Paroxetine hydrochloride and paroxetine mesylate, selective serotonin-reuptake inhibitors (SSRIs), are antidepressant agents.1, 312, 612
Paroxetine is commercially available in the US as paroxetine hydrochloride and as paroxetine mesylate.1, 312, 612
Paroxetine hydrochloride conventional tablets and oral suspension are used in the treatment of major depressive disorder, obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder (PTSD).1 Paroxetine hydrochloride extended-release tablets are used in the treatment of major depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder (PMDD).312
Paroxetine mesylate capsules are used to treat moderate to severe vasomotor symptoms (VMS) associated with menopause; they are not indicated for the treatment of any psychiatric condition, because they contain lower dosages of paroxetine than those used to treat psychiatric disorders.612
In addition, paroxetine has been used in the treatment of premature ejaculation†628 and depression associated with bipolar disorder† .305
Paroxetine is used in the treatment of major depressive disorder.1, 312
The efficacy of paroxetine hydrochloride for the management of major depression has been established in multiple placebo-controlled studies in adult outpatients from 18-73 years of age with major depressive disorder.1, 9, 10, 11, 12, 13, 14, 15, 16, 17, 76 In these studies, paroxetine hydrochloride was found to be more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression-Severity of Illness scale.1, 76 Paroxetine hydrochloride also was more effective than placebo in improving HDRS subfactor scores, including the depressed mood item, sleep disturbance factor, and the anxiety factor.1, 76
The efficacy of paroxetine hydrochloride extended-release tablets for the management of major depressive disorder has been established in 2 flexible-dosage, controlled studies of 12-weeks' duration in adults 18-65 years of age and 1 flexible-dosage, controlled study of 12-weeks' duration in geriatric patients 60-88 years of age.312, 410, 411 In these studies, paroxetine was more effective than placebo in improving scores on the HDRS, the Hamilton depressed mood item, and the Clinical Global Impression-Severity of Illness scale.312, 410, 411
In a study of depressed outpatients who had responded by the end of an initial 8-week open treatment phase to paroxetine (mean dosage: approximately 30 mg daily; HDRS total score of less than 8) and were randomized to continue paroxetine or receive placebo for 1 year, the relapse rate in the paroxetine-treated patients (16%) was substantially lower than that in those who received placebo (43%).1, 133 An analysis of these data for possible gender-related effects on treatment outcome did not suggest any difference in efficacy based on the gender of the patient.1 In controlled studies of depressed patients who had responded to a 6-week course of paroxetine or imipramine and were randomized to receive either the same antidepressant or placebo for up to 1 year, both paroxetine and imipramine were more effective than placebo in maintaining euthymia; however, paroxetine was better tolerated than imipramine during long-term therapy.130
Most clinical studies have shown that the antidepressant effect of usual dosages of paroxetine in patients with depression is greater than that of placebo1, 9, 10, 11, 16, 17, 76, 112, 113 and comparable to that of usual dosages of tricyclic antidepressants (e.g., amitriptyline,114, 115, 116, 117, 118, 121, 134, 135 imipramine,13, 15, 16, 119, 130 doxepin20 ) other SSRIs (e.g., fluoxetine,26, 131 fluvoxamine74 ), and other antidepressants (e.g., nefazodone).122 A Cochrane review concluded that citalopram and mirtazapine may be more effective than paroxetine in the acute phase of treatment, but data are overall insufficient to draw definitive conclusions regarding the efficacy of paroxetine relative to other antidepressants.412
Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.613, 614, 615, 616 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.613, 614, 615, 616 In general, these drugs have shown similar effectiveness; therefore, treatment is guided by specific patient- and drug-related factors.613, 615, 616
A legacy practice guideline from the American Psychiatric Association (APA) states that the effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of these medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and other antidepressants (e.g., bupropion, mirtazapine, trazodone).613 Therefore, the initial selection of an antidepressant can be based mainly on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, actions on cytochrome P-450 [CYP] isoenzymes, other drug interactions); and cost.613
The Department of Veterans Affairs and Department of Defense have developed guidelines for the management of major depressive disorder.614 Treatment of uncomplicated major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.614 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, an SSRI, SNRI, trazodone, vilazodone, or vortioxetine is suggested.614 No evidence is available to suggest superiority of one agent over another.614 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.614 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic.614
Immediate-release formulations of paroxetine hydrochloride are used for the treatment of obsessive-compulsive disorder (OCD) in adults.1 Paroxetine hydrochloride has also been used for the treatment of OCD in pediatric patients ≥7 years of age† .422
The efficacy of paroxetine hydrochloride for the management of OCD in adults has been established by 2 multicenter, placebo-controlled studies of 12 weeks' duration.1 In these clinical studies, paroxetine was more effective than placebo in reducing the severity of obsessive-compulsive manifestations in adult outpatients with moderate to severe OCD (Yale-Brown Obsessive-Compulsive Scale [YBOCS] baseline values of 23-26).1 In a fixed-dose study of 12 weeks' duration involving paroxetine dosages of 20, 40, or 60 mg daily, patients receiving 40 or 60 mg of the drug daily experienced substantially greater reductions in the YBOCS total score (approximately 6 and 7 points, respectively) than those receiving paroxetine 20 mg daily (approximately 4 points) or placebo (approximately 3 points).1 The effective dosage of paroxetine was 40 or 60 mg daily.1 In a 12-week study with flexible dosing of paroxetine (20-60 mg daily) or clomipramine (25-250 mg daily) compared with placebo, paroxetine-treated patients exhibited a mean reduction of approximately 7 points on the YBOCS total score, which was substantially greater than the mean reduction of approximately 4 points in patients receiving placebo.1 No age- or gender-related differences in outcome were noted in either of these studies.1
The efficacy of paroxetine for long-term use (i.e., longer than 12 weeks) has been demonstrated in a 6-month relapse prevention trial, which was an extension of the fixed-dose study of 12 weeks' duration in patients who had responded to paroxetine.1 Patients who received paroxetine relapsed substantially less frequently than those receiving placebo in a double-blind placebo-controlled study.1
One randomized controlled trial of 12 weeks' duration compared paroxetine (titrated up to 60 mg/day) to extended-release venlafaxine (titrated up to 300 mg/day) for the treatment of OCD in patients 18-65 years of age with YBOCS scores ≥18 at baseline (or YBOCS score ≥12 if only obsessions or only compulsions were present).617 The mean change from baseline in YBOCS score was similar between groups (-7.2 for venlafaxine and -7.8 for paroxetine).617
Legacy practice guidelines from the APA list cognitive behavioral therapy and pharmacotherapy as safe and effective first-line treatments for OCD.619 For pharmacotherapy, SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) are first-line.619 All SSRIs appear to be equally effective, but individual patient response is variable; when selecting an SSRI, clinicians should consider the safety and acceptability of particular side effects for the patient, potential drug interactions, past treatment response, and the presence of comorbid medical conditions.619 If a patient does not respond to one SSRI, they may switch to a different SSRI, switch to clomipramine, augment their current SSRI with a second-generation antipsychotic, switch to venlafaxine, or switch to mirtazapine.619 Updated guidelines from international experts state that escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline are first-line treatments for OCD in adults.618
Paroxetine is used in the treatment of panic disorder with or without agoraphobia.1, 312
The efficacy of paroxetine hydrochloride for the management of panic disorder has been established by multicenter, double-blind, placebo-controlled studies in adult outpatients who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-IIIR criteria for panic disorder with or without agoraphobia.1, 48, 53, 187 In a fixed-dose study of 10 weeks' duration in which paroxetine was given in dosages of 10, 20, and 40 mg daily, a substantially greater reduction in panic attack frequency from placebo was noted only in the patients receiving paroxetine 40 mg daily; at the end of the study, 76% of patients receiving paroxetine 40 mg daily were free of panic attacks compared with 44% of those receiving placebo.1, 53 In 2 studies of 12 weeks' duration employing a flexible dosing schedule, greater improvement was reported in patients receiving paroxetine 10-60 mg daily than in those receiving placebo.1, 48, 187 In one study, 51% of the paroxetine recipients compared with 32% of the placebo recipients were free of panic attacks at the end of the study,1, 187 and in the other study, which was conducted in patients receiving standardized cognitive behavioral therapy, 33% of patients receiving paroxetine 10-60 mg daily had a reduction in panic attack frequency to 0 or 1 panic attacks during the study period compared with 14% of those receiving placebo.1, 48 The mean paroxetine dosage for those completing these 2 flexible-dose studies was approximately 40 mg daily.1, 48, 187
In these studies, paroxetine was found to be substantially more effective than placebo in the treatment of panic disorder in at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness Scale.1, 48, 53, 187 The results of the studies conducted to date demonstrate that paroxetine reduces global anxiety,48, 53, 54, 187, 190 depressive symptoms,53, 54, 190 phobic avoidance,53, 54, 187, 190 and improves overall impairment associated with panic disorder.54, 187, 190
The efficacy of paroxetine hydrochloride extended-release tablets for the management of panic disorder has been established in 10-week, multicenter, placebo-controlled, flexible-dosage studies in adult outpatients with panic disorder with or without agoraphobia.312 In 2 studies, paroxetine extended-release tablets were more effective than placebo, but a third study failed to show any benefit compared with placebo.312
The efficacy of paroxetine for long-term use (i.e., longer than 12 weeks) has been demonstrated in controlled studies.1, 54, 184, 192 In a 3-month relapse prevention trial, which was an extension of the 10-week, fixed-dose study, patients who were responders to paroxetine were randomized to receive either paroxetine (10, 20, or 40 mg daily) or placebo.1, 192 The patients receiving long-term therapy with paroxetine relapsed substantially less frequently than those receiving placebo.1, 192 In another controlled study, patients receiving paroxetine therapy for 1 year demonstrated not only long-term efficacy but also continued improvement.54
Subgroup analysis in controlled studies for possible age- or gender-related effects on treatment outcome did not suggest any difference in efficacy based on either the age or sex of the patient.1, 312
The results of controlled studies suggest that paroxetine is as effective as and better tolerated than clomipramine in the treatment of panic disorder.54, 187 In addition, paroxetine was found to have a more rapid onset of action than clomipramine in reducing the number of panic attacks in one study.187 A Cochrane review of pharmacological treatments for panic disorder found that, among antidepressants, paroxetine, venlafaxine, clomipramine, and fluoxetine demonstrated the strongest effect versus placebo in terms of treatment response; among SSRIs, paroxetine and fluoxetine had stronger evidence for efficacy than sertraline.413
Legacy guidelines from the APA state that SSRIs, SNRIs, TCAs, benzodiazepines, and cognitive behavioral therapy have all demonstrated efficacy for the initial treatment of panic disorder.620 Evidence is insufficient to recommend any of these pharmacological or psychosocial interventions over others; choice of initial therapy should be based on patient preference, past treatment history, the presence of comorbid medical or psychiatric conditions, potential adverse effects, potential drug interactions, cost, and treatment availability.620 For patients who prefer to initiate pharmacological treatment, SSRIs and SNRIs are typically recommended first line.620 TCAs and benzodiazepines have similar efficacy to SSRIs and SNRIs, but are less favorable as initial therapy due to their side effect profiles and warnings for use.620 Updated guidelines from international experts state that first-line medications for the treatment of panic disorder include citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, and venlafaxine.621
Paroxetine hydrochloride is used for the treatment of social anxiety disorder in adults.1, 312 Paroxetine hydrochloride has also been used for the treatment of social anxiety disorder in pediatric patients ≥8 years of age† .423
The efficacy of paroxetine hydrochloride in the treatment of social anxiety disorder has been established in 3 multicenter, placebo-controlled studies in adult outpatients who met DSM-IV criteria for social anxiety disorder.1 In 2 studies of 12 weeks' duration in which paroxetine was given in dosages ranging from 20-50 mg daily, significant improvement in the Clinical Global Impressions (CGI) Improvement score and Liebowitz Social Anxiety Scale (LSAS) were noted.1 In these studies, 69 or 77% of paroxetine-treated patients were CGI Improvement responders compared with 29 or 42% of placebo-treated patients.1 In the third study, paroxetine was given in fixed dosages of 20, 40, or 60 mg daily for 12 weeks.1 There was significant improvement in the CGI Improvement responder criterion and LSAS Total Score in patients receiving 20 mg daily compared with those receiving placebo.1 Although there were trends in superiority noted in those receiving 40 or 60 mg daily compared with placebo, the results did not reach statistical significance and there was no indication that dosages exceeding 20 mg daily provide any additional benefit.1
Subgroup analysis of these controlled studies in adult outpatients with social anxiety disorder did not reveal any evidence of age- or gender-related differences in treatment outcome.1
An additional randomized, placebo-controlled study evaluated the efficacy of maintenance treatment with paroxetine in adults with social anxiety disorder.414 After a 12-week single-blind acute treatment phase in which all patients received paroxetine 20-50 mg/day, patients were randomized to continue paroxetine or switch to placebo for an additional 24 weeks of treatment (maintenance phase).414 Patients who continued paroxetine were less likely to relapse during the maintenance phase than patients who received placebo; relapse rates were 14 and 39% in the paroxetine and placebo groups, respectively.414
The efficacy of paroxetine hydrochloride extended-release tablets for the treatment of social anxiety disorder has been established in a 12-week, multicenter, flexible-dose, placebo-controlled trial in adult outpatients who met DSM-IV criteria for social anxiety disorder.312 In this trial, more patients receiving extended-release paroxetine (12.5-37.5 mg daily) were CGI Improvement responders at week 12 (64% compared with 35% of patients receiving placebo).312 Patients receiving paroxetine also demonstrated greater improvement in LSAS total score at week 12 compared with patients receiving placebo.312
Two 12-week randomized controlled trials have compared flexible dosages of extended-release venlafaxine (75-225 mg/day), paroxetine (20-50 mg/day), and placebo for the treatment of social anxiety disorder.415, 416 In these trials, extended-release venlafaxine and paroxetine both resulted in greater improvements in LSAS total score compared to placebo; no substantial differences were noted between extended-release venlafaxine and paroxetine.415, 416
Guidelines from international experts state that escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine are recommended first-line agents for the pharmacological treatment of social anxiety disorder in adults.621
Immediate-release formulations of paroxetine hydrochloride are used for the management of generalized anxiety disorder in adults.1
Efficacy of paroxetine hydrochloride for the management of generalized anxiety disorder has been established in 2 randomized, multicenter, placebo-controlled studies of 8 weeks' duration in adult outpatients who met DSM-IV criteria for generalized anxiety disorder.1, 290, 417 One study employed fixed paroxetine dosages, and the other employed a flexible dosing schedule.1, 290, 417 In the flexible-dose study, approximately 62% of patients receiving paroxetine (20-50 mg daily; mean dosage of 26.8 mg daily) had a score of 1 (“very much improved”) or 2 (“much improved”) on the Clinical Global Impressions (CGI) Global Improvement scale, and approximately 36% of these patients had complete or nearly complete resolution of anxiety (defined as a Hamilton Rating Scale for Anxiety [HAM-A] total score of 7 or less), compared with approximately 47 and 23%, respectively, of patients receiving placebo.290 These results were similar to those seen in the fixed-dose study, in which a score of 1 or 2 on the CGI Global Improvement scale was attained by 61.7, 68, or 45.6%, respectively, and a HAM-A total score of 7 or less was attained by 30, 36, or 20%, respectively, of patients receiving paroxetine 20 or 40 mg daily or placebo.417 However, in a third study, reductions in HAM-A total score attained by patients receiving flexible dosages of paroxetine (20-50 mg daily) were not substantially different than those attained by patients receiving placebo.1 Subgroup analysis of these controlled studies in adult outpatients with generalized anxiety disorder did not reveal any evidence of gender- or race-related differences in treatment outcome.1
Systematic evaluation of continuing paroxetine for periods of up to 6 months in patients with generalized anxiety disorder who had responded while taking paroxetine during an 8-week acute treatment phase has demonstrated a benefit of such maintenance therapy.1, 321 In a double-blind, 24-week relapse prevention trial that was an extension of a single-blind, 8-week acute treatment study, patients who had responded to paroxetine 20-50 mg daily were randomized to receive either paroxetine at the same dosage or placebo.1, 321 Relapse during the double-blind phase was defined as an increase of 2 or more points on the CGI-Severity of Illness scale to a score of 4 or higher or drug discontinuance due to lack of efficacy.1, 321 The paroxetine-treated patients experienced a significantly lower relapse rate over the 24-week period compared with those receiving placebo.1, 321 In addition, 73% of patients receiving a total of 32 weeks of paroxetine therapy achieved remission (defined as a HAM-A total score of 7 or less) compared with about 34% of those who received 8 weeks of therapy and then received 24 weeks of placebo.1, 321
One randomized, double-blind, 24-week trial compared flexible dosages of escitalopram (10-20 mg/day) and paroxetine (20-50 mg/day) in adults with generalized anxiety disorder; in this trial, reductions in HAM-A scores at week 24 were not substantially different between treatment groups.418 An 8-week randomized controlled trial enrolling 53 patients compared flexible dosages of paroxetine and sertraline for the treatment of generalized anxiety disorder and found similar reductions in HAM-A scores across treatment groups.424
Guidelines from international experts state that the SSRIs escitalopram, paroxetine, and sertraline, as well as the SNRIs venlafaxine and duloxetine, are first-line treatments for generalized anxiety disorder.621
Immediate-release formulations of paroxetine hydrochloride are used for the treatment of PTSD in adults.1
Efficacy of paroxetine hydrochloride in the treatment of PTSD has been established in 2 multicenter, placebo-controlled studies of 12 weeks' duration in adult outpatients (66-68% women) with a primary diagnosis (DSM-IV) of PTSD following physical or sexual assault (48-54%), witnessing injury or death (17-19%), serious accident or injury (6-13%), or exposure to combat (5-8%).1, 296, 297 The mean duration of PTSD for these patients was approximately 13 years and 41 or 40% of patients had secondary depressive disorders or non-PTSD anxiety disorders, respectively.1, 296, 297 In these studies, patients receiving fixed (20 or 40 mg daily) or flexible (20-50 mg daily) dosages of paroxetine had substantially greater changes from baseline on the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score, a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: reexperiencing/intrusion, avoidance/numbing, and hyperarousal; these patients also were more likely to have a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Global Improvement Scale (CGI-I) compared with those receiving placebo.1 Treatment response in the fixed-dose study appeared to be unaffected by patient's gender, type of trauma, duration of PTSD, or severity of baseline PTSD or comorbid conditions.296 A third study, also a flexible-dose study comparing paroxetine (20-50 mg daily) with placebo, demonstrated paroxetine to be substantially superior to placebo as assessed by improvement from baseline for CAPS-2 total score, but not by proportion of responders on the CGI-I.1
Legacy guidelines from the APA state that treatment for PTSD involves 3 different approaches, used alone or in combination: psychopharmacology, psychotherapy, and education/supportive measures.622 The selection of a specific treatment strategy will depend on patient-specific factors, such as age, gender, history, comorbid medical and psychiatric conditions, and propensity for aggression or self-harm.622 SSRIs are considered the first-line treatment of choice for patients with PTSD because they have been shown to improve all major symptoms of PTSD (reexperiencing, avoidance/numbing, and hyperarousal), they are effective treatments for common comorbidities of PTSD (e.g., depression, panic disorder, social anxiety disorder, OCD), they may reduce clinical symptoms that often complicate PTSD (e.g., suicidal, impulsive, and aggressive behaviors), and they have relatively few side effects.622 SSRIs with evidence for efficacy in PTSD include fluoxetine, sertraline, and paroxetine.622
The Department of Veterans Affairs and Department of Defense have developed guidelines for the treatment of PTSD.623 These guidelines recommend specific types of psychotherapy (e.g., cognitive processing therapy, eye movement desensitization and reprocessing, prolonged exposure therapy) over pharmacologic interventions for PTSD.623 If pharmacologic therapy is used, the guidelines recommend paroxetine, sertraline, or venlafaxine; there is insufficient evidence to recommend for or against other medications (including other SSRIs) for the treatment of this condition.623
Premenstrual Dysphoric Disorder
Paroxetine hydrochloride extended-release tablets are used for the treatment of PMDD in adults.312
The efficacy of continuously-dosed paroxetine hydrochloride extended-release tablets for the treatment of PMDD has been established in 2 placebo-controlled trials in female patients 18-45 years of age with PMDD.312, 419, 420 Patients receiving systemic hormonal contraceptives were excluded from these trials.312 Patients were randomized to receive extended-release paroxetine 12.5 mg/day, extended-release paroxetine 25 mg/day, or placebo continuously throughout the menstrual cycle for a period of 3 menstrual cycles.312, 419, 420 Efficacy was measured using a visual analog scale (VAS) that mirrored the diagnostic criteria for PMDD and included assessments for mood, physical symptoms, and other symptoms associated with PMDD.312, 419, 420 In both studies, both dosages of extended-release paroxetine were more effective than placebo as measured by change from baseline to month 3 in luteal phase VAS score.312, 419, 420
An additional study established the efficacy of luteal phase dosing for extended-release paroxetine hydrochloride tablets in PMDD.312, 421 In this study, patients were randomized to receive extended-release paroxetine 12.5 mg/day, extended-release paroxetine 25 mg/day, or placebo; patients received their assigned treatment for the 2 weeks prior to the onset of menses for a period of 3 months.312, 421 Both dosages of extended-release paroxetine were more effective than placebo as measured by change from baseline to month 3 in luteal phase VAS score.312, 421
The American College of Obstetricians and Gynecologists (ACOG) has published a clinical practice guideline on the management of premenstrual disorders, including PMDD.624 Treatment options for premenstrual disorders range from lifestyle and behavioral interventions to medical management with SSRIs or hormonal agents.624 Many patients may benefit from a multimodal approach to management.624 In this guideline, ACOG recommends SSRIs for the management of affective premenstrual symptoms; SSRIs with evidence to support their use in PMDD include sertraline, paroxetine, and fluoxetine.624 SSRIs may be administered continuously or intermittently (i.e., during the luteal phase).624
Vasomotor Symptoms Due to Menopause
Paroxetine mesylate capsules are used for the treatment of moderate to severe VMS associated with menopause.612
The efficacy of paroxetine mesylate capsules for the treatment of VMS associated with menopause was established in 2 randomized, placebo-controlled trials enrolling postmenopausal women with a minimum of 7-8 moderate to severe VMS per day (≥50 per week).425, 612 Patients in these studies were randomized to receive paroxetine mesylate 7.5 mg daily at bedtime or placebo for 12 weeks (study 1) or 24 weeks (study 2).425, 612 In study 1, patients treated with paroxetine had a greater decrease in the median daily frequency of moderate to severe VMS at week 4 and week 12.425, 612 At week 4, the change in median daily VMS frequency from baseline was -4.3 and -3.1 for paroxetine and placebo respectively; at week 12, the change in median daily VMS frequency from baseline was -5.9 and -5 respectively.612 Median daily VMS severity was reduced to a greater degree with paroxetine compared to placebo at week 4, but not at week 12.425, 612 In study 2, paroxetine was similarly more effective than placebo for reducing the median daily frequency of moderate to severe VMS at week 4 and week 12; median reductions from baseline were -3.8 and -2.5 at week 4 and -5.6 and -3.9 at week 12 for paroxetine and placebo, respectively.612 Median daily VMS severity was substantially reduced at both week 4 and week 12 with paroxetine compared to placebo.425, 612 At week 24, the proportion of patients achieving a ≥50% reduction from baseline in the frequency of moderate to severe VMS was 47.5% among patients receiving paroxetine and 36.3% among patients receiving placebo.425, 612
Recommendations for the management of menopausal symptoms have been published by ACOG, the Endocrine Society, and the North American Menopause Society (NAMS).625, 626, 627 In general, systemic hormone therapy with estrogen alone or estrogen in combination with progestin is considered the most effective therapy for VMS related to menopause.625, 626, 627 For women who either cannot or choose not to take systemic hormone therapy, effective nonhormonal alternatives for VMS associated with menopause may include SSRIs (including paroxetine), SNRIs, gabapentin, and fezolinetant.625, 626, 627
Like some other SSRIs, paroxetine has been used with some success in the treatment of premature ejaculation†.169, 170, 171, 172, 173 In a placebo-controlled study in men with premature ejaculation, paroxetine (20 mg daily for the first week followed by 40 mg daily for 5 additional weeks) produced substantially greater clinical improvement (increased intravaginal ejaculation latency time, increased number of thrusts before ejaculation) than placebo.169 Nearly all the patients in this study reported some improvement in ejaculatory latency during the first week of paroxetine therapy.169 In an open study, paroxetine 20 mg daily improved premature ejaculation within about 14 days with all patients studied reporting a longer interval before ejaculation.171 When dosages of 20 or 40 mg daily were compared in patients with primary premature ejaculation, 20 mg daily was found to be sufficient; further study is needed to determine whether higher dosages may further increase ejaculation latency.172 In a study comparing paroxetine 20 mg daily for 6 months with paroxetine 20 mg daily for 14 days followed by 10 mg daily for a total of 6 months, both regimens were found to be similarly effective in improving premature ejaculation and were well tolerated.173
Additional studies have investigated the use of paroxetine on an “as needed” basis for the treatment of premature ejaculation.280, 281 In one study, men with premature ejaculation (mean age: 39.5 years; mean pretreatment ejaculatory latency time: 0.3 minutes) were randomized to receive 20 mg of paroxetine or placebo 3-4 hours before planned intercourse; at 4 weeks, the mean ejaculatory latency time was 3.2-3.5 minutes in those receiving the drug compared with 0.45-0.6 minutes in those receiving placebo.280 However, mean ejaculatory latency time was even longer in another group of men (mean age: 40.5 years; mean pretreatment ejaculatory latency time: 0.5 minutes) who received an initial regimen of paroxetine 10 mg daily for 3 weeks and then received paroxetine 20 mg on an as needed basis for 4 weeks.280
Guidelines from the American Urological Association and the Sexual Medicine Society of North America strongly recommend daily SSRIs, on-demand clomipramine, and topical penile anesthetics as first-line agents of choice in the treatment of premature ejaculation.628 Daily treatment with paroxetine, sertraline, fluoxetine, citalopram, or clomipramine has been found to be effective in delaying ejaculation; on-demand administration of clomipramine, paroxetine, sertraline, or fluoxetine 3-6 hours prior to intercourse is modestly efficacious, but with substantially less ejaculatory delay than daily treatment.628
Paroxetine has been used for the short-term management of acute depressive episodes in patients with bipolar disorder†.305 While antidepressants such as SSRIs have shown good efficacy in the treatment of unipolar depression, the drugs generally have been studied as adjuncts to mood stabilizing agents such as lithium or valproate in the management of bipolar disorder; antidepressant monotherapy is not recommended, given the risk of precipitating a switch into mania.305 A legacy guideline from the American Psychiatric Association (APA) recommends that paroxetine be reserved for patients who had an inadequate therapeutic response to optimal therapy with first-line agents (i.e., lithium, lamotrigine) or who do not tolerate these drugs.305 Guidelines from the Department of Veterans Affairs and Department of Defense state that there is insufficient evidence to recommend for or against antidepressants to augment treatment with second-generation antipsychotics or mood stabilizers for acute bipolar depression; quetiapine monotherapy is recommended first line for this use, with cariprazine, lumateperone, lurasidone, or olanzapine monotherapy suggested as alternatives to quetiapine.629
Paroxetine is commercially available in the US as paroxetine hydrochloride conventional, film-coated tablets (e.g., Paxil®), extended-release tablets (e.g., Paxil CR®), and oral suspension and as paroxetine mesylate capsules.1, 312, 612 Conventional tablets of Paxil® and paroxetine mesylate capsules are not bioequivalent.366
Paroxetine hydrochloride and paroxetine mesylate are administered orally.1, 312, 612
Paroxetine hydrochloride conventional film-coated tablets, extended-release tablets, and suspension usually are administered once daily in the morning with or without food.1, 312 Paroxetine hydrochloride oral suspension should be shaken well just prior to administration of each dose.1 Extended-release tablets of paroxetine hydrochloride should be swallowed whole and should not be chewed or crushed.312
Paroxetine mesylate capsules are administered once daily at bedtime with or without food.612
Paroxetine hydrochloride conventional tablets should be stored at 15-30°C.1 The oral suspension and extended-release tablets of paroxetine hydrochloride should be stored at or below 25°C.1, 312 Paroxetine hydrochloride extended-release tablets may be exposed to temperatures ranging between 15° to 30°C.312
Paroxetine mesylate conventional capsules should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C; the capsules should be protected from light and humidity.612
Dosages of paroxetine hydrochloride and paroxetine mesylate are expressed in terms of paroxetine.1, 312, 612
When discontinuing paroxetine hydrochloride, gradually reduce the dosage rather than stopping the drug abruptly whenever possible.1, 312 Adverse reactions may occur upon discontinuation of paroxetine.1, 312
Paroxetine hydrochloride conventional tablets or suspension: For the treatment of major depressive disorder (MDD), the starting dose is 20 mg once daily.1 In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dose of 50 mg daily.1
Paroxetine hydrochloride extended-release tablets: For the treatment of MDD, the starting dose is 25 mg once daily.312 In patients with an inadequate response, increase dosage in increments of 12.5 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dose of 62.5 mg daily.312
Paroxetine hydrochloride conventional tablets or suspension: For the treatment of obsessive-compulsive disorder (OCD), the starting dose is 20 mg once daily.1 In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dose of 60 mg daily.1
Paroxetine hydrochloride conventional tablets or suspension: For the treatment of panic disorder (PD), the starting dose is 10 mg once daily.1 In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dose of 60 mg daily.1
Paroxetine hydrochloride extended-release tablets: For the treatment of PD, the starting dose is 12.5 mg once daily.312 In patients with an inadequate response, increase dosage in increments of 12.5 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dose of 75 mg daily.312
Paroxetine hydrochloride conventional tablets or suspension: For the treatment of posttraumatic stress disorder (PTSD), the starting dose is 20 mg once daily.1 In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dose of 50 mg daily.1
Paroxetine hydrochloride conventional tablets or suspension: For the treatment of social anxiety disorder (SAD), the starting and recommended dosage is 20 mg once daily.1 The safety and effectiveness of the drug in patients with SAD have been evaluated at doses up to 60 mg daily; however, additional benefit at doses above 20 mg daily has not been demonstrated.1
Paroxetine hydrochloride extended-release tablets: For the treatment of SAD, the starting dose is 12.5 mg once daily.312 In patients with an inadequate response, increase dosage in increments of 12.5 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dose of 37.5 mg daily.312
Paroxetine hydrochloride conventional tablets or suspension: For the treatment of generalized anxiety disorder (GAD), the starting and recommended dosage is 20 mg once daily.1 The effectiveness of the drug in patients with GAD has been evaluated at doses up to 50 mg daily; however, additional benefit at doses above 20 mg daily has not been demonstrated.1
Premenstrual Dysphoric Disorder
Paroxetine hydrochloride extended-release tablets: For the treatment of premenstrual dysphoric disorder (PMDD), the starting dose is 12.5 mg once daily.312 The dose can be administered continuously (daily throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle [i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses]).312 Intermittent dosing is repeated with each new cycle.312 In patients with an inadequate response, increase dosage at intervals of at least 1 week to the maximum dose of 25 mg daily, depending on tolerability.312
Vasomotor Symptoms Due to Menopause
Paroxetine mesylate capsules: For the treatment of moderate to severe vasomotor symptoms associated with menopause, the recommended dosage is 7.5 mg once daily at bedtime.612
Paroxetine hydrochloride conventional tablets or suspension: In patients with severe hepatic impairment, the recommended initial dosage is 10 mg daily.1 Do not exceed 40 mg daily.1
Paroxetine hydrochloride extended-release tablets: In patients with severe hepatic impairment, the recommended initial dosage is 12.5 mg daily; if necessary, reduce the initial dose and increase the intervals between upward titration of the dosage.312 Do not exceed 50 mg daily for MDD or PD treatment.312 Do not exceed 37.5 mg daily for SAD treatment.312
Paroxetine mesylate capsules: No dosage adjustment is necessary.612
Paroxetine hydrochloride conventional tablets or suspension: In patients with severe renal impairment, the recommended initial dosage is 10 mg daily.1 Do not exceed 40 mg daily.1
Paroxetine hydrochloride extended-release tablets: In patients with severe renal impairment, the recommended initial dosage is 12.5 mg daily; if necessary, reduce the initial dose and increase the intervals between upward titration of the dosage.312 Do not exceed 50 mg daily for MDD or PD treatment.312 Do not exceed 37.5 mg daily for SAD treatment.312
Paroxetine mesylate capsules: No dosage adjustment is necessary.612
Paroxetine hydrochloride conventional tablets or suspension: For elderly patients, the recommended initial dosage is 10 mg daily.1 Do not exceed 40 mg daily.1
Paroxetine hydrochloride extended-release tablets: In elderly patients, the recommended initial dosage is 12.5 mg daily; if necessary, reduce the initial dose and increase the intervals between upward titration of the dosage.312 Do not exceed 50 mg daily for MDD or PD treatment.312 Do not exceed 37.5 mg daily for SAD treatment.312
Paroxetine mesylate capsules: No dosage adjustment is necessary.612
Pharmacogenomic Considerations
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide dosing recommendations for paroxetine based on cytochrome P-450 (CYP) 2D6 phenotype.700 For patients identified as CYP2D6 ultrarapid metabolizers, select an alternative drug not predominantly metabolized by CYP2D6.700 For CYP2D6 intermediate metabolizers, consider a lower starting dose and a slower titration schedule compared to the recommended starting dose.700 For CYP2D6 poor metabolizers, consider a 50% reduction of the recommended starting dose, a slower titration schedule, and a 50% lower maintenance dose as compared with normal metabolizers.700
Suicidal Thoughts and Behaviors in Pediatric and Young Adults
Paroxetine carries a boxed warning regarding the increased risk of suicidal thoughts and behaviors in pediatric and young adult patients.1, 312, 612 In pooled analyses of placebo-controlled trials of antidepressant drugs, including selective serotonin-reuptake inhibitor (SSRIs) , that included approximately 77,000 adult patients and 4500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients 24 years of age and younger was greater than in placebo-treated patients.1, 312 For patients younger than 18 years of age, 14 additional cases of increased suicidal thoughts/behaviors per 1000 patients treated with antidepressants were observed compared to those receiving placebo; 5 additional cases per 1000 patients treated with antidepressants were observed in those between 18—24 years of age.1, 312 It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extend to longer-term use (i.e., beyond 4 months).1, 312 However, there is substantial evidence from studies in adults with major depressive disorder (MDD) that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.1, 312 Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of therapy, and at times of dosage changes.1, 312, 612 Counsel family members or caregivers to monitor for changes and to alert the clinician.1, 312, 612 Consider changing the therapeutic regimen, including discontinuation of paroxetine, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.1, 312, 612
SSRIs, including paroxetine, can precipitate serotonin syndrome, a potentially life-threatening condition.1, 312, 612 The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John's Wort) and with drugs that impair metabolism of serotonin (i.e., MAOIs).1, 312, 612 Serotonin syndrome can also occur when these drugs are used alone.1, 312, 612
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 GI symptoms (e.g., nausea, vomiting, diarrhea).1, 312, 612
The concomitant use of paroxetine with MAOIs is contraindicated.1, 312, 612 In addition, do not initiate paroxetine in a patient being treated with MAOIs such as linezolid or IV methylene blue.1, 312, 612 If it is necessary to initiate treatment with an MAOI such as linezolid or IV methylene blue, discontinue paroxetine before initiating treatment with the MAOI.1, 312, 612
Monitor all patients for the emergence of serotonin syndrome.1, 312, 612 Discontinue treatment with paroxetine and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.1, 312, 612 If concomitant use with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.1, 312, 612
Drug Interactions Leading to QT Prolongation
The cytochrome P-450 (CYP) 2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide.1, 312, 612 Since thioridazine and pimozide given alone produce prolongation of the QT interval corrected for rate (QTc interval) and increase the risk of serious ventricular arrhythmias, the use of paroxetine is contraindicated in combination with thioridazine or pimozide.1, 312, 612
Fetal/Neonatal Morbidity and Mortality
Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants.1, 312, 612
For women who intend to become pregnant or who are in their first trimester of pregnancy, initiate paroxetine only after consideration of the other available treatment options.1, 312, 612 Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.1, 312
Drugs that interfere with serotonin reuptake inhibition, including paroxetine, increase the risk of bleeding events.1, 312, 612 Concomitant use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk.1, 312, 612 Case reports and epidemiological studies (case-control and cohort designs) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding.1, 312, 612 Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage.1, 312, 612 Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1, 312, 612
Inform patients about the increased risk of bleeding associated with the concomitant use of paroxetine and antiplatelet agents or anticoagulants.1, 312, 612 For patients taking warfarin, carefully monitor the INR.1, 312, 612
Activation of Mania or Hypomania
In patients with bipolar disorder, treating a depressive episode with paroxetine or another antidepressant may precipitate a mixed/manic episode.1, 312, 612 During controlled clinical trials of paroxetine, hypomania or mania occurred in approximately 1% of unipolar patients receiving paroxetine compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients.1, 312
Prior to initiating treatment, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.1, 312, 612
Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.1, 312
Reduce paroxetine dosage gradually rather than discontinuing the drug abruptly.1, 312
Patients with a history of seizures were excluded from clinical studies evaluating the efficacy and safety of paroxetine.1, 312 During clinical studies, seizures occurred in 0.1% of patients treated with paroxetine.1, 312, 612
Use paroxetine with caution in patients with a seizure disorder, and discontinue the drug in any patient who develops seizures.1, 312, 612
Cases of angle-closure glaucoma associated with paroxetine use have been reported.1, 312, 612 Avoid use of paroxetine in patients with untreated anatomically narrow angles.1, 312, 612
Hyponatremia may occur as a result of treatment with SSRIs, including paroxetine.1, 312, 612 Cases with serum sodium lower than 110 mmol/L have been reported.1, 312, 612 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.1, 312, 612 Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.1, 312, 612 In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1, 312, 612
Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs.1, 312, 612
In patients with symptomatic hyponatremia, discontinue paroxetine and institute appropriate medical intervention.1, 312, 612
Reduction of Efficacy of Tamoxifen
The efficacy of tamoxifen may be reduced with concomitant use of paroxetine due to irreversible CYP2D6 inhibition by paroxetine, resulting in lower tamoxifen blood levels.1, 312, 612
When tamoxifen is used for prevention or treatment of breast cancer, consider using an antidepressant with little to no CYP2D6 inhibition.1, 312, 612
Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures.1, 312, 612
Use of SSRIs, including paroxetine, may cause symptoms of sexual dysfunction.1, 312, 612 In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.1, 312 In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.1, 312, 612
It is important for prescribers to inquire about sexual function prior to initiation and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.1, 312, 612 When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.1, 312, 612 Discuss potential management strategies to support patients in making informed decisions about treatment.1, 312, 612
Paroxetine mesylate capsules are contraindicated for use in pregnant women because menopausal vasomotor symptoms do not occur during pregnancy and paroxetine can cause fetal harm.612
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including paroxetine, during pregnancy.1, 312 Advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866-961-2388 or visiting online at [Web].1, 312
Paroxetine is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester.1, 312 There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure during pregnancy.1, 312 Use of paroxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.1, 312 There also are risks associated with untreated depression in pregnancy.1, 312 Additionally, women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants.1, 312 Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.1, 312 For women who intend to become pregnant or who are in their first trimester of pregnancy, initiate paroxetine only after consideration of the other available treatment options.1, 312
Data from the published literature report the presence of paroxetine in human milk.1, 312, 612 There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to paroxetine through breast milk.1, 312 Monitor for these symptoms in infants exposed to paroxetine.1, 312 There are no data on the effect of paroxetine on milk production.1, 312 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for paroxetine and any potential adverse effects on the breast-fed child from paroxetine or from the underlying maternal condition.1, 312, 612
Females and Males of Reproductive Potential
Paroxetine may affect sperm quality, thereby impairing fertility; these effects may or may not be reversible.1, 312
The safety and effectiveness of paroxetine in pediatric patients have not been established.1, 312, 612 Effectiveness was not established in 3 studies comparing paroxetine to placebo in pediatric patients with MDD.1, 312 The main safety concern is the increased risk of suicidal thoughts and behaviors.1, 312
Paroxetine mesylate capsules are not indicated for use in the pediatric population.612
In premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older.1, 312 Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose of paroxetine hydrochloride is recommended; however, no overall differences in safety or effectiveness were observed between elderly and younger patients.1, 312 SSRIs including paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.1, 312, 612
Clinical studies of paroxetine mesylate capsules did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger subjects.612 Elderly patients may have elevated paroxetine plasma concentrations compared to younger patients.612 However, no dosage adjustment of paroxetine mesylate capsules is considered necessary in elderly patients.612
Increased plasma concentrations of paroxetine occur in patients with hepatic impairment.1, 312 Reduce the initial dosage of paroxetine hydrochloride in patients with severe hepatic impairment.1, 312
Hepatic impairment may increase plasma concentrations twofold.612 No dosage adjustment of paroxetine mesylate capsules is required.612
Increased plasma concentrations of paroxetine occur in patients with renal impairment.1, 312 Reduce the initial dosage of paroxetine hydrochloride in patients with severe renal impairment.1, 312
In patients with renal impairment (creatinine clearance <30 mL/minute), mean plasma paroxetine concentrations are approximately 4 times greater than those seen in healthy individuals.612 No dosage adjustment of paroxetine mesylate capsules is required.612
The most common adverse effects with paroxetine hydrochloride conventional tablets and suspension (≥5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, and yawn.1
The most common adverse effects with paroxetine hydrochloride extended-release tablets (≥5% and at least twice placebo) are abnormal ejaculation, abnormal vision, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, insomnia, libido decreased, nausea, somnolence, sweating, and tremor.312
The most common adverse effects with paroxetine mesylate capsules (≥2% and at a higher incidence that placebo) are headache, fatigue, malaise, lethargy, nausea, and vomiting.612
Paroxetine undergoes extensive hepatic metabolism via the cytochrome P-450 (CYP) 2D6 enzyme.1, 312, 612 Paroxetine is a strong CYP2D6 inhibitor.1, 312, 612
Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes
The metabolism and pharmacokinetics of paroxetine may be affected by a number of drugs that induce (e.g., phenobarbital) or inhibit (e.g., cimetidine, tricyclic antidepressants) drug-metabolizing enzymes.1, 312, 612
Paroxetine is a strong CYP2D6 inhibitor.1, 312, 612 Concomitant use of paroxetine with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.1, 312, 612 Examples of drugs that are CYPD2D6 substrates include propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, and risperidone.1, 312, 612 When used concomitantly with paroxetine, reduce the dosage of the CYP2D6 substrate.1, 312, 612 If paroxetine is discontinued, an increase in dosage of the CYP2D6 substrate may be needed.1, 312, 612
Concomitant use of paroxetine and tamoxifen leads to reduced plasma levels of the active metabolite, endoxifen, and reduced efficacy of tamoxifen.1, 312, 612 For patients taking tamoxifen who require an antidepressant, consider use of an antidepressant with little or no CYP2D6 inhibition.1, 312, 612
In an in vivo drug interaction study, concomitant administration of paroxetine and the CYP3A4 substrate, terfenadine (no longer commercially available in the US), had no effect on the pharmacokinetics of terfenadine.1, 312, 612 In vitro studies of ketoconazole, which is a potent inhibitor of CYP3A4 activity, found it 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 (no longer commercially available in the US), cisapride, triazolam, and cyclosporine.1, 312, 612 Based on the assumption that the relationship between paroxetine's inhibitory activity in vitro and its lack of effect on terfenadine's clearance in vivo predicts its effect on other CYP3A4 substrates, the manufacturer states that these data suggest that the extent of paroxetine's inhibition of CYP3A4 activity is unlikely to be of clinical importance.1, 312, 612
Cimetidine is known to inhibit many CYP oxidative enzymes and can affect the pharmacokinetics of paroxetine.612 In a study in which oral paroxetine (30 mg once daily) was given for 4 weeks, steady-state plasma paroxetine concentrations were increased by approximately 50% during concomitant use of oral cimetidine (300 mg 3 times daily) for the final week.612 Dosage adjustment for paroxetine is not recommended; monitor for efficacy of paroxetine.612
Phenobarbital is known to induce many CYP oxidative enzymes and can affect the pharmacokinetics of paroxetine.612 Following administration of a single 30-mg oral dose of paroxetine in individuals who had achieved steady-state serum phenobarbital concentrations (100 mg of phenobarbital daily for 14 days), the AUC and elimination half-life of paroxetine were reduced by an average of 25 and 38%, respectively, compared with administration of paroxetine alone.612 The influence of paroxetine on the pharmacokinetics of phenobarbital has not been studied to date.612 Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not apply in situations in which both drugs are administered chronically.612 Dosage adjustment for paroxetine is not recommended; monitor for efficacy of paroxetine.
Use of selective serotonin-reuptake inhibitors (SSRIs) such as paroxetine concurrently with other drugs that affect serotonergic neurotransmission increases the risk of serotonin syndrome.1, 312, 612 Examples of serotonergic drugs include SSRIs (other than paroxetine), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John's Wort.1, 312, 612
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases.1, 312, 612 If serotonin syndrome occurs, consider discontinuation of paroxetine and/or concomitant serotonergic drugs.1, 312, 612
Drugs Highly Bound to Plasma Protein
Because paroxetine is highly protein bound, the drug theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as warfarin.1, 312, 612 In vitro studies to date have shown that paroxetine has no effect on the protein binding of 2 highly protein-bound drugs, phenytoin and warfarin.1, 312, 612
Monitor for adverse reactions and reduce dosage of paroxetine or other protein-bound drugs as warranted.1, 312, 612
Drugs that Interfere with Hemostasis
Concurrent use of an antiplatelet agent or anticoagulant such as aspirin, clopidogrel, heparin, or warfarin, with paroxetine can potentiate the risk of bleeding.1, 312, 612 Inform patients of the increased risk of bleeding associated with the concomitant use of paroxetine and antiplatelet and anticoagulant agents.1, 312, 612 For patients taking warfarin, closely monitor the INR.1, 312, 612
Use of SSRIs such as paroxetine concurrently with monoamine oxidase inhibitors (MAOIs), including selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue, increases the risk of serotonin syndrome.1, 312, 612
Concomitant use of paroxetine with MAOIs is contraindicated.1, 312, 612 At least 14 days must elapse between discontinuation of an MAOI and initiation of paroxetine; additionally, at least 14 days must elapse after stopping paroxetine before starting an MAOI.1, 312, 612
In one study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single-dose desipramine (100 mg) peak plasma concentrations, AUC, and elimination half-life by an average of approximately 2-, 5-, and 3-fold, respectively.612 This interaction appears to result from paroxetine-induced inhibition of CYP2D6.1, 312, 612 Thus, the manufacturers recommend that caution be exercised during concomitant use of tricyclics with paroxetine since paroxetine may inhibit the metabolism of the tricyclic antidepressant.1, 312, 612 In addition, the dosage of the tricyclic should be reduced during concomitant use and increased when paroxetine is discontinued.1, 312, 612
Under steady-state conditions, diazepam does not appear to affect the pharmacokinetics of paroxetine.1, 312, 612
The steady-state pharmacokinetics of paroxetine were not altered when administered concurrently with digoxin at steady state.1, 312, 612 The mean AUC of digoxin at steady state decreased by 15% in the presence of paroxetine.1, 312, 612 The dosage of digoxin may need to be increased.612 Monitor digoxin concentrations and clinical effect.612
Concurrent administration of fosamprenavir and ritonavir with paroxetine substantially decreased plasma paroxetine concentrations.1, 312, 612 The manufacturers recommend that paroxetine dosage adjustments in patients receiving these drugs concurrently be guided by clinical effect (tolerability and efficacy).1, 312, 612
In vitro studies to date have shown that paroxetine has no effect on the protein binding of phenytoin.1, 312, 612 When a single 30-mg oral dose of paroxetine was administered in individuals in whom steady-state plasma phenytoin concentrations (300 mg once daily for 14 days) had been achieved, the AUC and elimination half-life of paroxetine were reduced by an average of 50 and 35%, respectively, compared with paroxetine administered alone.612 In another study, when a single 300-mg oral dose of phenytoin was administered to individuals in whom steady-state plasma paroxetine concentrations (30 mg once daily for 14 days) had been achieved, the AUC of phenytoin was slightly reduced (by an average of 12%) compared with phenytoin administered alone.612 However, because both paroxetine and phenytoin exhibit nonlinear pharmacokinetics, these studies may not address the case in which both drugs are given chronically.612
CYPD26 inhibition by paroxetine can increase plasma concentrations of pimozide or thioridazine leading to an increased risk of QTc prolongation and ventricular arrhythmias.1, 312, 612 Use of paroxetine in patients taking pimozide or thioridazine is contraindicated.1, 312, 612
In a study in which propranolol (80 mg twice daily) was given orally for 18 days, the steady-state plasma concentrations of propranolol were not affected when paroxetine (30 mg once daily) was used concurrently during the last 10 days.1, 312, 612 The manufacturers state that the effect(s) of propranolol on paroxetine have not been systematically evaluated.612
Elevated serum theophylline concentrations associated with paroxetine therapy have been reported.1, 312, 612 Although this interaction has not been systematically studied to date, the manufacturers recommend that serum concentrations of theophylline be monitored during concomitant paroxetine therapy.1, 312, 612
Paroxetine is a potent and highly selective reuptake inhibitor of serotonin and has little or no effect on other neurotransmitters.1, 4, 6, 84, 312, 612 At therapeutic dosages in humans, paroxetine has been shown to inhibit the reuptake of serotonin into platelets.1, 312
The precise mechanism of antidepressant action of paroxetine is unclear, but the drug has been shown to selectively inhibit the reuptake of serotonin at the presynaptic neuronal membrane.1, 4, 5, 6, 84, 85 Paroxetine-induced inhibition of serotonin reuptake causes increased synaptic concentrations of serotonin in the CNS, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission.1 Like other selective serotonin-reuptake inhibitor (SSRIs) (e.g., citalopram, fluoxetine, fluvoxamine, sertraline), paroxetine appears to have only very weak effects on the reuptake of norepinephrine or dopamine1, 4, 6, 19, 84, 85 and does not exhibit clinically important anticholinergic, antihistaminic, or adrenergic (α1, α2, β) blocking activity at usual therapeutic dosages.1, 4, 84, 85
The precise mechanism of action that is responsible for the efficacy of paroxetine in the treatment of obsessive-compulsive disorder is unclear.1, 19, 55 However, because of the potency of clomipramine and SSRIs (e.g., citalopram, fluoxetine, fluvoxamine, sertraline) in inhibiting serotonin reuptake and their efficacy in the treatment of obsessive-compulsive disorder, a serotonin hypothesis has been developed to explain the pathogenesis of the condition.1, 19, 55 The hypothesis postulates that a dysregulation of serotonin is responsible for obsessive-compulsive disorder and that paroxetine and these other agents are effective because they correct this imbalance.1, 19, 55 Although the available evidence supports the serotonergic hypothesis of obsessive-compulsive disorder, additional studies are necessary to confirm this hypothesis.1, 55
The exact mechanism of action of paroxetine in panic disorder, social phobia, or generalized anxiety disorder has not been fully elucidated but appears to involve inhibition of reuptake of serotonin at the presynaptic membrane.1, 312
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt.1 The conventional oral tablets and suspension of paroxetine hydrochloride are bioequivalent.1 In healthy males receiving one 30-mg tablet of paroxetine (administered as paroxetine hydrochloride) once daily for 30 days, steady-state plasma paroxetine concentrations were achieved after approximately 10 days in most patients, although achievement of steady-state concentrations may take substantially longer in some patients.1, 6 At steady-state, mean peak plasma paroxetine concentrations of 61.7 ng/mL occurred after an average of 5.2 hours following oral administration; corresponding mean trough concentrations of 30.7 ng/mL were reported.1
Paroxetine hydrochloride extended-release tablets consist of 2 layers: one layer of the tablet consists of a degradable barrier layer and the other contains the active material in a hydrophilic matrix.312 The absorption rate of paroxetine extended-release tablets is reduced compared with immediate-release formulations.312 The degradable polymeric matrix is designed to control the dissolution rate of paroxetine over a period of approximately 4—5 hours.312 An enteric coating delays the start of drug release until the tablets have left the stomach.312 The time to maximum concentrations was observed between 6—10 hours post-dose.312 Steady state was achieved after 2 weeks of dosing.312
Paroxetine mesylate is completely absorbed following oral administration of the capsules.612 The time to maximum plasma paroxetine concentration following paroxetine mesylate capsules was reached at a median of 6 hours.612 Steady state concentration of paroxetine mesylate capsules was achieved by 12 days.612
Paroxetine can be administered with or without food.1, 312, 612 Administration of a single dose of paroxetine hydrochloride with food resulted in a 6% increase in the AUC, a 29% increase in peak plasma concentrations of the drug, and a decrease in the time to peak plasma concentrations from 6.4 to 4.9 hours.1
Paroxetine distributes throughout the body, including the CNS and into human milk, with only 1% remaining in the plasma.1 Approximately 95 and 93% of paroxetine is bound to plasma proteins at plasma concentrations of 100 and 400 ng/mL, respectively.1 Under usual clinical conditions, plasma paroxetine concentrations would be less than 400 ng/mL.1 In vitro, paroxetine does not alter the plasma protein binding of 2 other highly protein-bound drugs, phenytoin and warfarin.1
The elimination half-life of paroxetine when administered as paroxetine hydrochloride is approximately 21 hours with the immediate-release formulation and between 15—20 hours with the extended-release formulation.1, 312 Paroxetine is extensively metabolized.1, 312, 612 The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared by the body.1, 94 Conjugates with glucuronic acid and sulfate predominate, and the principal metabolites have been isolated and identified.1, 94 The metabolites of paroxetine have been shown to possess no more than 2% of the potency of the parent compound as inhibitors of serotonin reuptake;1, 6, 94 therefore, they are essentially inactive.1, 6, 84
Paroxetine is partially metabolized by the drug metabolizing isoenzyme cytochrome P-450 (CYP) 2D6.1 Saturation of this enzyme at dosages used clinically appears to account for the nonlinearity of paroxetine kinetics observed with increasing dosage and duration of treatment.1 The role of the CYP2D6 enzyme in paroxetine metabolism also suggests potential drug-drug interactions.1
In steady-state, dose-proportionality studies involving elderly and nonelderly patients receiving 20-40 and 20-50 mg daily of paroxetine (administered as paroxetine hydrochloride), respectively, some nonlinearity was observed in both groups, which suggests a saturable metabolic pathway.1 When compared with trough paroxetine concentrations after 20 mg of the drug daily, trough concentrations after 40 mg daily were approximately 2-3 times higher than doubled.1
Following oral administration, paroxetine and its metabolites are excreted in both urine and feces.1, 94 Following oral administration of a single, 30-mg dose of paroxetine (administered as paroxetine hydrochloride) as an oral solution approximately 64% of the dose was excreted in the urine within 10 days; unchanged paroxetine accounted for 2% of the dose and metabolites accounted for the remaining 62% of the dose.1, 94 During the same period, approximately 36% of the dose was eliminated in feces (probably via the bile), mostly as metabolites and less than 1% as the parent drug.1, 94
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Suspension | 10 mg (of paroxetine) per 5 mL* | Paroxetine Oral Suspension | |
Tablets, extended-release, film-coated | 12.5 mg (of paroxetine)* | Paroxetine Extended-release Tablets | ||
Apotex | ||||
25 mg (of paroxetine)* | Paroxetine Extended-release Tablets | |||
Paxil CR® | Apotex | |||
37.5 mg (of paroxetine)* | Paroxetine Extended-release Tablets | |||
Paxil CR® | Apotex | |||
Tablets, film-coated | 10 mg (of paroxetine)* | Paroxetine Hydrochloride Film-coated Tablets | ||
Paxil® (scored) | Apotex | |||
20 mg (of paroxetine)* | Paroxetine Hydrochloride Film-coated Tablets | |||
Paxil® (scored) | Apotex | |||
30 mg (of paroxetine)* | Paroxetine Hydrochloride Film-coated Tablets | |||
Paxil® | Apotex | |||
40 mg (of paroxetine)* | Paroxetine Hydrochloride Film-coated Tablets | |||
Paxil® | Apotex |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 7.5 mg (of paroxetine)* | Paroxetine Mesylate Capsules | |
Brisdelle® | Padagis |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Apotex. Paxil® (paroxetine hydrochloride) tablets and oral suspension prescribing information. 2024 Nov.
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