Quetiapine fumarate is an atypical antipsychotic agent.1, 113
Quetiapine fumarate conventional (immediate-release) tablets (Seroquel®) are used orally for the treatment of schizophrenia in adults and pediatric patients 13-17 years of age, for the acute treatment of manic episodes associated with bipolar I disorder (as monotherapy and as an adjunct to lithium or divalproex) in adults and pediatric patients 10-17 years of age, for the acute treatment of depressive episodes associated with bipolar disorder (as monotherapy) in adults, and for the maintenance treatment of bipolar I disorder (as an adjunct to lithium or divalproex) in adults.1 Quetiapine fumarate extended-release tablets (Seroquel XR®) are used orally for the acute treatment of schizophrenia in adults and pediatric patients 13-17 years of age, for the acute treatment of manic or mixed episodes associated with bipolar I disorder (as monotherapy and as an adjunct to lithium or divalproex) in adults and pediatric patients 10-17 years of age, for the acute treatment of depressive episodes associated with bipolar disorder in adults, for the maintenance treatment of bipolar I disorder (as an adjunct to lithium or divalproex) in adults, and for the treatment of major depressive disorder (as adjunctive therapy to antidepressants) in adults.113
Pediatric schizophrenia and bipolar I disorder are serious mental disorders, but diagnosis can be challenging.1, 113 For pediatric patients with schizophrenia, symptom profiles can be variable.1, 113 Pediatric patients with bipolar I disorder may have variable patterns of periodicity of manic or mixed symptoms.1, 113 Medication therapy for pediatric patients with schizophrenia and bipolar disorder should only be initiated after a thorough diagnostic evaluation and careful consideration of risks associated with medication treatment.1, 113 Medication treatment for pediatric patients is indicated as part of a total treatment program that often includes psychological, educational, and social interventions.1, 113
Quetiapine fumarate conventional tablets (Seroquel®) and extended-release tablets (Seroquel XR®) are used orally for the treatment of schizophrenia in adults and pediatric patients 13-17 years of age.1, 113
Efficacy of quetiapine fumarate conventional tablets for the management of schizophrenia in adults has been established by placebo-controlled studies of 6 weeks' duration in hospitalized patients with schizophrenia.1, 2, 3, 4, 5, 6, 18, 22, 23, 26, 114 The studies primarily used the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) scale to assess the effects of drug treatment in schizophrenia.1, 2, 4, 114 In one of the 6-week studies, 361 patients were randomized to receive quetiapine 75, 150, 300, 600, or 750 mg daily, haloperidol 12 mg daily, or placebo.1, 4 Differences in change from baseline to week 6 in BPRS and CGI-Severity of Illness scores were substantially greater in patients who received quetiapine 150, 300, 600, or 750 mg daily versus patients who received placebo.1, 4 In another 6-week study, 286 patients were randomized to receive high doses of quetiapine (up to 750 mg daily), low doses of quetiapine (up to 250 mg daily), or placebo.1, 2 At the end of 6 weeks, only the high dose group of quetiapine (average dose of 500 mg daily) had substantial differences in BPRS and CGI Severity of Illness score compared with placebo.1, 2 In a third 6-week study, 618 patients were randomized to receive quetiapine 50 mg per day (given as 25 mg twice daily), 450 mg per day (given as 225 mg twice daily), or 450 mg per day (given as 150 mg three times daily).1, 114 At the end of this 6-week study, only the group receiving 450 mg per day (given as 225 mg twice daily) had substantial improvements in BPRS and CGI severity scores compared to the quetiapine 50 mg per day group.1, 114
Efficacy of quetiapine fumarate extended-release tablets for the management of schizophrenia in adults has been established by a 6-week, placebo-controlled study of adult inpatients and outpatients with schizophrenia.113, 115 The main efficacy outcome was the change from baseline to the end of week 6 of the Positive and Negative Syndrome Scale (PANSS) total score.113, 115 Adult patients were randomized to receive either quetiapine extended-release 400, 600, or 800 mg once daily in the evening, quetiapine immediate-release 400 mg daily (given as 200 mg twice daily), or placebo.115 All dosages of extended-release quetiapine were superior to placebo in the change in PANSS total score from baseline to week 6.113, 115 Immediate-release quetiapine was also superior to placebo in the PANSS total score change from baseline to week 6 in this study.115
In a longer-term study, adult outpatients with schizophrenia who were clinically stable following 16 weeks of open-label treatment of quetiapine mesylate extended-release capsules were randomized to continue on their current quetiapine mesylate extended-release dosage or to be switched to placebo.113, 123 Clinically stable was defined as receiving a stable dose of quetiapine mesylate extended-release capsules, having a CGI-Severity score ≤4 and a PANSS score ≤60, with no increase of ≥10 points in PANSS total score during the open-label phase.113, 123 The main efficacy outcome was the time from randomization to relapse, defined as hospitalization due to worsening schizophrenia, increase in PANSS score ≥30% from baseline, CGI-Improvement score ≥6, or need for any additional antipsychotic medication.113, 123 Patients who were randomized to continue on quetiapine had a substantially longer time to relapse than patients randomized to placebo.113, 123
The efficacy of quetiapine for the management of schizophrenia in pediatric patients 13-17 years of age was evaluated in a double-blind, placebo-controlled trial of 6 weeks' duration in inpatients or outpatients with schizophrenia.1, 116 The main efficacy measure was change in PANSS total score from baseline to the end of week 6.1, 33, 116 Pediatric patients were randomized to receive quetiapine 400 or 800 mg daily or placebo.1, 113, 116 Both dosages of quetiapine were found to result in substantial reductions of PANSS total score from baseline to week 6 compared with placebo.1, 33, 116 Quetiapine appears to improve both positive23, 26, 27 and negative23, 26, 27 manifestations of schizophrenia.2, 3, 4, 5, 6, 12, 13, 15, 18
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic medication.117 The APA states that, with the possible exception of clozapine, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.117 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).117 Patients whose symptoms improve on an antipsychotic medication should continue treatment with an antipsychotic medication long-term; in most patients, it is appropriate to continue the same antipsychotic medication rather than switch to another antipsychotic medication for maintenance therapy.117
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic medication for acute and maintenance treatment of schizophrenia.118 Choice of antipsychotic medication should be based on patient-specific factors and the adverse effect profiles of the different antipsychotic medications.118 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.118
A practice parameter from the American Academy of Child and Adolescent Psychiatry (AACAP) recommends antipsychotic medication as a primary treatment for schizophrenia spectrum disorders in children and adolescents.119 The AACAP states that most atypical and typical antipsychotic medications, with the exception of clozapine, can be used as primary treatment in early-onset schizophrenia (i.e., onset of schizophrenia before 18 years of age).119 Depot antipsychotics (i.e., IM formulations) have not been studied in pediatric patients.119 Choice of antipsychotic medication in pediatric patients should be individualized based on FDA-labeling, adverse effect profiles, patient and family preferences, cost, and clinician familiarity.119
Quetiapine fumarate is used orally for the acute treatment of manic episodes (immediate-release tablets) or manic or mixed episodes (extended-release tablets) associated with bipolar I disorder, either as monotherapy in adults and pediatric patients 10-17 years of age, or in conjunction with lithium or divalproex sodium in adults.1, 113
Quetiapine fumarate is also used orally as an adjunct to lithium or divalproex for the maintenance treatment of bipolar I disorder in adults.1, 113
Quetiapine fumarate is also used orally as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder in adults.1, 113
Efficacy of quetiapine fumarate monotherapy in the treatment of acute manic episodes in adults has been demonstrated in 2 placebo-controlled studies of 12 weeks' duration in patients who met the DSM-IV criteria for bipolar disorder and who met diagnostic criteria for an acute manic episode (with or without psychotic features).1, 113, 120, 121 Patients with rapid cycling and mixed episodes were excluded from these studies.1, 113, 120, 121 The principal rating instrument used for assessing manic symptoms in these studies was the Young Mania Rating Scale (YMRS) score, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score).1, 113, 120, 121 In these studies, quetiapine was shown to be superior to placebo in reduction of the YMRS total score after 3 and 12 weeks of treatment.1, 113, 120, 121
Efficacy of quetiapine fumarate extended-release tablets as monotherapy for the acute treatment of manic episodes in adults was also established in an additional 3-week, placebo-controlled trial in patients with bipolar I disorder with manic or mixed episodes (with or without psychotic features).113, 122 The main efficacy measure in this study was the change from baseline to week 3 in the YMRS total score.113, 122 Patients were randomized to receive placebo or extended-release quetiapine as monotherapy once daily (300 mg on day 1, 600 mg on day 2, and flexible dosing between 400 and 800 mg daily thereafter).113, 122 From baseline to week 3, patients randomized to receive extended-release quetiapine had substantial reductions in the YMRS total score compared to patients randomized to receive placebo.113, 122 Efficacy of quetiapine fumarate when used in combination with lithium or divalproex sodium in the management of acute manic episodes in adults has been demonstrated in a placebo-controlled study of 3 weeks' duration in patients who met the DSM-IV criteria for bipolar I disorder with acute manic episodes (with or without psychotic features).1, 113 Patients with rapid cycling and mixed episodes were excluded from enrollment and patients included in the study may or may not have received an adequate course of therapy with lithium or divalproex sodium prior to randomization.1, 113 Quetiapine was shown to be superior to placebo when added to lithium or divalproex sodium alone in the reduction of YMRS total score.1, 113 However, in a similarly designed study, quetiapine was associated with an improvement of YMRS scores but did not demonstrate superiority to placebo.1
Efficacy of quetiapine fumarate as monotherapy for the acute treatment of manic episodes associated with bipolar I disorder in pediatric patients 10-17 years of age was demonstrated in a placebo-controlled study of 3 weeks' duration in patients who met the DSM-IV criteria for a manic episode associated with bipolar I disorder.1, 113, 124 Patients were randomized to receive quetiapine 400 mg or 600 mg daily or placebo, given in divided doses 2 or 3 times daily.1, 113, 124 From baseline to week 3, patients who received either dosage of quetiapine had substantial reductions of the main efficacy endpoint, YMRS total score, compared to patients who received placebo.1, 113, 124
Efficacy of quetiapine fumarate as an adjunct to lithium or divalproex in the maintenance treatment of bipolar I disorder in adults was established in 2 placebo-controlled trials in patients with bipolar I disorder whose most recent episode was manic, depressed, or mixed, with or without psychotic features.1, 113, 126 The main efficacy outcome of both studies was the time to recurrence of a mood event (manic, mixed, or depressed), defined as YMRS score ≥20 or Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20 at 2 consecutive assessments, medication initiation or hospitalization for a mood episode, or study discontinuation due to a mood event.1, 113, 126 The trials included an open-label phase where patients were required to be stable on immediate-release quetiapine (at divided doses of 400-800 mg daily) plus lithium or divalproex for at least 12 weeks prior to randomization.1, 113, 126 Only patients who achieved clinical stability during the open-label phase qualified for the randomization phase.126 Clinical stability was defined as YMRS and MADRS total scores ≤12, which were assessed at a minimum of 4 consecutive visits during the open-label phase.126 In the randomization phase, clinically stable patients were randomized to either continue quetiapine (given twice daily for a total of 400-800 mg daily) or to switch to placebo; both groups continued treatment with lithium or divalproex.1, 113, 126 In both studies, patients randomized to continue quetiapine had substantial increases in time to recurrence of any mood event compared to patients who received placebo.1, 113, 126
Efficacy of quetiapine fumarate in the treatment of depressive episodes associated with bipolar disorder in adults has been demonstrated in 2 randomized, double-blind, placebo-controlled studies of 8 weeks' duration in patients with bipolar I or II disorder (with or without a rapid cycling course).1, 104, 106 Patients in these studies received fixed daily quetiapine dosages of 300 or 600 mg once daily.1, 104, 106 The principal rating instrument used for assessing depressive symptoms in these studies was the MADRS, a 10-item clinician-rated scale with scores ranging from 0 to 60.1, 104, 106 In both studies, quetiapine was found to be superior to placebo in reduction of MADRS scores at week 8, with improvements in scores evident within one week of treatment.1, 104, 106
Efficacy of extended-release quetiapine fumarate tablets in the treatment of depressive episodes associated with bipolar disorder in adults has also been demonstrated in an additional 8-week, randomized, double-blind, placebo-controlled study.113, 125 Patients with depressive episodes associated with bipolar I or II disorder (with or without rapid cycling) were randomized to receive either extended-release quetiapine 300 mg once daily or placebo.113, 125 From baseline to week 8, patients who received extended-release quetiapine had substantial reductions in MADRS scores, the main efficacy endpoint, compared to patients who received placebo.113, 125
Legacy practice guidelines from APA recommend lithium plus an antipsychotic agent or valproate plus an antipsychotic agent for the first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.33 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to adverse effect profiles.33 Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic agent.33 Atypical antipsychotics are generally preferred over conventional antipsychotics because of their more benign adverse effect profile.33 Following remission of an acute episode, maintenance pharmacologic treatment is recommended; first-line options for maintenance therapy include lithium and valproate.33 The guidelines state that, for patients treated with an antipsychotic agent during the acute episode, the need for ongoing antipsychotic therapy should be reassessed upon entering the maintenance phase; antipsychotics should generally be gradually tapered and discontinued, unless they are required to control persistent psychosis or prevent recurrence.33
Guidelines from the Department of Veterans Affairs and Department of Defense suggest lithium or quetiapine monotherapy for the first-line treatment of acute mania in patients with bipolar disorder.127 If lithium or quetiapine is not selected based on patient preference or characteristics, olanzapine, paliperidone, and risperidone are recommended as alternative treatments.127 If none of these therapies are considered suitable based on patient preference or characteristics, other suggested options include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.127 For patients who experience breakthrough episodes of mania or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic agent (e.g., haloperidol, asenapine, quetiapine, olanzapine, or risperidone) is recommended.127 For prevention of mania recurrence, lithium or quetiapine is recommended; alternatives include olanzapine, paliperidone, or risperidone.127
Aripiprazole, olanzapine, quetiapine, or ziprasidone may also be used in combination with lithium or valproate for prevention of mania recurrence.127 A practice parameter from the AACAP recommends pharmacotherapy as primary treatment for mania in bipolar I disorder in children and adolescents.128 The AACAP states that standard therapy in pediatric patients should be lithium, valproate, and/or atypical antipsychotic agents, based on the adult literature.128 Choice of medication in pediatric patients should be based on evidence for efficacy, phase of illness, presence of confounding symptoms, adverse effect profiles, patient history of response to medication, and patient and family preferences.128
Quetiapine fumarate extended-release tablets (Seroquel XR®) are used as an adjunct to antidepressants for the treatment of major depressive disorder in adults.113
The efficacy of quetiapine fumarate extended-release tablets as an adjunctive treatment in major depressive disorder in adults has been demonstrated in 2 short-term, double-blind, placebo-controlled trials of 6 weeks' duration in adults with major depressive disorder who had an inadequate response to at least one previous antidepressant.113, 129, 130 In both trials, patients were randomized to receive extended-release quetiapine 150 or 300 mg or placebo once daily.113, 129, 130 Patients in both trials initially received extended-release quetiapine at a daily dosage of 50 mg for 2 days, then the dosage was increased to 150 mg daily on day 3.113, 129, 130 The dosage was increased to 300 mg daily for patients randomized to receive 300 mg of extended-release quetiapine daily for the trial.113, 129, 130 All patients were on background therapy of either a selective serotonin-reuptake inhibitor (SSRI; paroxetine, fluoxetine, sertraline, escitalopram, or citalopram), a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI; duloxetine or venlafaxine), bupropion, or amitriptyline.113, 129, 130 For both studies, the primary efficacy endpoint was the mean change in the MADRS total score from baseline to week 6.113, 129, 130 Adjunct extended-release quetiapine at a dosage of 300 mg daily was substantially better than antidepressant therapy alone in reduction of MADRS total score from baseline to week 6 in both trials.113, 129, 130 Adjunct extended-release quetiapine at a dosage of 150 mg daily was substantially better than antidepressant therapy alone in reduction of MADRS total score for one of the two trials.113, 129, 130
Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.131, 132, 133, 134, 135 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.131, 132, 133, 134, 135 In general, antidepressants have shown similar effectiveness; therefore, initial treatment is guided by specific patient- and drug-related factors.131, 132, 133, 134, 135 For patients who do not respond or have an inadequate response to initial treatment with an antidepressant, changing to a different antidepressant or psychotherapy, or augmentation with psychotherapy or another pharmacological agent is suggested.131, 132, 133, 134, 135
The Department of Veterans Affairs and Department of Defense have developed guidelines for the management of major depressive disorder.132 Treatment of 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.132 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, an SSRI, SNRI, trazodone, vilazodone, or vortioxetine is suggested.132 No evidence is available to suggest superiority of one agent over another.132 The guidelines recommend against using esketamine, ketamine, monoamine oxidase inhibitors (MAOIs), nefazodone, or tricyclic antidepressants (TCAs) as initial therapy.132 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 an atypical antipsychotic agent (e.g., aripiprazole, brexpiprazole).132
A guideline from the American College of Physicians (ACP) provides recommendations for nonpharmacologic and pharmacologic regimens for initial and second-line treatments for the acute phase of major depressive disorder.135 For initial pharmacotherapy, ACP recommends the use of a second-generation antidepressant (e.g., SSRIs, SNRIs).135 For patients in the acute phase of moderate to severe major depressive disorder who do not respond to initial treatment with an adequate dosage of a second-generation antidepressant, ACP suggests switching to or augmenting therapy with cognitive behavioral therapy or switching to a different second-generation antidepressant or augmenting with a second pharmacologic treatment.135 Suggested second-line augmentation agents include mirtazapine, bupropion, or buspirone.135
Quetiapine has been used in adults for the management of refractory generalized anxiety disorder†, obsessive-compulsive disorder (OCD)†, and posttraumatic stress disorder† .136, 137, 138, 139
Guidelines from international experts state that quetiapine has been found to be effective as monotherapy for generalized anxiety disorder; however, given concerns about its adverse effect profile (e.g., metabolic changes, potentially arrhythmias), it is not considered a first-line treatment.136
Legacy guidelines from APA for OCD state that first-line pharmacotherapy treatment includes SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).137 If a patient does not respond to one SSRI, they may switch to a different SSRI, switch to clomipramine, augment their current SSRI with an atypical antipsychotic agent, switch to venlafaxine, or switch to mirtazapine.137
A Cochrane review of pharmacological treatments for posttraumatic stress disorder (PTSD) assessed the effects of several classes of medications, including alpha-blockers, anticonvulsants, antihistamines, SSRIs, SNRIs, and atypical antipsychotics for reducing PTSD symptoms in adults.138 This review found evidence of benefit following treatment with quetiapine compared to placebo in reducing total PTSD symptoms on the Clinician Administered PTSD Scale (CAPS), CGI Severity score, and in the reduction of depression symptoms.138 Guidelines from international experts state that quetiapine has been found to be effective in treating PTSD based on a double-blind, randomized, placebo-controlled trial; however, due to a higher rate of adverse effects, it should only be used when standard treatments have failed or have not been tolerated.139 The Department of Veterans Affairs and Department of Defense guidelines for the treatment of PTSD state that there is insufficient evidence to recommend for or against quetiapine for the treatment of PTSD.140
Dispensing and Administration Precautions
Quetiapine fumarate is administered orally.1, 113 Quetiapine conventional (immediate-release) tablets are administered 2<3 times daily without regard to food, while the extended-release tablets should be administered once daily, preferably in the evening, without food or with a light meal (<300 calories).1, 113 Quetiapine extended-release tablets should be swallowed whole, and not split, chewed, or crushed.113
Store quetiapine conventional and extended-release tablets at 25°C; excursions permitted from 15<30°C.1, 113
Dosage of quetiapine fumarate is expressed in terms of quetiapine.1, 113 The dosage may be carefully adjusted upward or downward, if necessary, after initial dosing according to clinical response and tolerability.1, 113
The manufacturer states that if quetiapine therapy is reinitiated after a drug-free period of <1 week, dosage titration is not necessary.1, 113 However, if quetiapine therapy is reinitiated after a drug-free period of >1 week, dosage generally should be titrated as with initial therapy.1, 113
Patients who are receiving quetiapine conventional tablets can be switched to quetiapine extended-release tablets at the equivalent daily dosage given once daily.113 Individual dosage adjustments may be necessary.113
For the acute treatment of schizophrenia in adults, the recommended initial dosage of quetiapine conventional tablets is 25 mg twice daily.1 Dosage should be increased in increments of 25-50 mg 2 or 3 times daily on the second and third day, as tolerated, to a target dosage range of 300-400 mg daily in 2 or 3 divided doses by the fourth day.1 Because steady-state plasma concentrations of quetiapine may not be attained for 1-2 days at a given dosage, subsequent dosage adjustments generally should be made at intervals of not less than 2 days, usually in increments or decrements of 25-50 mg twice daily.1 Effective dosages of quetiapine conventional tablets for the acute management of schizophrenia in clinical trials generally ranged from 150-750 mg daily; the maximum recommended daily dosage is 750 mg.1 For the maintenance treatment of schizophrenia in adults, the recommended target dosage range of the conventional tablets is 400-800 mg daily given in divided doses 2 or 3 times daily; the maximum recommended dosage is 800 mg daily.1 The manufacturer states that efficacy of the conventional tablets has not been systematically evaluated for the maintenance treatment of schizophrenia in controlled clinical trials of longer than 6 weeks' duration.1
The recommended initial dosage of quetiapine extended-release tablets for the treatment of schizophrenia in adults is 300 mg once daily.113 Dosage may be increased in increments of up to 300 mg daily in intervals of at least 1 day to a target dosage range of 400-800 mg daily; the maximum recommended daily dosage is 800 mg.113 For the maintenance treatment of schizophrenia in adults, the recommended target dosage range of the extended-release tablets is 400-800 mg once daily.113
Patients responding to quetiapine therapy should be periodically assessed to determine the need for maintenance therapy and the appropriate dosage for such treatment.1, 113
For the acute management of depressive episodes associated with bipolar disorder, the recommended dosage of quetiapine conventional or extended-release tablets in adults is 50 mg administered once daily at bedtime (conventional tablets) or once daily preferably in the evening (extended-release tablets) on the first day of therapy.1, 113 When using the conventional or extended-release tablets, the dosage of quetiapine should then be increased to 100 mg once daily on the second day of therapy, 200 mg once daily on the third day of therapy, and 300 mg once daily on the fourth day of therapy.1, 113 The target and maximum recommended dosage of quetiapine conventional or extended-release tablets for depressive episodes associated with bipolar disorder is 300 mg daily.1, 113 The manufacturer of quetiapine states that efficacy of the drug has not been systematically evaluated for more than 8 weeks in the management of depressive episodes in patients with bipolar disorder.1, 113 If quetiapine is used for extended periods, the need for continued therapy should be reassessed periodically on an individualized basis.1, 113
For the management of acute mania associated with bipolar I disorder (alone or in conjunction with lithium or divalproex sodium), the recommended initial dosage of quetiapine conventional tablets in adults is 100 mg daily, administered in 2 divided doses.1 The dosage of quetiapine should be increased in increments of 100 mg daily in 2 divided doses to 400 mg daily on the fourth day of therapy.1 Subsequent dosage adjustments up to 800 mg daily by the sixth day of therapy should be made in increments not exceeding 200 mg daily.1 The recommended target dosage of the conventional tablets is 400-800 mg daily, and the maximum recommended dosage is 800 mg daily.1 When quetiapine extended-release tablets are given, the recommended initial dosage is 300 mg once daily.113 The dosage of quetiapine extended-release tablets should be increased to 600 mg once daily on the second day of therapy, and increased on the third day of therapy, if needed, to a target dosage of 400-800 mg once daily; the maximum recommended dosage is 800 mg once daily.113 The manufacturer of quetiapine states that efficacy of the drug has not been systematically evaluated for >12 weeks as monotherapy of acute manic episodes associated with bipolar I disorder or for >3 weeks as combined therapy with divalproex or lithium.1, 113 If quetiapine is used for extended periods, the need for continued therapy should be reassessed periodically on an individualized basis.1, 113
For the maintenance management of bipolar I disorder (in conjunction with lithium or divalproex sodium), the recommended maintenance dosage of quetiapine in adults is 400-800 mg daily (given as either the conventional or immediate-release tablets); the maximum recommended dosage is 800 mg daily.1, 113 Patients responding to quetiapine therapy should be periodically assessed for the appropriate dosage and their need for continued therapy with the drug.1, 113
For the adjunctive treatment of major depressive disorder in combination with antidepressant therapy, the recommended initial dosage of quetiapine extended-release tablets in adults is 50 mg administered once daily at bedtime on the first day of therapy.113 The dosage of quetiapine should be maintained at 50 mg once daily on the second day of therapy, and then increased on the third day of therapy to 150 mg once daily.113 The target dosage of quetiapine for major depressive disorder generally ranges from 150-300 mg once daily, and the maximum recommended dosage is 300 mg once daily.113 Patients responding to quetiapine therapy should be periodically assessed for the appropriate dosage and their need for continued therapy with the drug.113
When used for the treatment of generalized anxiety disorder† in adults, quetiapine daily dosages of 50-300 mg have been used.136
When used for the treatment of obsessive-compulsive disorder (OCD)† in adults, quetiapine dosages of 25-400 mg daily have been used.136, 137
When used for the treatment of posttraumatic stress disorder† in adults, quetiapine dosages of 50-300 mg daily have been used.136, 139
Because the presentation of pediatric schizophrenia and bipolar I disorder can be highly variable, the diagnosis of these pediatric mental disorders can be challenging.1, 113 It is recommended to only initiate medication therapy for pediatric schizophrenia or bipolar I disorder after performing a thorough diagnostic evaluation and considering the risks associated with medication.1, 113 In adolescents with schizophrenia and bipolar I disorder, quetiapine is indicated as an integral component of a comprehensive treatment program that often includes other measures such as psychological, educational, and social interventions.1, 113
For the acute management of schizophrenia in pediatric patients 13-17 years of age, the recommended initial dosage of quetiapine conventional tablets is 25 mg twice daily.1 The dosage of quetiapine conventional tablets should then be increased to 50 mg 2 times daily the second day of therapy, 100 mg 2 times daily on the third day of therapy, 150 mg 2 times daily on the fourth day of therapy, and 200 mg 2 times daily on the fifth day of therapy.1 Dosage thereafter may be adjusted in increments of 100 mg daily, as tolerated, to a target dosage of 400-800 mg daily administered in 2 or 3 divided doses.1 The recommended initial dosage of quetiapine extended-release tablets in pediatric patients 13-17 years of age is 50 mg once daily.113 The dosage of quetiapine extended-release tablets should then be increased to 100 mg once daily on the second day of therapy, 200 mg once daily on the third day of therapy, 300 mg once daily on the fourth day of therapy, and 400 mg once daily on the fifth day of therapy.113 Dosage thereafter may be adjusted, as tolerated, to a target dosage of 400-800 mg once daily (the maximum recommended dosage is 800 mg once daily).113 The manufacturer of quetiapine states that efficacy of the drug has not been systematically evaluated for durations of >6 weeks in the maintenance management of schizophrenia.1, 113 Patients responding to quetiapine therapy should be periodically assessed for their need for continued therapy with the drug.1, 113
For the management of acute mania associated with bipolar I disorder, the recommended initial dosage of quetiapine conventional tablets in pediatric patients 10-17 years of age is 25 mg twice daily.1 The dosage of quetiapine conventional tablets should then be increased to 50 mg 2 times daily on the second day of therapy, 100 mg 2 times daily on the third day of therapy, 150 mg 2 times daily on the fourth day of therapy, and 200 mg 2 times daily on the fifth day of therapy.1 Dosage thereafter may be adjusted in increments of up to 100 mg daily, as tolerated, to a target dosage of 400-600 mg daily in 2 or 3 divided doses (maximum recommended dosage is 600 mg daily).1 The recommended initial dosage of quetiapine extended-release tablets for acute mania associated with bipolar I disorder in pediatric patients 10-17 years of age is 50 mg once daily.113 The dosage of quetiapine extended-release tablets should then be increased to 100 mg once daily on the second day of therapy, 200 mg once daily on the third day of therapy, 300 mg once daily on the fourth day of therapy, and 400 mg once daily on the fifth day of therapy.113 Dosage thereafter may be adjusted, as tolerated, to a target dosage of 400-600 mg once daily (maximum recommended dosage is 600 mg daily).113 The manufacturer states that efficacy of quetiapine has not been systematically evaluated for durations of >3 weeks in the management of acute mania in pediatric patients with bipolar I disorder.1, 113 Patients responding to quetiapine therapy should be periodically assessed for their need for continued therapy with the drug.1, 113
Dosage Modifications for Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
In patients receiving concomitant therapy with potent cytochrome P-450 (CYP) isoenzyme 3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone), the dosage of quetiapine conventional or extended-release tablets should be reduced to one-sixth of the original dosage.1, 113 The quetiapine dosage should be increased by 6-fold when the potent CYP3A4 inhibitor is discontinued.1, 113
In patients receiving chronic (e.g., longer than 7-14 days) therapy with potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, St. John's wort [ Hypericum perforatum ]), the dosage of quetiapine conventional or extended-release tablets should be increased by up to 5-fold of the original dosage.1, 113 Dosage adjustments should be made based on clinical response and tolerability.1, 113 The quetiapine dosage should be returned to the original dosage within 7-14 days when the potent CYP3A4 inducer is discontinued.1, 113
Switching to or Concomitant Use with Other Antipsychotic Agents
The manufacturer states that there are no systematically collected data that specifically address switching from other antipsychotic agents to quetiapine or concerning concomitant use of quetiapine with other antipsychotic agents.1, 113 Although abrupt discontinuance of the previous antipsychotic agent may be acceptable for some patients with schizophrenia, gradual discontinuance may be most appropriate for others.1, 113 In all cases, the period of overlapping antipsychotic administration should be minimized.1, 113 In patients being switched from long-acting (depot) parenteral antipsychotic therapy to oral quetiapine therapy, the first oral dose of quetiapine (conventional or extended-release tablets) should be administered in place of the next scheduled dose of the long-acting preparation.1, 113 The need for continuing existing drugs used for the symptomatic relief of extrapyramidal manifestations should be reevaluated periodically.1, 113
The manufacturer states that because quetiapine is substantially metabolized in the liver and because the pharmacokinetics of quetiapine appear to be altered in patients with hepatic impairment, an initial conventional tablet dosage of 25 mg daily should be used in adults with hepatic impairment.1 The dosage should be increased daily in increments of 25-50 mg daily according to clinical response and tolerability until an effective dosage is reached.1 In patients receiving extended-release tablets, the recommended initial dosage is 50 mg once daily, with subsequent dosage increases of 50 mg daily based on clinical response and tolerability until an effective dosage is reached.113
Although elimination of quetiapine was reduced in patients with severe renal impairment (e.g., creatinine clearance of 10-30 mL/minute), the plasma quetiapine concentrations were similar to those in patients with normal renal function; therefore, the manufacturer states that dosage adjustment is not necessary in such patients.1, 113
Geriatric or debilitated patients and patients predisposed to hypotension or in whom hypotension would pose a risk (e.g., patients with dehydration or hypovolemia, those receiving antihypertensive drugs, patients with known cardiovascular or cerebrovascular disease) should have a slower rate of dosage titration and should receive lower target dosages of quetiapine.1, 113 The risk of orthostatic hypotension can be minimized by limiting the initial dosage of quetiapine conventional tablets to 25 mg twice daily.1 Additionally, dosage of the extended-release tablets should be limited to 50 mg once daily.113 Subsequent dosage adjustments of the conventional or extended-release tablets generally should be made in increments of 50 mg daily.1, 113 If orthostatic hypotension occurs during titration to the target dosage, the manufacturer recommends a return to the previous dosage in the titration schedule.1, 113
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
A boxed warning is included in the prescribing information for quetiapine concerning the increased risk of death in geriatric patients with dementia-related psychosis treated with antipsychotic drugs.1, 113 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed a 1.6- to 1.7-fold increase in mortality among geriatric patients receiving antipsychotic drugs compared with that in patients receiving placebo.1, 113 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1, 113 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1, 113 The manufacturer states that quetiapine is not approved for the treatment of patients with dementia-related psychosis.1, 113
Suicidal Thoughts and Behaviors in Adolescents and Young Adults
A boxed warning is included in the prescribing information for quetiapine regarding the increased risk of suicidal ideation and behavior in children and adolescents taking antidepressants.1, 113 Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric patients with major depressive disorder.1, 113 This risk may persist until clinically important remission occurs with therapy.1, 113 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1, 113 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.1, 113 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1, 113 An increased suicidality risk was not demonstrated with antidepressants compared to placebo in adults >24 years of age and a reduced risk was observed in adults ≥65 years of age.1, 113
All patients being treated with antidepressants for any indication should be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1, 113 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.1, 113
Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.1, 113 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.1, 113 It is recommended that quetiapine be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1, 113
It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.1, 113 Therefore, patients with depressive symptoms should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).1, 113
Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis
An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1, 113 The manufacturer states that quetiapine is not approved for the treatment of patients with dementia-related psychosis.1, 113
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment and monitoring, has been reported in patients receiving antipsychotic agents, including quetiapine.1, 113 Clinical signs and symptoms include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, in addition to possible elevations in creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.1, 113
Metabolic changes associated with atypical antipsychotic agents include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain.1, 113 While metabolic changes have been observed with all drugs in the class, the risk profile varies across agents.1, 113 Metabolic changes due to use of antipsychotic agents should be managed as clinically appropriate.1, 113
Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents, including quetiapine.1, 113 While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies.1, 113
Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics currently are not available.1, 113
The manufacturers of quetiapine state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be periodically monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.1, 113 Any patient who develops manifestations of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.1, 113 In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.1, 113
Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotic agents.1, 113 Appropriate clinical monitoring is recommended during quetiapine therapy, including fasting blood lipid testing at the beginning of therapy and periodically during treatment.1, 113
Weight gain has been observed in patients receiving quetiapine in clinical trials.1, 113 Patients receiving the drug should receive regular monitoring of weight.1, 113 When treating pediatric patients with quetiapine for any indication, weight gain should be assessed against that expected with normal growth.1, 113
Use of antipsychotic agents, including quetiapine, may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements.1, 113
Orthostatic hypotension with associated dizziness, tachycardia, and/or syncope, particularly during the initial dosage titration period, has been reported.1, 113 The risk of orthostatic hypotension and syncope may be minimized by limiting initial dosage.1 Use with caution in patients with known cardiovascular (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities) or cerebrovascular disease and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).1, 113
Quetiapine therapy may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.1, 113 For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.1, 113
Increased Blood Pressure (Children and Adolescents)
During clinical studies in children and adolescents with schizophrenia or bipolar mania of up to 6 weeks duration, systolic blood pressure increases of ≥20 mm Hg occurred in 15.2% of patients receiving quetiapine conventional tablets, while diastolic blood pressure increases of ≥10 mm Hg occurred in 40.6% of patients.1, 113 During an open-label 26-week study, one patient experienced a hypertensive crisis.1, 113
In a clinical study of 8 weeks duration evaluating quetiapine extended-release tablets in children and adolescents with bipolar depression, 6.5% of patients receiving quetiapine extended-release tablets had systolic blood pressure increases of ≥20 mm Hg and 46.7% of patients had diastolic blood pressure increases of ≥10 mmHg.1, 113
Children and adolescents should have their blood pressure measured during quetiapine initiation and periodically during therapy.1, 113
Leukopenia, Neutropenia, and Agranulocytosis
During clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including quetiapine.1, 113 Agranulocytosis also has been reported.1, 113
Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia.1, 113 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their CBC monitored frequently during the first few months of therapy.1, 113 In such patients, quetiapine should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.1, 113
Patients with clinically significant neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.1, 113 In patients with severe neutropenia (absolute neutrophil count [ANC] <1000/mm3), quetiapine should be discontinued and the leukocyte count monitored until recovery occurs.1, 113
The development of cataracts in association with quetiapine was observed in animal studies.1, 113 Lens changes also have been reported in some patients receiving long-term quetiapine therapy, although a causal relationship has not been established.1, 113 Because the possibility of lens changes cannot be excluded, the manufacturer recommends ophthalmologic examination of the lens by methods adequate to detect cataract formation (e.g., slit lamp exam) be performed at the initiation of quetiapine therapy, or shortly thereafter, and at 6-month intervals during chronic quetiapine therapy.1, 113
Persistent increases in the QT interval were not observed in clinical trials with quetiapine therapy; however, the effect of quetiapine on the QT interval has not been thoroughly studied.1, 113 Cases of QT prolongation have been reported as a result of overdose, in patients with concomitant illness, and in patients receiving other drugs known to cause electrolyte imbalance or prolong the QT interval.1, 113
Quetiapine should be avoided in patients receiving concomitant drugs known to prolong the QT interval, such as class IA antiarrhythmics (e.g., quinidine, procainamide) or class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic agents (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or other classes of agents known to prolong the QT interval (e.g., pentamidine, methadone).1, 113
Quetiapine should also be avoided in situations where the risk of torsades de pointes and/or sudden death is increased, including in patients with low potassium or magnesium levels, a history of cardiac arrhythmias such as bradycardia or those concomitantly receiving other drugs that prolong the QTc interval, and in patients with congenital QT-interval prolongation.1, 113
Exercise caution when quetiapine is administered in patients with an increased risk of QT prolongation such as those with cardiovascular disease, a family history of QT prolongation, in geriatric patients, and in patients with congestive heart failure and cardiac hypertrophy.1, 113
Seizures occurred in 0.5% of patients receiving quetiapine conventional tablets and in 0.05% of patients receiving extended-release tablets of the drug in controlled clinical trials.1, 113 Use with caution in patients with a history of seizures or with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer's type, geriatric patients).1, 113
Dose-related decreases in total and free thyroxine (T4) concentrations of approximately 20% were observed in patients receiving quetiapine dosages at the higher end of the therapeutic dosage range during clinical studies.1, 113 These decreases were maximal during the first 6 weeks of therapy and were maintained without adaptation or progression during more chronic therapy.1, 113 Generally, these changes were reversible upon discontinuance of quetiapine, regardless of duration of therapy.1, 113 In patients receiving quetiapine monotherapy, thyroid replacement therapy was necessary in some patients who experienced increases in thyroid stimulating hormone (TSH).1, 113
The mechanism by which quetiapine affects the thyroid axis is not known.1, 113 Measurement of TSH may not be an accurate reflection of the thyroid status, therefore, both TSH and free T4 should be measured in addition to a clinical assessment at baseline and during follow-up.1, 113
Clinically significant increases in prolactin levels occurred in 3.6% of adults receiving quetiapine in clinical trials.1, 113 Increases in prolactin levels (>20 mcg/L in males or >26 mcg/L in females) in children and adolescents occurred in 13.4% of males and 8.7% of females receiving quetiapine.1, 113
Quetiapine, like other drugs that antagonize dopamine D2receptors, can increase prolactin levels and that elevation may persist during chronic administration of the drug.1, 113 Hyperprolactinemia can cause the suppression of hypothalamic gonadotropin releasing hormone (GnRH), resulting in reduced secretion of gonadotropin.1, 113 These effects can inhibit reproductive function in both female and male patients because of impaired gonadal steroidogenesis.1, 113 Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving drugs that increase prolactin levels.1, 113 Chronic hyperprolactinemia associated with hypogonadism can caused decreased bone density in female and male patients.1, 113
If quetiapine therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin dependent in vitro.1, 113 However, published epidemiologic studies have not shown consistent findings of a relationship between hyperprolactinemia and the development of breast cancer.1, 113
Potential for Cognitive and Motor Impairment
Quetiapine can potentially impair judgment, thinking, and motor skills.1, 113 Somnolence is a commonly reported adverse effect of quetiapine (occurring in 18-52% of patients in clinical trials), particularly during the 3-5 day period of initial dosage titration.1, 113
Caution patients about performing activities that require mental alertness, such as operating a motor vehicle or hazardous machinery or until they are reasonably certain that quetiapine does not affect them adversely.1, 113 Somnolence can increase a patient's fall risk.1, 113
Although not reported with quetiapine, disruption of the body's ability to reduce core body temperature has been associated with use of antipsychotic agents.1, 113 The manufacturer recommends appropriate caution when quetiapine is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1, 113
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1, 113 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia.1, 113 Quetiapine should be used with caution in patients at risk for aspiration pneumonia.1, 113
Acute withdrawal symptoms, such as insomnia, nausea, and vomiting, have been reported after abrupt cessation of antipsychotic agents, including quetiapine.1, 113 In short-term, placebo-controlled clinical trials with the extended-release tablets of quetiapine, which included a discontinuation phase that evaluated discontinuation symptoms following abrupt cessation of the drug, 12.1% of the quetiapine-treated patients experienced one or more discontinuation symptoms compared with 6.7% of placebo recipients.1, 113 The incidence of individual adverse reactions (e.g., insomnia, nausea, headache, diarrhea, vomiting, dizziness, irritability) did not exceed 5.3% in any treatment group and the reactions usually resolved after one week following drug discontinuance.1, 113 Gradual dosage reduction is advised when discontinuing the medication.1, 113
The active metabolite of quetiapine, norquetiapine, has moderate to strong affinity for several muscarinic receptors, which contributes to anticholinergic adverse effects when quetiapine is given at therapeutic dosages, taken concomitantly with other anticholinergic medications, or taken in overdose.1, 113 Use quetiapine with caution in patients receiving other medications with anticholinergic effects.1, 113
Constipation was commonly reported in patients receiving quetiapine, and is a risk factor for intestinal obstruction.1, 113 Intestinal obstruction has been reported with quetiapine, including fatal cases in patients receiving multiple concomitant medications that decrease intestinal motility.1, 113
Quetiapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, or constipation.1, 113
A pregnancy exposure registry is available that monitors outcomes in women exposed to atypical antipsychotics, including quetiapine, during pregnancy.1, 113 Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at [Web].1, 113
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1, 113 Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1, 113 Neonates exhibiting such symptoms should be monitored and symptoms managed appropriately.1, 113 The complications have varied in severity; some neonates recovered within hours to days without specific treatment, while others have required prolonged hospitalization.1, 113
Available data from epidemiologic studies of pregnant women exposed to quetiapine have not indicated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1, 113 However, there are risks associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotic agents during pregnancy.1, 113 In animal studies, embryofetal toxicity (e.g., delays in skeletal ossification, carpal/tarsal flexure, decreased fetal weights) and maternal toxicity were reported.1, 113
Quetiapine appears to be distributed into human milk at a relative infant dose of <1% of the maternal weight-adjusted dosage.1, 113 No consistent adverse effects have been reported in infants exposed to quetiapine through maternal breast milk.1, 113 It is not known if quetiapine affects milk production.1, 113 Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for the drug and the potential for adverse effects on the breastfed infant from exposure to quetiapine through the breast milk or from the mother's underlying condition.1, 113
Females and Males of Reproductive Potential
Due to dopamine (D2) receptor antagonism, use of quetiapine can cause increased serum prolactin concentrations, which may lead to reversible decreases in fertility in females of reproductive potential.1, 113
Safety and efficacy of quetiapine have been established in pediatric patients 13-17 years of age with schizophrenia.1, 113 Safety and efficacy of quetiapine for schizophrenia in patients 13-17 years of age have been established in a placebo-controlled study of 6 weeks' duration.1, 113
Safety and efficacy of quetiapine have been established in pediatric patients 10-17 years of age with manic episodes associated with bipolar I disorder.1, 113 Safety and efficacy of quetiapine for the treatment of mania in patients 10-17 years of age with bipolar I disorder have been established in a placebo-controlled study of 3 weeks' duration.1, 113
Safety and efficacy of quetiapine for schizophrenia in pediatric patients <13 years of age are not established.1, 113
Safety and efficacy of quetiapine for bipolar mania in pediatric patients <10 years of age are not established.1, 113
Safety and efficacy of quetiapine have not been established in pediatric patients <18 years of age for the maintenance treatment of bipolar disorder.1, 113 Safety and efficacy of quetiapine have not been established in pediatric patients <18 years of age for the maintenance treatment of schizophrenia.1, 113
Safety and efficacy of quetiapine have not been established in pediatric patients <18 years of age with bipolar depression.1, 113 A controlled study of extended-release quetiapine was conducted in pediatric patients 10-17 years of age with bipolar depression, and efficacy of the drug was not established.1, 113
After adjustment for weight, AUC and peak plasma concentrations of quetiapine are 41% and 39% lower in pediatric patients 10-17 years of age compared to adults; however, pharmacokinetics of the active metabolite norquetiapine were similar.1, 113
Generally, adverse effects observed in clinical studies were similar in children and adolescents compared to adults, except for systolic and diastolic blood pressure increases that were not observed in adults.1, 113 Additionally, orthostatic hypotension occurred less frequently in children (<1%) compared to adults (4-7%).1, 113
Based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants), a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders.1, 113 No suicides occurred in these pediatric trials.1, 113 It is unclear if the risk of suicidality extends to longer-term use (i.e., beyond several months).1, 113
In clinical studies of quetiapine conventional tablets, approximately 7% of 3400 patients were ≥65 years of age.1 In clinical studies of quetiapine extended-release tablets, approximately 68 patients were ≥65 years of age.113 While no substantial differences in safety relative to younger adults were observed, factors that decrease pharmacokinetic clearance, increase the pharmacodynamic response, or cause poorer tolerance (e.g., orthostasis) may be present in geriatric patients.1, 113
Increased plasma concentrations expected in patients with hepatic impairment; dosage adjustment may be necessary.1, 113
Clearance may be decreased in patients with severe renal impairment (creatinine clearance of 10-30 mL/minute), but dosage adjustment is not necessary.1, 113
The most common adverse effects reported in ≥5% of adult patients receiving quetiapine therapy and at a frequency twice that reported among patients receiving placebo in clinical trials include somnolence/sedation, asthenia, lethargy, dizziness, dry mouth, constipation, increased ALT, weight gain, dyspepsia, abdominal pain, postural hypotension, and pharyngitis.1, 113
The most common adverse effects reported in ≥5% of children and adolescents receiving quetiapine therapy and at a frequency twice that reported among patients receiving placebo in clinical trials include somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, and weight gain.1, 113
Drugs Affecting Hepatic Microsomal Enzymes
Potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone): Potential pharmacokinetic interaction (increased quetiapine exposure).1, 113 Dosage of quetiapine should be reduced to one sixth of the original dosage when these drugs are used concomitantly.1, 113 When the potent CYP3A4 inhibitor is discontinued, the quetiapine dosage should be increased by 6-fold.1, 113
Potent inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampin, St. John's wort [ Hypericum perforatum ]): Potential pharmacokinetic interaction (increased quetiapine metabolism and decreased serum quetiapine concentrations).1, 113 Dosage of quetiapine should be increased with chronic (e.g., longer than 7-14 days) use of these drugs.1, 113 Upon discontinuation of the potent inducer, the quetiapine dosage should be returned to the original dosage.1, 113
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP1A2, CYP3A4, CYP2C9, CYP2C19, or CYP2D6: Pharmacokinetic interaction unlikely.1, 113
Drugs that Prolong the QT Interval
Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of drugs known to prolong the QT interval (e.g., quinidine, procainamide, amiodarone, sotalol, and other class 1A and III antiarrhythmics; chlorpromazine, thioridazine, ziprasidone; gatifloxacin, moxifloxacin; pentamidine, methadone).1, 113
Potential pharmacologic interaction (additive CNS effects).1, 113 In a clinical trial in individuals with selected psychotic disorders, quetiapine potentiated the cognitive and motor effects of alcohol.1, 113 Avoid alcoholic beverages during quetiapine therapy.1, 113
Potential pharmacologic interaction (possible disruption of body temperature regulation).1, 113
Concomitant use of quetiapine with other anticholinergic drugs can increase the risk of severe GI adverse reactions related to decreased intestinal motility.1, 113
Use quetiapine with caution in patients concurrently receiving other drugs with anticholinergic activity.1, 113
Concomitant administration of antipyrine (single 1-g dose) and quetiapine (250 mg 3 times daily) did not alter the clearance of antipyrine or urinary recovery of its metabolites.1, 113
Concomitant use of cimetidine (400 mg 3 times daily for 4 days) and quetiapine (150 mg 3 times daily) decreased mean clearance of quetiapine by 20%.1, 113
Concomitant use of divalproex (500 mg twice daily) and quetiapine (150 mg twice daily) decreased peak plasma concentrations and total exposure to free valproic acid (based on AUC) at steady state by 10<12%.1, 113 Maximum plasma quetiapine concentrations were increased by 17%, with no effect on extent of quetiapine absorption or mean clearance.1, 113
Fluoxetine, Haloperidol, Imipramine, Risperidone
No effect on steady-state pharmacokinetics of quetiapine observed.1, 113
Potential pharmacologic interaction (possible potentiation of hypotensive effects); use with caution.1, 113
Concomitant use of ketoconazole (200 mg once daily for 4 days), a potent CYP3A4 inhibitor, and a single 25-mg dose of quetiapine decreased the oral clearance of quetiapine by 84%, resulting in a 6.2-fold increase in exposure to quetiapine.1, 113 When ketoconazole is used concomitantly with quetiapine, the dosage of quetiapine should be reduced to one-sixth of the original dosage.1, 113
Levodopa and Dopamine Agonists
Potential pharmacologic interaction (antagonistic effects).1, 113
Concomitant use of lithium (up to 2400 mg/day given in 2 divided doses) and quetiapine (250 mg 3 times daily) resulted in no effect on steady-state lithium pharmacokinetics.1, 113
Potential pharmacokinetic interaction (decreased clearance of lorazepam).1, 113
Concomitant use of quetiapine (250 mg 3 times daily) and lorazepam (single 2-mg dose) resulted in a 20% decrease in the mean clearance of lorazepam.1, 113
Concomitant use of quetiapine (250 mg 3 times daily) and phenytoin (100 mg 3 times daily) resulted in a 5-fold increase in quetiapine clearance.1, 113 Up to a 5-fold dosage increase of quetiapine may be required to maintain control of schizophrenia symptoms in patients receiving concomitant quetiapine with phenytoin or other potent CYP3A4 inducers.1, 113 The quetiapine dosage should be returned to the original dosage within 7-14 days when the potent CYP3A4 inducer is discontinued.1, 113
Concomitant use of thioridazine (200 mg twice daily) and quetiapine (300 mg twice daily) resulted in a 65% increase in the oral clearance of quetiapine.1, 113
Potential pharmacologic interaction (additive CNS effects).1 Use with caution.1, 113
Smoking does not affect the oral clearance of quetiapine.1, 113
Quetiapine fumarate is a dibenzothiazepine-derivative antipsychotic agent.1, 2, 3, 4, 5, 6, 7, 8, 9, 21, 23, 26, 27, 28, 32 The drug is pharmacologically similar to clozapine,2, 3, 5, 6, 8, 10, 23, 26, 28 but differs pharmacologically from other currently available first-generation (typical) antipsychotic agents (e.g., phenothiazines, butyrophenones).9, 15, 26 Because of these pharmacologic differences, quetiapine is considered an atypical or second-generation antipsychotic agent.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 22, 23, 26, 27, 28
The exact mechanism of quetiapine's action in the treatment of schizophrenia and bipolar disorder has not been fully elucidated but may involve antagonism at dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2]) receptors.1, 113 The active metabolite, norquetiapine, has similar activity at D2 receptors but greater activity at 5-HT2A compared to quetiapine.1, 113
Current evidence suggests that the clinical potency and antipsychotic efficacy of both typical and atypical antipsychotic drugs generally are related to their affinity for and blockade of central dopamine D2 receptors;2, 7, 15, 17, 19 however, antagonism at dopamine D2 receptors does not appear to account fully for the antipsychotic effects of quetiapine.2, 3, 5, 6, 7, 9, 10, 15, 16, 17, 19, 23, 26, 28 Results of in vivo and in vitro studies indicate that quetiapine is a comparatively weak antagonist at dopamine D2 receptors.3, 5, 6, 8, 10, 11, 15, 16, 17, 23, 26, 28, 32 Receptor binding studies show quetiapine is a weak antagonist at D1 receptors.1, 3, 5, 6, 7, 14, 15, 17, 26 Although their role in eliciting the pharmacologic effects of antipsychotic agents remains to be fully elucidated, dopamine D3, D4, and D5 receptors also have been identified;9, 12 quetiapine possesses no affinity for the dopamine D4 receptor.6, 17
The therapeutic effects of antipsychotic drugs are thought to be mediated by dopaminergic blockade in the mesolimbic and mesocortical areas of the CNS, while antidopaminergic effects in the neostriatum appear to be associated with extrapyramidal effects.1, 7, 14 The apparently low incidence of extrapyramidal effects associated with quetiapine therapy26, 27, 28 suggests that the drug is more active in the mesolimbic3, 5, 10, 28 than in the neostriatal dopaminergic system.6, 12, 16 In contrast to typical antipsychotic agents (e.g., chlorpromazine) but like other atypical antipsychotic drugs (e.g., clozapine), quetiapine does not cause sustained elevations in serum prolactin concentrations2, 5, 6, 7, 8, 14, 15, 17, 18, 22, 23, 26, 27, 28 and therefore is unlikely to produce adverse effects such as amenorrhea, galactorrhea, and impotence.2, 5, 6
Quetiapine exhibits α1-11, 23 and α2-adrenergic7, 23 blocking activity;1, 3, 5, 6, 9, 12, 14, 15, 17, 19, 26 blockade of α1-adrenergic receptors may explain the occasional orthostatic hypotension associated with the drug.1, 9 Quetiapine also blocks histamine H1 receptors,3, 5, 11, 17, 19, 23, 26 which may explain the sedative effects associated with the drug.1, 9, 17 Quetiapine possesses little or no affinity for β-adrenergic, γ-aminobutyric acid (GABA), benzodiazepine,1, 3, 7, 15, 17, 23 or muscarinic receptors.1, 3, 5, 6, 8, 9, 12, 15, 17, 23
Following oral administration, quetiapine conventional tablets are rapidly absorbed and reach peak plasma concentrations in 1.5 hours.1 The extended-release tablets reach peak concentrations after 6 hours.113 Although the absorption of the conventional tablets is marginally affected by food, administration of the extended-release tablets with a high-fat (approximately 800-1000 calories) meal produces significant increases in quetiapine exposure.1, 113 In contrast, when the extended-release tablets are taken with a light meal (approximately 300 calories), quetiapine exposure is not significantly affected.113 It is recommended to take the extended-release tablets without food or with a light meal.113 Quetiapine is extensively metabolized in the liver principally via sulfoxidation and oxidation to inactive metabolites.1, 113 In vitro studies suggest that the cytochrome P-450 (CYP) 3A4 isoenzyme is involved in the metabolism of quetiapine to the inactive sulfoxide metabolite and the active metabolite, norquetiapine.1, 113 The mean terminal half-life of quetiapine conventional tablets is about 6 hours.1 The mean terminal half-life of quetiapine extended-release tablets is about 7 hours for quetiapine, and about 12 hours for the active metabolite norquetiapine.113 Following oral administration of a single dose of quetiapine, approximately 73 and 20% of the dose is excreted in urine and feces, respectively; less than 1% of the dose is excreted unchanged.1, 113 Based on in vitro studies, quetiapine and 9 of its metabolites do not appear likely to inhibit CYP isoenzymes 1A2, 3A4, 2C9, 2C19, or 2D6.1, 113 Pharmacokinetics of quetiapine at steady state are similar in children and adolescents 10-17 years of age compared to adults; however, when adjusted for weight, AUC and peak plasma concentrations of quetiapine are 41% and 39% lower in pediatric patients compared to adults.1, 113 The pharmacokinetics of the active metabolite norquetiapine were similar.1, 113
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 | Tablets, film-coated | 25 mg (of quetiapine)* | Quetiapine Fumarate Tablets | |
50 mg (of quetiapine)* | Quetiapine Fumarate Tablets | |||
SEROquel® | AstraZeneca | |||
100 mg (of quetiapine)* | Quetiapine Fumarate Tablets | |||
SEROquel® | AstraZeneca | |||
150 mg (of quetiapine)* | Quetiapine Fumarate Tablets | |||
200 mg (of quetiapine)* | Quetiapine Fumarate Tablets | |||
SEROquel® | AstraZeneca | |||
300 mg (of quetiapine)* | Quetiapine Fumarate Tablets | |||
SEROquel® | AstraZeneca | |||
400 mg (of quetiapine)* | Quetiapine Fumarate Tablets | |||
SEROquel® | AstraZeneca | |||
Tablets, Extended-release | 50 mg (of quetiapine)* | Quetiapine Fumarate Extended-release Tablets | ||
SEROquel XR® | ||||
150 mg (of quetiapine)* | Quetiapine Fumarate Extended-release Tablets | |||
SEROquel XR® | ||||
200 mg (of quetiapine)* | Quetiapine Fumarate Extended-release Tablets | |||
SEROquel XR® | ||||
300 mg (of quetiapine)* | Quetiapine Fumarate Extended-release Tablets | |||
SEROquel XR® | ||||
400 mg (of quetiapine)* | Quetiapine Fumarate Extended-release Tablets | |||
SEROquel XR® |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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