Paxil (paroxetine hydrochloride), Paxil CR (paroxetine hydrochloride) Controlled Release - 7 indications

Scroll down for information on each indication:

• for the treatment of major depressive disorder, panic disorder and obsessive-compulsive disorders; approved May 1996 as Paxil
• for the treatment of social anxiety disorder; approved 1999 as Paxil
• for the treatment of post-traumatic stress disorder; approved 2000 as Paxil
• for the treatment of generalized anxiety disorder; approved 2001 as Paxil   
• for major depressive disorder; approved March 1999 as Paxil CR
• for the treatment of panic disorder; approved February 2002 as Paxil CR
• for the symptomatic treatment of premenstrual dysphoric disorder (PMDD); approved August 2003 as Paxil CR
• for the treatment of social anxiety disorder; approved October 2003 as Paxil CR

General Information

Paxil (paroxetine hydrochloride) is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI).

Paxil, Paxil CR is specifically indicated for the following:

• the symptomatic relief of Major Depressive Disorder (MDD)
• the symptomatic treatment of obsessive-compulsive disorder (OCD)
• the symptomatic treatment of panic disorder, with or without agoraphobia
• the symptomatic relief of generalized social phobia (social anxiety disorder)
• for the symptomatic relief of Generalized Anxiety Disorder (GAD)
• for the symptomatic treatment of posttraumatic stress disorder (PTSD)
• for the symptomatic treatment of premenstrual dysphoric disorder (PMDD)

Paxil, Paxil CR is supplied as a tablet/controlled release tablet for oral administration. It should be administered once daily in the morning and may be taken with or without food. The tablet should be swallowed rather than chewed. Discontinuing treatment: 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, dose titration should be managed on the basis of the patient’s clinical response.

Scroll down for recommended dosing/administration for each indication.

Mechanism of Action

Paxil (paroxetine) is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant and anxiolytic action in the treatment of depression, obsessivecompulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (α1, α2, β), dopaminergic, serotonergic (5HT1, 5HT2), or histaminergic receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine receptor was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors

Side Effects

Adverse effects associated with the use of Paxil and Paxil CR may include, but are not limited to, the following:

• nausea/vomiting
• dry mouth
• drowsiness
• weakness
• dizziness
• sweating
• tremor
• nervousness
• feeling agitated
• blurred vision
• sleep disturbances
• weight gain
• sexual problems

Paxil

Indication 1 - major depressive disorder, panic disorder and obsessive-compulsive disorders

approved May 1996 

Dosing/Administration

Major Depressive Disorder

• Usual Adult Dose: The administration of Paxil should be initiated at 20 mg daily. For most patients, 20 mg daily will also be the optimum dose. The therapeutic response may be delayed until the third or fourth week of treatment.
• Dose Range: For those patients who do not respond adequately to the 20 mg daily dose, a gradual increase in dosage up to 40 mg daily may be considered. The maximum recommended daily dose is 50 mg.

Panic Disorder

• Usual Adult Dose: The recommended starting dose of Paxil in the treatment of panic disorder is 10 mg/day. The recommended dose of Paxil in the treatment of panic disorder is 40 mg daily.
• Dose Range: For those patients who do not respond adequately to the 40 mg daily dose, a gradual increase in dosage may be considered. The maximum recommended daily dose is 60 mg.

Obsessive Compulsive Disorder

• Usual Adult Dose: The administration of Paxil  should be initiated at 20 mg/day. The recommended dose of Paxil  in the treatment of OCD is 40 mg daily. 
• Dose Range: For those patients who do not respond adequately to the 40 mg daily dose, a gradual increase in dosage may be considered. The maximum recommended daily dose is 60 mg.

Clinical Trial Results

Major Depressive Disorder

The efficacy of Paxil for MDD was established in six placebo-controlled clinical trials of 6 weeks in duration performed in patients with depression (ages 18 to 73). In these studies, Paxil was shown to be significantly more effective than placebo in treating depression according to the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI) – Severity of Illness. A study of outpatients with recurrent major depressive disorder who had responded to Paxil (HDRS total score < 8) during an initial 8-week open-treatment phase and were then randomized to continuation on Paxil or placebo for 1 year demonstrated that a significantly lower proportion of patients treated with Paxil (15%) compared to placebo (39%) met criteria for partial relapse . Criteria for full relapse were met by a significantly lower percentage of Paxil treated patients (12%) compared to placebo treated patients (28%). 

Panic Disorder

FDA approval was based on one 10-week double-blind clinical study. Of subjects treated with 40 mg per day of Paxil, 76% were completely free of full panic attacks at the end point, compared with 44% of subjects who received placebo. Patients who responded to Paxil during the initial 10-week phase and a three-month double-blind extension phase were randomly assigned to continue on Paxil or be switched to placebo for an additional three months. Of the subjects switched to placebo, 30% experienced a relapse, as compared with only 5% of those who were treated with Paxil.

Obsessive Compulsive Disorder

Three double-blind, placebo-controlled clinical trials of 12 weeks in duration evaluated the efficacy of Paxil in obsessive-compulsive disorder: two flexible dose studies (20 to 60 mg/day) and one fixed dose study (20, 40, & 60 mg/day). Results for the fixed dose study and one of the flexible dose studies showed statistically significant differences from placebo in favor of Paxil on mean change from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive-Compulsive Scale. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at endpoint according to a Clinical Global Impression of Improvement was 15% (13/88) in the placebo group, 20% (17/85) in the 20 mg/day group, 36% (30/83) in the 40 mg/day group, and 37% (31/83) in the 60 mg/day group. In the two flexible dose studies, placebo response rates according to this criterion were 28% (28/99) and 25% (19/75), while Paxil response rates were 45% (89/198) and 35% (28/79), respectively.

Indication 2 - social anxiety disorder

approved 1999

Dosing/Administration

• Usual Adult Dose: The recommended initial dosage is 20 mg/day. No clear dose relationship has been demonstrated over a 20 to 60 mg/day dose range.
• Dose Range: Some patients not responding adequately to a 20 mg dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Clinical Trial Results

One fixed dose and two flexible dose placebo-controlled clinical trials of 12 weeks in duration investigated the efficacy of Paxil in social phobia (social anxiety disorder). These studies showed statistically significant differences from placebo in favor of Paxil in terms of mean change from baseline to endpoint on the Liebowitz Social Anxiety Scale and the percentage of therapeutic responders according to the Clinical Global Impression of Improvement. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at week 12 of treatment according to the Clinical Global Impression of Improvement was 28.3% (26/92) in the placebo group, 44.9% (40/89) in the 20 mg/day group, 46.6% (41/88) in the 40 mg/day group, and 42.9% (39/91) in the 60 mg/day group. In the two flexible dose (20-50 mg/day) studies, placebo response rates according to this criterion were 23.9% (22/92) and 32.4% (47/145), while Paxil response rates were 54.9% (50/91) and 65.7% (90/137), respectively.

Indication 3 - post-traumatic stress disorder

approved 2000 

Dosing/Administration

• Usual Adult Dose: The recommended starting dosage is 20 mg/day.
• Dose Range: Some patients not responding adequately to a 20 mg/day dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Clinical Trial Results

The efficacy of Paxil in the treatment of PTSD was demonstrated in two 12 week, multi-center placebo controlled studies (Study 1 and Study 2) in adult patients who met the DSM-IV criteria for PTSD. Study outcome was assessed by (i) the Clinician Administered PTSD Scale Part (CAPS-2) score and (ii) the Clinical Global Impression Global Improvement Item (CGI-I). The CAPS-2 is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of: reexperiencing/intrusion, avoidance/numbing and hyperarousal. The two primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). Study 1 was a 12 week study comparing fixed paroxetine doses of 20 or 40 mg/day to placebo. Paxil 20 mg and 40 mg were demonstrated to be significantly superior to placebo for the CAPS-2 total score, and on proportion of responders on the CGI-I. Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo. Paxil was demonstrated to be significantly superior to placebo for the CAPS-2 total scorer, and on proportion of responders on the CGI-I.

Indication 4 - generalized anxiety disorder

approved 2001

Dosing/Administration

• Usual Adult Dose: The recommended initial dosage is 20 mg/day.
• Dose Range: Some patients not responding adequately to a 20 mg dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Clinical Trial Results

The effectiveness of Paxil in the treatment of Generalized Anxiety Disorder (GAD) (DSM IV) was demonstrated in two 8-week, multi center, placebo-controlled studies. One trial was a flexible dose (20 to 50 mg/day) study while the other was a multiple fixed dose (20 or 40 mg/day) study. In both studies Paxil demonstrated statistically significant superiority over placebo on the primary outcome measure - the Hamilton Rating Scale for Anxiety (HAM-A) total score, and on a number of secondary outcomes including the HAM-A anxiety and tension items, the Clinical Global Impression (CGI) responder criterion and the Sheehan Disability Scale (SDS). An additional 8-week flexible dose study did not demonstrate a significant difference between Paxil (20 to 50 mg/day), and placebo on the primary outcome measure. However, Paxil (20 to 50 mg/day) was more effective than placebo on many secondary study outcomes.

Paxil CR 

Indication 1 - major depressive disorder

approved March 1999

Dosing/Administration

• Usual Initial Dosage: The recommended initial dose is 25 mg/day; however the dose can range from 25 to 62.5 mg/day as seen in the clinical trials demonstrating the effectiveness of Paxil CR in the treatment of depression. As with all drugs effective in the treatment of depression, the full effect may be delayed. Some patients not responding to a 25 mg dose may benefit from dose increases, in 12.5 mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at intervals of at least 1 week.
• Maintenance Therapy: There is no body of evidence available to answer the question of how long a patient should continue to be treated with PAXIL CR for the symptoms of panic and depression. It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Clinical Trial Results

The efficacy of Paxil CR controlled release tablets as a treatment for depression was established in two 12 week, flexible dose, placebo-controlled studies of patients with DSM-IV Major Depressive Disorder. One study included patients in the age range 18-65 years, and a second study included elderly patients, ranging in age from 60-88. In both studies, Paxil CR was shown to be significantly more effective than placebo in treating depression as measured by the following: Hamilton Depression Rating Scale Total Score (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness score. A study of outpatients with recurrent major depressive disorder who had responded to immediate-release paroxetine tablets (HDRS total score < 8) during an initial 8 week open treatment phase and were then randomized to continuation on immediate-release paroxetine tablets or placebo for 1 year demonstrated that a significantly lower proportion of patients treated with Paxil (15%) compared to placebo (39%) met criteria for partial relapse . Criteria for full relapse were met by a significantly lower percentage of Paxil treated patients (12%) compared to placebo treated patients (28%). 

Indication 2- panic disorder

approved February 2002

Dosing/Administration

• Usual Initial Dosage: Patients should be started on 12.5 mg/day. Dose changes should occur in 12.5 mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of Paxil CR. The maximum dosage should not exceed 75 mg/day.
• Maintenance Therapy: Panic disorder is a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patient.

Clinical Trial Results

The effectiveness of Paxil CR in the treatment of panic disorder was evaluated in three 10-week, multi-center, flexible dose studies (Studies 1, 2, and 3) comparing paroxetine controlled release (12.5 to 75 mg daily) to placebo in adult outpatients who had panic disorder (DSM-IV), with or without agoraphobia. These trials were assessed on the basis of their outcomes on three variables: (1) the proportions of patients free of full panic attacks at endpoint; (2) change from baseline to endpoint in the median number of full panic attacks; and (3) change from baseline to endpoint in the median Clinical Global Impression Severity score. For Studies 1 and 2, Paxil CR was consistently superior to placebo on two of these three variables. Study 3 failed to consistently demonstrate a significant difference between Paxil CR and placebo on any of these variables. For all three studies, the mean Paxil CR dose for completers at endpoint was approximately 50 mg/day. 

Indication 3 - the symptomatic treatment of premenstrual dysphoric disorder (PMDD)

approved August 2003

Dosing/Administration

• Usual Initial Dosage: In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective with continuous dosing, or intermittent luteal phase dosing. The recommended dose is 12.5 mg/day limited to the luteal phase of the menstrual cycle, starting 14 days prior to the expected onset of menses, and terminating on the first day of menses. Some patients not responding to a 12.5 mg/day dose may benefit from a dose increase to 25 mg/day. Dose changes should occur at intervals of at least 1 week. Continuous dosing of Paxil CR, administered daily throughout the menstrual cycle may be considered if efficacy with luteal phase dosing is sub-optimal. Dose changes should occur at intervals of at least 1 week.
• Maintenance/Continuation Therapy: The effectiveness of Paxil CR in long-term use, that is, for more than 3 menstrual cycles has not been evaluated in controlled trials. Therefore, the physician who elects to use Paxil CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Clinical Trial Results

The effectiveness of Paxil CR for the treatment for Premenstrual Dysphoric Disorder (PMDD) was assessed in 4 placebo-controlled trials. Patients in these trials met DSM-IV criteria for PMDD. In 3 studies, patients (n=1,030) were treated with Paxil CR 12.5 or 25 mg/day, or placebo, continuously throughout the menstrual cycle for a period of 3 months. In the fourth study, patients (n=366) were treated for the 2 weeks prior to the onset of menses (luteal phase dosing, also known as intermittent dosing) with Paxil CR 12.5 or 25 mg/day, or placebo, for a period of 3 months. The Visual Analogue Scale (VAS)-Mood score which consists of the mean VAS scores for the 4 core PMDD symptoms, irritability, tension, depressed mood and affective lability, was the primary efficacy measure. Paxil CR 25 mg/day as continuous dosing and as luteal phase dosing were significantly more effective than placebo as measured by change from baseline luteal phase VAS-Mood score in all 4 studies. Paxil CR 12.5 mg/day was significantly more effective than placebo as measured by change from baseline luteal phase VAS-Mood score in 2 of the 3 continuous studies and in the one luteal phase study.

Indication 4- social anxiety disorder

approved October 2003

Dosing/Administration

• Usual Initial Dosage: The recommended initial dose is 12.5 mg/day. In the clinical trial demonstrating the effectiveness of Paxil CR in the treatment of social anxiety disorder, patients were dosed in a range of 12.5 to 37.5 mg/day. Some patients not responding to a 12.5 mg dose may benefit from dose increases, in 12.5 mg/day increments, up to a maximum of 37.5 mg/day. Dose changes should occur at intervals of at least 1 week.
• Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with Paxil CR should remain on it. Although the efficacy of Paxil CR beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Clinical Trial Results

The effectiveness of Paxil CR in the treatment of social anxiety disorder was demonstrated in a 12 week, multi-center, double-blind, flexible dose, placebo-controlled study of adult outpatients with a primary diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness of Paxil  CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1) change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and (2) the proportion of responders who scored 1 or 2 (very much improved or much improved) on the Clinical Global Impression (CGI) Global Improvement score. Paxil  CR demonstrated statistically significant superiority over placebo on both the LSAS total score and the CGI Improvement responder criterion. For patients who completed the trial, 64% of patients treated with Paxil  CR compared to 34.7% of patients treated with placebo were CGI Improvement responders.