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Paroxetine
Overview
What is Paroxetine?
Paroxetine hydrochloride is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)--4-(4’-fluorophenyl)-3-[(3’,4’-methylenedioxyphenoxy)methyl]piperidine hydrochloride and has the molecular formula of CHFNOHCl. The molecular weight is 365.8 (329.4 as free base). The structural formula is:
Paroxetine hydrochloride is an odorless, white to off-white powder, slightly soluble in water and soluble in methanol and in alcohol.
Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 10 mg-white; 20 mg-white; 30 mg-white; 40 mg-white. Inactive ingredients consist of anhydrous dibasic calcium phosphate, hypromellose 6 cP, lactose anhydrous, magnesium stearate, polyethylene glycol 6000, povidone, sodium starch glycolate, talc, and titanium dioxide.
What does Paroxetine look like?
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What are the available doses of Paroxetine?
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What should I talk to my health care provider before I take Paroxetine?
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How should I use Paroxetine?
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 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see ). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The effects of paroxetine in hospitalized depressed patients have not been adequately studied.
The efficacy of paroxetine in maintaining a response in major depressive disorder for up to 1 year was demonstrated in a placebo-controlled trial (see ). Nevertheless, 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.
What interacts with Paroxetine?
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or thioridazine is contraindicated (see and ).
Concomitant use in patients taking pimozide is contraindicated (see ).
Paroxetine is contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in Paroxetine Tablets USP.
What are the warnings of 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 longstanding 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 to 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 4400 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 1000 patients treated) are provided in Table 1.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see and , 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 health care providers. Such monitoring should include daily observation by families and caregivers.
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
| Drug-Related Increases | |
| <18 | 14 additional cases |
| 18-24 | 5 additional cases |
| Drug-Related Decreases | |
| 25-64 | 1 fewer case |
| >65 | 6 fewer cases |
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.
Potential for Interaction With Monoamine Oxidase Inhibitors:
In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with paroxetine, limited animal data on the effects of combined use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that paroxetine not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. At least 2 weeks should be allowed after stopping paroxetine before starting an MAOI.
Serotonin Syndrome:
The development of a potentially life-threatening serotonin syndrome may occur with the use of paroxetine, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia,), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of paroxetine with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS – Potential for Interaction With Monoamine Oxidase Inhibitors).
If concomitant use of paroxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS – Drug Interactions).
The concomitant use of paroxetine with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS – Drug Interactions).
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 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:
Epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that aresymptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. 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 - ). 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.
A study based on Swedish national registry data evaluated infants of 6,896 women exposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations following early pregnancy paroxetine exposure was 2% versus 1% in the entire registry population. Among the same paroxetine exposed infants, an examination of the data showed no increase in the overall risk for congenital malformations.
A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants of mothers dispensed paroxetine or other antidepressants during the first trimester (n=815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine compared to other antidepressants (OR 1.5; 95% confidence interval 0.8 - 2.9). The prevalence of cardiovascular malformations following first trimester dispensing was 1.5% for paroxetine versus 1% for other antidepressants. Nine out of 12 infants with cardiovascular malformations whose mothers were dispensed paroxetine in the first trimester had VSDs. This study also suggested an increased risk of overall major congenital malformations (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR 1.8; 95% confidence interval 1.2to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine versus 2 % for other antidepressants.
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 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 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.
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 feeling. 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 - ).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistant pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20 week gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see ). Physicans should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant mediciation.
What are the precautions of Paroxetine?
General:
During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with paroxetine compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine should be used cautiously in patients with a history of mania.
During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
Recent clinical trials supporting the various approved indications for paroxetine employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped.
With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention.
During marketing of paroxetine and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring, upon the 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 discontinutation 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 ).
See also , for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients.
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.
Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when paroxetine was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see ). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of paroxetine with NSAIDs, aspirin, or other drugs that affect coagulation.
Clinical experience with paroxetine in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine in 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.A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine is prescribed for patients with narrow angle glaucoma.
Paroxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Similarly, paroxetine 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 ).
Information for patients:
Paroxetine Tablets USP 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.
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 about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” 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 observe 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.
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine 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.
While patients may notice improvement with treatment with paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed.
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.
Although paroxetine 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.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see -).
Patients should be advised to notify their physician if they are breast-feeding an infant (see ).
Laboratory tests:
There are no specific laboratory tests recommended.
Drug interactions:
As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine with tryptophan is not recommended (see ).
See and .
In a controlled study of healthy volunteers, after paroxetine 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. 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 ).
Based on the mechanism of action of paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see ). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see .
See and .
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 ).
There have been rare postmarketing 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 ).
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 paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration 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 20-mg 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-mgdose of 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 two drugs are both being chronically dosed. No initial dosage adjustment of paroxetine is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
When a single oral 30-mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and Twere reduced (by an average of 50% and 35%, respectively) compared to 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 two drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ).
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 dosing with paroxetine. In one study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C, AUC, and T by an average of approximately two-, five-, and three-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In one study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately four-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 six- to eight-fold greater and in atomoxetine C values that were three- to four-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 it is 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, coadministration 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 coadministered (see and ).
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 ).
An interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, 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 K and its lack of effect on terfenadine’s 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 coadministration of tricyclic antidepressants (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 coadministered with paroxetine (see -).
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 psychoptropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with paroxetine.
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 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 paroxetine is coadministered 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 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.
ADVERSE REACTIONS
Postmarketing Reports
Reports of elevated theophylline levels associated with treatment with paroxetine 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, GAD, and PTSD on a mg/m basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.
Paroxetine produced no genotoxic effects in a battery of five and two assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in mouse bone marrow and in human lymphocytes and in a dominant lethal test in rats.
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD 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 (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m basis).
Pregnancy:
Pregnancy Category D.
WARNINGS - Usage in Pregnancy: .
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 ). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with 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.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine 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 paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine 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 ).
Geriatric Use:
In worldwide premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see and ).
What are the side effects of Paroxetine?
Associated with Discontinuation of Treatment:
Twenty percent (1,199/6,145) of patients treated with paroxetine in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with paroxetine in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD, and PTSD, respectively, discontinued treatment due to an adverse event. The most common events (≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) included the following:
Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not >1% or was not greater than or equal to two times the incidence of placebo.
Array
| Somnolence | 2.3% | 0.7% | 1.9% | 0.3% | 3.4% | 0.3% | 2.0% | 0.2% | 2.8% | 0.6% | ||
| Insomnia | 1.7% | 0% | 1.3% | 0.3% | 3.1% | 0% | ||||||
| Agitation | 1.1% | 0.5% | ||||||||||
| Tremor | 1.1% | 0.3% | 1.7% | 0% | 1.0% | 0.2% | ||||||
| Anxiety | 1.1% | 0% | ||||||||||
| Dizziness | 1.5% | 0% | 1.9% | 0% | 1.0% | 0.2% | ||||||
| Constipation | - | 1.1% | 0% | |||||||||
| Nausea | 3.2% | 1.1% | 1.9% | 0% | 3.2% | 1.2% | 4.0% | 0.3% | 2.0% | 0.2% | 2.2% | 0.6% |
| Diarrhea | 1.0% | 0.3% | - | |||||||||
| Dry mouth | 1.0% | 0.3% | - | |||||||||
| Vomiting | 1.0% | 0.3% | - | 1.0% | 0% | |||||||
| Flatulence | 1.0% | 0.3% | ||||||||||
| Asthenia | 1.6% | 0.4% | 1.9% | 0.4% | 2.5% | 0.6% | 1.8% | 0.2% | 1.6% | 0.2% | ||
| Abnormal ejaculation | 1.6% | 0% | 2.1% | 0% | 4.9% | 0.6% | 2.5% | 0.5% | - | - | ||
| Sweating | 1.0% | 0.3% | - | 1.1% | 0% | 1.1% | 0.2% | - | - | |||
| Impotence | - | 1.5% | 0% | - | - | |||||||
| Libido decreased | 1.0% | 0% | - | - |
Commonly Observed Adverse Events:
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 2) were: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders.
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence and abnormal ejaculation.
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence.
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence of paroxetine at least twice that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence.
Incidence in Controlled Clinical Trials:
The prescriber should be aware that the figures in the tables following 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, doprovide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied.
Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
1. Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: Abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”), trauma, and vomiting.
2. Includes mostly “lump in throat” and “tightness in throat.”
3. Percentage corrected for gender.
4. Mostly “ejaculatory delay.”
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,”and “impotence.”
6. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
| Body as a Whole | Headache | 18% | 17% |
| Asthenia | 15% | 6% | |
| Cardiovascular | Palpitation | 3% | 1% |
| Vasodilation | 3% | 1% | |
| Dermatologic | Sweating | 11% | 2% |
| Rash | 2% | 1% | |
| Gastrointestinal | Nausea | 26% | 9% |
| Dry Mouth | 18% | 12% | |
| Constipation | 14% | 9% | |
| Diarrhea | 12% | 8% | |
| Decreased Appetite | 6% | 2% | |
| Flatulence | 4% | 2% | |
| Oropharynx Disorder | 2% | 0% | |
| Dyspepsia | 2% | 1% | |
| Musculoskeletal | Myopathy | 2% | 1% |
| Myalgia | 2% | 1% | |
| Myasthenia | 1% | 0% | |
| Nervous System | Somnolence | 23% | 9% |
| Dizziness | 13% | 6% | |
| Insomnia | 13% | 6% | |
| Tremor | 8% | 2% | |
| Nervousness | 5% | 3% | |
| Anxiety | 5% | 3% | |
| Paresthesia | 4% | 2% | |
| Libido Decreased | 3% | 0% | |
| Drugged Feeling | 2% | 1% | |
| Confusion | 1% | 0% | |
| Respiration | Yawn | 4% | 0% |
| Special Senses | Blurred Vision | 4% | 1% |
| Taste Perversion | 2% | 0% | |
| Urogenital System | Ejaculatory Disturbance | 13% | 0% |
| Other Male Genital Disorders | 10% | 0% | |
| Urinary Frequency | 3% | 1% | |
| Urination Disorder | 3% | 0% | |
| Female Genital Disorders | 2% | 0% |
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine who participated in placebo- controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day.
1. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and sinusitis.
2. Percentage corrected for gender.
| Body as a Whole | Asthenia | 22% | 14% | 14% | 5% | 22% | 14% |
| Abdominal Pain | - | - | 4% | 3% | - | - | |
| Chest Pain | 3% | 2 % | - | - | - | - | |
| Back Pain | - | - | 3% | 2% | - | - | |
| Chills | 2% | 1% | 2% | 1% | - | - | |
| Trauma | - | - | - | - | 3% | 1% | |
| Cardiovascular | Vasodilation | 4% | 1% | - | - | - | - |
| Palpitation | 2% | 0% | - | - | - | - | |
| Dermatologic | Sweating | 9% | 3% | 14% | 6% | 9% | 2% |
| Rash | 3% | 2% | - | - | - | - | |
| Gastrointestinal | Nausea | 23% | 10% | 23% | 17% | 25% | 7% |
| Dry mouth | 18% | 9% | 18% | 11% | 9% | 3% | |
| Constipation | 16% | 6% | 8% | 5% | 5% | 2% | |
| Diarrhea | 10% | 10% | 12% | 7% | 9% | 6% | |
| Appetite | 9% | 3% | 7% | 3% | 8% | 2% | |
| Dyspepsia | - | - | - | - | 4% | 2% | |
| Flatulence | - | - | - | - | 4% | 2% | |
| Increased Appetite | 4% | 3% | 2% | 1% | - | - | |
| Vomiting | - | - | - | - | 2% | 1% | |
| Musculoskeletal | Myalgia | - | - | - | - | 4% | 3% |
| Nervous System | Insomnia | 24% | 13% | 18% | 10% | 21% | 16% |
| Somnolence | 24% | 7% | 19% | 11% | 22% | 5% | |
| Dizziness | 12% | 6% | 14% | 10% | 11% | 7% | |
| Tremor | 11% | 1% | 9% | 1% | 9% | 1% | |
| Nervousness | 9% | 8% | - | - | 8% | 7% | |
| Libido Decreased | 7% | 4% | 9% | 1% | 12% | 1% | |
| Agitation | - | - | 5% | 4% | 3% | 1% | |
| Anxiety | - | - | 5% | 4% | 5% | 4% | |
| Abnormal Dreams | 4% | 1% | - | - | - | - | |
| Concentration Impaired | 3% | 2% | - | - | 4% | 1% | |
| Depersonalization | 3% | 0% | - | - | - | - | |
| Myoclonus | 3% | 0% | 3% | 2% | 2% | 1% | |
| Amnesia | 2% | 1% | - | - | - | - | |
| Respiratory System | Rhinitis | - | - | 3% | 0% | - | - |
| Pharyngitis | - | - | - | - | 4% | 2% | |
| Yawn | - | - | - | - | 5% | 1% | |
| Special Senses | Abnormal Vision | 4% | 2% | - | - | 4% | 1% |
| Taste Perversion | 2% | 0% | - | - | - | - | |
| Urogenital System | Ejaculation | 23% | 1% | 21% | 1% | 28% | 1% |
| Dysmenorrhea | - | - | - | - | 5% | 4% | |
| Disorder | 3% | 0% | 9% | 1% | 9% | 1% | |
| Impotence | 8% | 1% | 5% | 0% | 5% | 1% | |
| Urinary Frequency | 3% | 1% | 2% | 0% | - | - | |
| Urination Impaired | 3% | 0% | - | - | - | - | |
| Infection |
Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg/day to 50 mg/day.
1. Events reported by at least 2% of GAD and PTSD in patients treated with paroxetine are included, except he following events which had an incidence on placebo ≥ paroxetine [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain, headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis.
2. Percentage corrected for gender.
| Body as a Whole | Asthenia | 14% | 6% | 12% | 4% |
| Headache | 17% | 14% | - | - | |
| Infection | 6% | 3% | 5% | 4% | |
| Abdominal Pain | 4% | 3% | |||
| Trauma | 6% | 5% | |||
| Cardiovascular | Vasodilation | 3% | 1% | 2% | 1% |
| Dermatologic | Sweating | 6% | 2% | 5% | 1% |
| Gastrointestinal | Nausea | 20% | 5% | 19% | 8% |
| Dry Mouth | 11% | 5% | 10% | 5% | |
| Constipation | 10% | 2% | 5% | 3% | |
| Diarrhea | 9% | 7% | 11% | 5% | |
| Decreased | |||||
| Appetite | 5% | 1% | 6% | 3% | |
| Vomiting | 3% | 2% | 3% | 2% | |
| Dyspepsia | - | - | 5% | 3% | |
| Nervous System | Insomnia | 11% | 8% | 12% | 11% |
| Somnolence | 15% | 5% | 16% | 5% | |
| Dizziness | 6% | 5% | 6% | 5% | |
| Tremor | 5% | 1% | 4% | 1% | |
| Nervousness | 4% | 3% | - | - | |
| Libido Decreased | 9% | 2% | 5% | 2% | |
| Abnormal Dreams | 3% | 2% | |||
| Respiratory System | Disorder | 7% | 5% | - | - |
| Sinusitis | 4% | 3% | - | - | |
| Yawn | 4% | - | 2% | <1% | |
| Special Senses | Abnormal Vision | 2% | 1% | 3% | 1% |
| Urogenital System | Ejaculation | 25% | 2% | 13% | 2% |
| Disorder | 4% | 1% | 5% | 1% | |
| Impotence | 4% | 3% | 9% | 1% |
A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine, as shown in the following table:
*Rule for including adverse events in table: Incidence at least 5% for one of paroxetine groups and ≥ twice the placebo incidence for at least one paroxetine group.
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned.
In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation.
In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of posttraumatic stress disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for impotence and abnormal ejaculation.
| Asthenia | 0.0% | 2.9% | 10.6% | 13.9% | 12.7% |
| Sweating | 2.0% | 1.0% | 6.7% | 8.9% | 11.8% |
| Constipation | 5.9% | 4.9% | 7.7% | 9.9% | 12.7% |
| Decreased Appetite | 2.0% | 2.0% | 5.8% | 4.0% | 4.9% |
| Diarrhea | 7.8% | 9.8% | 19.2% | 7.9% | 14.7% |
| Dry Mouth | 2.0% | 10.8% | 18.3% | 15.8% | 20.6% |
| Nausea | 13.7% | 14.7% | 26.9% | 34.7% | 36.3% |
| Anxiety | 0.0% | 2.0% | 5.8% | 5.9% | 5.9% |
| Dizziness | 3.9% | 6.9% | 6.7% | 8.9% | 12.7% |
| Nervousness | 0.0% | 5.9% | 5.8% | 4.0% | 2.9% |
| Paresthesia | 0.0% | 2.9% | 1.0% | 5.0% | 5.9% |
| Somnolence | 7.8% | 12.7% | 18.3% | 20.8% | 21.6% |
| Tremor | 0.0% | 0.0% | 7.7% | 7.9% | 14.7% |
| Blurred Vision | 2.0% | 2.9% | 2.9% | 2.0% | 7.8% |
| Abnormal Ejaculation | 0.0% | 5.8% | 6.5% | 10.6% | 13.0% |
| Impotence | 0.0% | 1.9% | 4.3% | 6.4% | 1.9% |
| Male Genital Disorders | 0.0% | 3.8% | 8.7% | 6.4% | 3.7% |
Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia).
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 selective serotonin reuptake inhibitors (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.
In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.
There are no adequate and well-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.
| Decreased Libido | 6%-15% | 0%-5% |
| Ejaculatory Disturbance | 13%-28% | 0%-2% |
| Impotence | 2%-9% | 0%-3% |
| Decreased Libido | 0%-9% | 0%-2% |
| Orgasmic Disturbance | 2%-9% | 0%-1% |
Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine in controlled clinical trials.
In an analysis of ECGs obtained in 682 patients treated with paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group.
In placebo-controlled clinical trials, patients treated with paroxetine exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities.
In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving drug and 4 of 3,187 patients receiving placebo.
Other Events Observed During the Premarketing Evaluation of Paroxetine:
During its premarketing assessment in major depressive disorder, multiple doses of paroxetine were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to 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. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder 542, 469, 522, 735, and 676 patients, respectively, received multiple doses of paroxetine. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine who experienced an event of the type cited on at least one occasion while receiving paroxetine. All reported events are included except those already listed in Tables 2 to 4, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also described in the section.
Infrequent:
rare:
Frequent:
infrequent:
rare:
Infrequent:
rare:
Rare:
Infrequent:
rare:
Frequent:
infrequent:
rare:
Frequent:
infrequent:
rare:
Frequent:
infrequent:
rare:
Infrequent:
rare:
Frequent:
infrequent:
rare:
Frequent:
infrequent:
rare:
Infrequent:
rare:
Postmarketing Reports:
Voluntary reports of adverse events in patients taking paroxetine 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, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea, neuroleptic malignant syndrome-like events, serotonin syndrome; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic syndromes (such as Henoch-Schšnlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.
What should I look out for while using Paroxetine?
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or thioridazine is contraindicated (see and ).
Concomitant use in patients taking pimozide is contraindicated (see ).
Paroxetine is contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in Paroxetine Tablets USP.
What might happen if I take too much Paroxetine?
How should I store and handle Paroxetine?
StorageStore Pantoprazole sodium delayed-release tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]StorageStore Pantoprazole sodium delayed-release tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09Paroxetine Tablets USP, 10 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 15 and bisect on one side and plain on other side.Paroxetine Tablets USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of "ZC", 16 and bisect on one side and plain on other side.Paroxetine Tablets USP, 30 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC17" on one side and plain on other side.Paroxetine Tablets USP, 40 mg are white to off-white, round-shapped, biconvex, film-coated tablets debossed with the logo of "ZC18" on one side and plain on other sid.Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature).MANUFACTURED BY:Cadila Healthcare Ltd.Ahmedabad, IndiaRepackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--08/2010--NJWRev: 02/09
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) 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. 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. radio ligand 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
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or thioridazine is contraindicated (see and ).Concomitant use in patients taking pimozide is contraindicated (see ).
Paroxetine is contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in Paroxetine Tablets USP.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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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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