 0.3% |
| Concentration Impaired | 4.3% | 1.5% | 0.6% |
| Yawn | 3.2% | 0.9% | 0.3% |
| Paresthesia | 1.4% | 0.3% | 0.3% |
| Hyperkinesia | 1.1% | 0.3% | 0.0% |
| Vaginitis | 1.1% | 0.3% | 0.3% |
Male and Female Sexual Dysfunction With SSRIs
Array
| Decreased Libido | 10% | 5% | 9% | 6% | 13% | 1% | n/a | n/a | n/a | n/a |
| Ejaculatory Disturbance | 26% | 1% | 27% | 3% | 15% | 1% | n/a | n/a | n/a | n/a |
| Impotence | 5% | 3% | 10% | 1% | 9% | 0% | n/a | n/a | n/a | n/a |
| Decreased Libido | 4% | 2% | 8% | 2% | 4% | 1% | 12% | 5% | 9% | 6% |
| Orgasmic Disturbance | 10% | <1% | 7% | 1% | 3% | 0% | 8% | 1% | 2% | 0% |
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 Controlled-Release Tablets or the immediate-release formulation of paroxetine hydrochloride, 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 Controlled-Release Tablets, or immediate-release paroxetine hydrochloride, in controlled clinical trials.
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.
Liver Function Tests
Array
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.
Other Events Observed During the Clinical Development of Paroxetine
T
A
I
E
A
E
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, supraventricular extrasystoles, 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, throat tightness; 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, non-protein 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
Array
Postmarketing 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-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; 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, restless legs syndrome (RLS), 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), vasculitic syndromes (such as Henoch-Schönlein purpura) and premature births in pregnant women. 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.
What should I look out for while using Paroxetine Hydrochloride?
The use of MAOIs intended to treat psychiatric disorders with Paroxetine or within 14 days of stopping treatment with Paroxetine is contraindicated because of an increased risk of serotonin syndrome. The use of Paroxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION).
Starting Paroxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Concomitant use with thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Paroxetine is contraindicated in patients with a hypersensitivity to paroxetine or to any of the inactive ingredients in Paroxetine.
Clinical Worsening and Suicide Risk
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.
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:
, for a description of the risks of discontinuation of Paroxetine).
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.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Paroxetine is not approved for use in treating bipolar depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Paroxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of Paroxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Paroxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Paroxetine. Paroxetine should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Paroxetine with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Paroxetine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including Paroxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Potential Interaction With Thioridazine
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).
Usage in Pregnancy
Teratogenic Effects
Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below:
Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations.
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS:
). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options.
Animal Findings
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 approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m
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 approximately one-sixth of the MRHD on an mg/m
basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
Nonteratogenic Effects
Neonates exposed to Paroxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Paroxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with Paroxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS, Postmarketing Reports).
What might happen if I take too much Paroxetine Hydrochloride?
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 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.
Overdosage Management
No specific antidotes for paroxetine are known. 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. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, or exchange perfusion are unlikely to be of benefit.
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).
How should I store and handle Paroxetine Hydrochloride?
Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P) Paroxetine Extended-Release Tablets, USP are supplied as film-coated, extended-release, round convex tablets, as follows:12.5 mg white tablets (debossed with “KU” on one side and “470” on the other)NDC 42291-579-50 Bottles of 50025 mg pink tablets (debossed with “KU” on one side and “471” on the other)NDC 42291-580-50 Bottles of 50037.5 mg blue tablets (debossed with “KU” on one side and “472” on the other)NDC 42291-581-30 Bottles of 30Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/16 AV 10/16 (P)
Clinical Information
Chemical Structure
No Image foundClinical 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.
Non-Clinical Toxicology
The use of MAOIs intended to treat psychiatric disorders with Paroxetine or within 14 days of stopping treatment with Paroxetine is contraindicated because of an increased risk of serotonin syndrome. The use of Paroxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION).Starting Paroxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Concomitant use with thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Paroxetine is contraindicated in patients with a hypersensitivity to paroxetine or to any of the inactive ingredients in Paroxetine.
Clinical Worsening and Suicide Risk
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.
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: , for a description of the risks of discontinuation of Paroxetine).
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.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Paroxetine is not approved for use in treating bipolar depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Paroxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of Paroxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Paroxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Paroxetine. Paroxetine should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Paroxetine with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Paroxetine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including Paroxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Potential Interaction With Thioridazine
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).
Usage in Pregnancy
Teratogenic Effects
Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below:
Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations.
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS: ). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options.
Animal Findings
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 approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m 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 approximately one-sixth of the MRHD on an mg/m basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
Nonteratogenic Effects
Neonates exposed to Paroxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Paroxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with Paroxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS, Postmarketing Reports).
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 immediate-release paroxetine. Consequently, concomitant use of Paroxetine with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome).
See CONTRAINDICATIONS and WARNINGS.
In a controlled study of healthy volunteers, after immediate-release paroxetine hydrochloride was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C of 62%, compared to pimozide administered alone. The increase in pimozide AUC and C is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and Paroxetine is contraindicated (see CONTRAINDICATIONS).
Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when Paroxetine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS: Serotonin Syndrome).
The concomitant use of Paroxetine with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS). The concomitant use of Paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions, ).
See CONTRAINDICATIONS and WARNINGS.
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 and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere With Hemostasis).
There have been rare post-marketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of Paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome).
The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Cimetidine inhibits many cytochrome P (oxidative) enzymes. In a study where immediate-release paroxetine (30 mg once daily) 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 three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of Paroxetine after the starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied.
Phenobarbital induces many cytochrome P (oxidative) enzymes. When a single oral 30-mg dose of immediate-release paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T 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 exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment with Paroxetine is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
When a single oral 30-mg dose of immediate-release paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T were reduced (by an average of 50% and 35%, respectively) compared to immediate-release paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when Paroxetine is co-administered with phenytoin; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports).
Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs, and many tricyclics), are metabolized by the cytochrome P isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In 1 study, daily dosing of immediate-release paroxetine (20 mg once daily) under steady-state conditions increased single-dose desipramine (100 mg) C , AUC, and T by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine C values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when given with paroxetine.
Concomitant use of Paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either Paroxetine or the other drug.
Therefore, co-administration of Paroxetine with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be co-administered (see CONTRAINDICATIONS and WARNINGS).
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS).
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: ).
An in vivo interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 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 cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro K and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
Caution is indicated in the co-administration of TCAs with Paroxetine, 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 (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6).
Because paroxetine is highly bound to plasma protein, administration of Paroxetine 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.
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Paroxetine.
A multiple-dose study with immediate-release paroxetine hydrochloride has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when immediate-release paroxetine hydrochloride is co-administered with lithium.
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.
Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.
Daily oral dosing of immediate-release paroxetine (30 mg once daily) increased steady-state AUC , C , and C values of procyclidine (5 mg oral once daily) 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.
In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during co-administration with immediate-release paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing Reports).
Reports of elevated theophylline levels associated with immediate-release paroxetine 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.
Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
There are no clinical studies of the combined use of ECT and Paroxetine.
Activation of Mania/Hypomania
During premarketing testing of immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately 1.0% of paroxetine-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 immediate-release paroxetine and 11.6% for the combined active-control groups. Among 1,627 patients with major depressive disorder, panic disorder, social anxiety disorder, or PMDD treated with Paroxetine in controlled clinical studies, there were no reports of mania or hypomania. As with all drugs effective in the treatment of major depressive disorder, Paroxetine should be used cautiously in patients with a history of mania.
Seizures
During premarketing testing of immediate-release paroxetine hydrochloride, seizures occurred in 0.1% of paroxetine-treated patients, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Among 1,627 patients who received Paroxetine in controlled clinical trials in major depressive disorder, panic disorder, social anxiety disorder, or PMDD, 1 patient (0.1%) experienced a seizure. Paroxetine should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
Discontinuation of Treatment With Paroxetine
Adverse events while discontinuing therapy with Paroxetine were not systematically evaluated in most clinical trials; however, in recent placebo-controlled clinical trials utilizing daily doses of Paroxetine up to 37.5 mg/day, spontaneously reported adverse events while discontinuing therapy with Paroxetine were evaluated. Patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in dose. With this regimen in those studies, the following adverse events were reported for Paroxetine, at an incidence of 2% or greater for Paroxetine and were at least twice that reported for placebo: Dizziness, nausea, nervousness, and additional symptoms described by the investigator as associated with tapering or discontinuing Paroxetine (e.g., emotional lability, headache, agitation, electric shock sensations, fatigue, and sleep disturbances). These events were reported as serious in 0.3% of patients who discontinued therapy with Paroxetine.
During marketing of Paroxetine and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Paroxetine. 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 (see DOSAGE AND ADMINISTRATION).
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients.
Tamoxifen
Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of co-administration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
Akathisia
The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.
Hyponatremia
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Paroxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of Paroxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Abnormal Bleeding
SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
Bone Fracture
Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising.
Use in Patients With Concomitant Illness
Clinical experience with immediate-release paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using Paroxetinein patients with diseases or conditions that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with therapy with immediate-release paroxetine have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when Paroxetineis prescribed for patients with narrow angle glaucoma.
Paroxetine or the immediate-release formulation 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 premarket testing. Evaluation of electrocardiograms of 682 patients who received immediate-release paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Similarly, 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
Paroxetine 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 Paroxetine and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking Paroxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Paroxetine and should counsel them in its appropriate use. A patient Medication Guide is available for Paroxetine. 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 Paroxetine.
Clinical Worsening and Suicide Risk
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Interference With Cognitive and Motor Performance
Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies immediate-release paroxetine hydrochloride has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Paroxetine does not affect their ability to engage in such activities.
Completing Course of Therapy
While patients may notice improvement with use of Paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed.
Concomitant Medications
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 immediate-release paroxetine hydrochloride 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.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: nd ).
Nursing
Patients should be advised to notify their physician if they are breastfeeding an infant (see PRECAUTIONS: Nursing Mothers).
Laboratory Tests
There are no specific laboratory tests recommended.
The information included under the “Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paroxetine” 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 Paroxetine and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During the Clinical Development of Paroxetine).
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With Paroxetine
Adverse Events Associated With Discontinuation of Treatment
Major Depressive Disorder
Ten percent (21/212) of patients treated with Paroxetine discontinued treatment due to an adverse event in a pool of 2 studies of patients with major depressive disorder. 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 compared to placebo) included the following:
In a placebo-controlled study of elderly patients with major depressive disorder, 13% (13/104) of patients treated with Paroxetine discontinued due to an adverse event. Events meeting the above criteria included the following:
Panic Disorder
Eleven percent (50/444) of patients treated with Paroxetine in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following:
Social Anxiety Disorder
Three percent (5/186) of patients treated with Paroxetine in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following:
Premenstrual Dysphoric Disorder
Spontaneously reported adverse events were monitored in studies of both continuous and intermittent dosing of Paroxetine in the treatment of PMDD. Generally, there were few differences in the adverse event profiles of the 2 dosing regimens. Thirteen percent (88/681) of patients treated with Paroxetine in PMDD studies of continuous dosing discontinued treatment due to an adverse event.
The most common events (≥1%) associated with discontinuation in either group treated with Paroxetine with an incidence rate that is at least twice that of placebo in PMDD trials that employed a continuous dosing regimen are shown in the following table. This table also shows those events that were dose dependent (indicated with an asterisk) as defined as events having an incidence rate with 25 mg of Paroxetine that was at least twice that with 12.5 mg of Paroxetine (as well as the placebo group).
Commonly Observed Adverse Events
Major Depressive Disorder
The most commonly observed adverse events associated with the use of Paroxetine in a pool of 2 trials (incidence of 5.0% or greater and incidence for Paroxetine at least twice that for placebo, derived from Table 2) were: Abnormal ejaculation, abnormal vision, constipation, decreased libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma, tremor, and yawning.
Using the same criteria, the adverse events associated with the use of Paroxetine in a study of elderly patients with major depressive disorder were: Abnormal ejaculation, constipation, decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.
Panic Disorder
In the pool of panic disorder studies, the adverse events meeting these criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating, and female genital disorders (generally anorgasmia or difficulty achieving orgasm).
Social Anxiety Disorder
In the social anxiety disorder study, the adverse events meeting these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence, insomnia, and libido decreased.
Premenstrual Dysphoric Disorder
The most commonly observed adverse events associated with the use of Paroxetine either during continuous dosing or luteal phase dosing (incidence of 5% or greater and incidence for Paroxetine at least twice that for placebo, derived from Table 6) were: Nausea, asthenia, libido decreased, somnolence, insomnia, female genital disorders, sweating, dizziness, diarrhea, and constipation.
In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day of Paroxetine limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the 3 off-drug phases were combined, the following adverse events were reported at an incidence of 2% or greater for Paroxetine and were at least twice the rate of that reported for placebo: Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%), sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).
Incidence in Controlled Clinical Trials
Table 2 enumerates adverse events that occurred at an incidence of 1% or more among patients treated with Paroxetine, 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 Paroxetine 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 Paroxetine 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 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 Paroxetine 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.
Table 2. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine in a Pool of 2 Studies in Major Depressive Disorder
Table 3. Treatment-Emergent Adverse Events Occurring in ≥5% of Patients Treated With Paroxetine in a Study of Elderly Patients With Major Depressive Disorder
Table 4. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine in a Pool of 3 Panic Disorder Studies
Table 5. Treatment-Emergent Adverse Effects Occurring in ≥1% of Patients Treated With Paroxetine in a Social Anxiety Disorder Study
Table 6. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With Paroxetine in a Pool of 3 Premenstrual Dysphoric Disorder Studies With Continuous Dosing or in 1 Premenstrual Dysphoric Disorder Study With Luteal Phase Dosing
Table 7 shows results in PMDD trials of common adverse events, defined as events with an incidence of ≥1% with 25 mg of Paroxetine that was at least twice that with 12.5 mg of Paroxetine and with placebo.
Table 7. Incidence of Common Adverse Events in Placebo, 12.5 mg, and 25 mg of Paroxetine in a Pool of 3 Fixed-Dose PMDD Trials
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 2 placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of 3 placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients with social anxiety disorder, and in the intermittent dosing and the pool of 3 placebo-controlled continuous dosing trials in female patients with PMDD 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.
Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials with Paroxetine 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, or immediate-release paroxetine hydrochloride, in controlled clinical trials.
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.
In a pool of 2 placebo-controlled clinical trials, patients treated with Paroxetine or placebo exhibited abnormal values on liver function tests at comparable rates. In particular, the controlled-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 and none of 109 placebo patients experienced liver transaminase elevations of potential clinical concern.
Two of the patients treated with Paroxetine 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 3 studies of patients with panic disorder, 4 of 444 patients treated with Paroxetine and none of 445 placebo patients experienced liver transaminase elevations of potential clinical concern. Elevations in all 4 patients decreased substantially after discontinuation of Paroxetine. 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.
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.
Other Events Observed During the Clinical Development of Paroxetine
The following adverse events were reported during the clinical development of Paroxetine 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 Paroxetine 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 Paroxetine who experienced an event of the type cited on at least 1 occasion while receiving Paroxetine. All reported events are included except those already listed in Tables 2 through 7 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 Paroxetine is unknown.
Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in the PRECAUTIONS section.
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.
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, supraventricular extrasystoles, thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.
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, throat tightness; 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.
Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus, hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis.
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.
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, non-protein nitrogen (NPN) increased.
Infrequent were arthritis, bursitis, tendonitis; rare were myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis, tenosynovitis, tetany.
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.
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.
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.
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.
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.
* Based on the number of men and women as appropriate.
Postmarketing 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-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; 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, restless legs syndrome (RLS), 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), vasculitic syndromes (such as Henoch-Schönlein purpura) and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin co-administration. There has been a case report of severe hypotension when immediate-release paroxetine was added to chronic metoprolol treatment.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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