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Uses

Psychotic Disorders

Quetiapine fumarate is used for the symptomatic management of psychotic disorders (e.g., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

Schizophrenia

Short-term efficacy of quetiapine for the management of schizophrenia has been established by placebo-controlled studies of 6 weeks' duration principally in hospitalized patients with schizophrenia. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

In clinical studies in patients with schizophrenia, quetiapine was more effective than placebo in reducing the severity of symptoms associated with this disorder. Quetiapine appears to improve both positive and negative manifestations of schizophrenia. Results from comparative clinical studies and meta-analyses suggest that quetiapine is at least as effective as chlorpromazine or haloperidol in reducing positive and negative symptoms of schizophrenia.

The American Psychiatric Association (APA) considers certain atypical antipsychotic agents (i.e., quetiapine, aripiprazole, olanzapine, risperidone, ziprasidone) first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial. The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, 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. Conventional antipsychotic agents may be considered first-line therapy in patients who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, adverse effect profile (including the patient's experience of subjective effects such as dysphoria), and the patient's preference for a specific drug, including route of administration.

Although the efficacy of quetiapine for long-term use has not been established in controlled studies, the manufacturer states that beneficial effects of the drug were maintained for up to 4 years in some patients during an open-label extension study in patients who achieved an initial response to treatment during double-blind clinical studies. If quetiapine is used for extended periods, the need for continued therapy should be reassessed periodically on an individualized basis.(See Dosage and Administration: Dosage.)

For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program,

Bipolar Disorder

Quetiapine is used alone or in conjunction with lithium or divalproex sodium for the management of acute manic episodes associated with bipolar I disorder. Efficacy of quetiapine monotherapy in the treatment of acute manic episodes 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). Patients with rapid cycling and mixed episodes were excluded from these studies. 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). 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.

Efficacy of quetiapine when used in combination with lithium or divalproex sodium in the management of acute manic episodes 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). 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. Quetiapine was shown to be superior to placebo when added to lithium or divalproex sodium alone in the reduction of YMRS total score. However, in a similarly designed study, quetiapine was associated with an improvement of YMRS scores but did not demonstrate superiority to placebo.

For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic (e.g., olanzapine) may be adequate. For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy. For further information on the management of bipolar disorder,

Quetiapine also is used for the treatment of depressive episodes associated with bipolar disorder. Efficacy of quetiapine in the treatment of depressive episodes 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). Patients in these studies received fixed daily quetiapine dosages of 300 or 600 mg once daily. The principal rating instrument used for assessing depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 to 60. 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. In addition, patients receiving 300 mg of quetiapine daily demonstrated significant improvements compared to placebo recipients in overall quality of life and satisfaction related to various areas of functioning.

Dosage and Administration

Administration

Quetiapine fumarate is administered orally. While food reportedly can marginally increase the peak concentration and oral bioavailability of quetiapine, the drug generally can be administered without regard to meals.

Dispensing and Administration Precautions

Because of similarity in spelling between Seroquel (the trade name for quetiapine fumarate) and Serzone (the former trade name for nefazodone hydrochloride, an antidepressant agent; no longer commercially available in the US under this trade name), dispensing errors have been reported to the US Food and Drug Administration (FDA) and the manufacturer of Seroquel (AstraZeneca). According to the medication error reports, the overlapping strengths (100 and 200 mg), dosage forms (tablets), and dosing intervals (twice daily) and the fact that these 2 drugs were stored closely together in pharmacies also were critical in causing these errors. Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Seroquel and Serzone. Although the Serzone brand was discontinued in June 2004, clinicians may continue to refer to nefazodone by the former brand name in prescribing. Some experts recommend that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these agents by spelling both the trade and generic names to prescribers, using computerized name alerts, attaching reminders to drug containers and pharmacy shelves, separating the drugs on pharmacy shelves, counseling patients).(See Dispensing and Administration Precautions under Warnings/Precautions: General Precautions in Cautions.)

Dosage

Dosage of quetiapine fumarate is expressed in terms of quetiapine and must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.

Higher maintenance dosages of quetiapine may be required in patients receiving the antipsychotic drug concomitantly with phenytoin or other hepatic enzyme-inducing agents (e.g., carbamazepine, barbiturates, rifampin, glucocorticoids), and an increase in the maintenance dosage of quetiapine may be required to reestablish efficacy in patients receiving such concomitant therapy.(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes and also Phenytoin.)

Patients receiving quetiapine should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer states that if quetiapine therapy is reinitiated after a drug-free period of less than 1 week, dosage titration is not necessary. However, if quetiapine therapy is reinitiated after a drug-free period exceeding 1 week, dosage generally should be titrated as with initial therapy.

Schizophrenia

For the management of schizophrenia, the recommended initial dosage of quetiapine in adults is 25 mg twice daily. Dosage may be increased in increments of 25-50 mg 2 or 3 times daily on the second or third day, as tolerated, to a target dosage of 300-400 mg daily in 2 or 3 divided doses by the fourth day. 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. Effective dosages of quetiapine in clinical trials generally ranged from 150-750 mg daily. While the manufacturer states that increasing quetiapine dosages beyond 300 mg daily usually does not result in additional therapeutic effect, dosages of 400-500 mg daily apparently have been required in some patients, and a dosage range of 300-800 mg daily has been recommended. Safety of quetiapine in dosages exceeding 800 mg daily has not been established.

The optimum duration of quetiapine therapy currently is not known, but the efficacy of maintenance therapy with antipsychotic agents used in the treatment of schizophrenia is well established. Patients responding to quetiapine therapy should continue to receive the drug as long as clinically necessary and tolerated but at the lowest possible effective dosage, and the need for continued therapy with the drug should be reassessed periodically. The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with remitted first- or multiple-episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.

If antipsychotic therapy is to be discontinued in patients with schizophrenia, precautions should include slow, gradual dose reduction over many months, more frequent clinician visits, and use of early intervention strategies. Patients and their family and caregivers should be advised about early signs of relapse, and clinicians should collaborate with them to develop plans for action should they emerge. The treatment program should be designed to respond quickly to evidence of prodromal symptoms or behaviors or exacerbations of schizophrenic symptoms.

Bipolar Disorder

For the management of depressive episodes associated with bipolar I or II disorder, the recommended dosage of quetiapine in adults is 50 mg administered once daily at bedtime on the first day of therapy. 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. In clinical trials demonstrating clinical efficacy, quetiapine was given in a dosing schedule of 50, 100, 200, and 300 mg once daily on days 1-4, respectively; patients who received 600 mg daily received 400 mg daily on day 5 and 600 mg daily on day 8. Although antidepressant efficacy was demonstrated with quetiapine at dosages of 300 mg daily and 600 mg daily, no additional benefit was seen in the 600-mg daily group.

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 in adults is 100 mg daily, administered in 2 divided doses. The dosage of quetiapine should be increased in increments of up to 100 mg daily in 2 divided doses to 400 mg daily on the fourth day of therapy. Subsequent dosage adjustments up to 800 mg daily by the sixth day of therapy should be made in increments not exceeding 200 mg daily. Data indicate that most patients respond to 400-800 mg daily. The safety of quetiapine dosages exceeding 800 mg daily has not been established.

The APA states that for patients treated with an antipsychotic agent during an acute episode in bipolar disorder, the need for ongoing antipsychotic treatment should be reassessed upon entering the maintenance phase. The APA recommends that antipsychotics be slowly tapered and discontinued unless they are required to control persistent psychosis or provide prophylaxis against recurrence. While maintenance therapy with atypical antipsychotics may be considered, there currently is limited evidence regarding their efficacy in the maintenance phase compared with that of agents such as lithium or valproate. The manufacturer of quetiapine states that efficacy of the drug has not been systematically evaluated for more than 12 weeks as monotherapy of acute manic episodes associated with bipolar I disorder or for more than 3 weeks as combined therapy with divalproex or lithium. In addition, 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 I or II disorder. If quetiapine is used for extended periods, the need for continued therapy should be reassessed periodically on an individualized basis.

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. Although abrupt discontinuance of the previous antipsychotic agent may be acceptable for some patients with schizophrenia, gradual discontinuance may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. In patients being switched from long-acting (depot) parenteral antipsychotic therapy to oral quetiapine therapy, the first oral dose of quetiapine should be administered in place of the next scheduled dose of the long-acting preparation. The need for continuing existing drugs used for the symptomatic relief of extrapyramidal manifestations should be reevaluated periodically.

Special Populations

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 dosage of 25 mg daily should be used in adults with hepatic impairment. The dosage should be increased by 25-50 mg daily according to clinical response and tolerability until an effective dosage is reached.

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.

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. The risk of orthostatic hypotension can be minimized by limiting the initial dosage of quetiapine to 25 mg twice daily. If orthostatic hypotension occurs during titration to the target dosage, the manufacturer recommends a return to the previous dosage in the titration schedule

Cautions

Contraindications

The manufacturer states that there are no known contraindications to quetiapine use.

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Analyses of 17 placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., quetiapine, aripiprazole, olanzapine, risperidone) compared with that in patients receiving placebo. 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. 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. The manufacturer states that quetiapine is not approved for the treatment of dementia-related psychosis.(See Dosage and Administration: Special Populations and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Worsening of Depression and Suicidality Risk

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 (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs with therapy. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. 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. 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. An increased suicidality risk was not demonstrated with antidepressants compared to placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication 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. 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.

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. 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. FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.

Bipolar Disorder

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. Therefore, patients 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). Quetiapine is approved for use in treating bipolar depression in adults.(See Bipolar Disorder under Uses.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including quetiapine.(See Advice to Patients.) For additional information on NMS,

Tardive Dyskinesia

Use of antipsychotic agents, including quetiapine, may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements. For additional information on tardive dyskinesia,

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving all atypical antipsychotic agents, including quetiapine. 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 treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., quetiapine, clozapine, olanzapine, risperidone).

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While some evidence suggests that the risk for diabetes may be greater with some atypical antipsychotics (e.g., clozapine, olanzapine) than with others in the class (e.g., quetiapine, risperidone), available data are conflicting and insufficient to provide reliable estimates of relative risk associated with use of the various atypical antipsychotics.

The manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely 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. Any patient who develops manifestations of hyperglycemia (e.g., polydipsia, polyphagia, polyuria, weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing. 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.

For further information on the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents, .

Sensitivity Reactions

Contact dermatitis, maculopapular rash, and photosensitivity reactions were reported infrequently during clinical trials. Anaphylaxis and Stevens-Johnson syndrome have been reported during postmarketing surveillance.

General Precautions

Cardiovascular Effects

Orthostatic hypotension with associated dizziness, tachycardia, and/or syncope, particularly during the initial dosage titration period, has been reported. The risk of orthostatic hypotension and syncope may be minimized by limiting initial dosage.(See Dosage and Administration: Special Populations.) 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).

Ocular Effects

The development of cataracts in association with quetiapine was observed in animal studies. Lens changes also have been reported in some patients receiving long-term quetiapine therapy, although a causal relationship has not been established. 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.

Nervous System Effects

Seizures occurred in 0.6% of patients receiving quetiapine in controlled clinical trials. 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).

Somnolence occurred in 16-18 or 34% of patients receiving quetiapine as monotherapy (for the treatment of schizophrenia or bipolar disorder) or in conjunction with lithium or divalproex sodium (for the treatment of bipolar disorder), respectively, during clinical studies compared with 4-11% of those receiving placebo.

Endocrine Effects

Dose-related decreases in total and free thyroxine (T4) of approximately 20% were observed in patients receiving quetiapine dosages at the higher end of the therapeutic dosage range during clinical studies. These decreases were maximal during the first 2-4 weeks of therapy and were maintained without adaptation or progression during more chronic therapy. Generally, these changes were not considered clinically important and were reversible upon discontinuance of quetiapine, regardless of duration of therapy. Increases in TSH were observed in about 0.4 or 12% of patients receiving quetiapine alone or in conjunction with lithium or divalproex sodium, respectively. In patients receiving quetiapine monotherapy, thyroid replacement therapy was necessary in some patients who experienced increases in TSH.

Although not observed in patients receiving quetiapine during clinical trials, increases in prolactin concentrations and associated increases in mammary gland neoplasia were reported in animal studies.

Metabolic Effects

During clinical studies, 23 or 21% of patients with schizophrenia or acute mania receiving quetiapine gained at least 7% of their baseline weight compared with 6-7% of those receiving placebo. In patients receiving quetiapine as adjunctive therapy for acute mania, 13% gained at least 7% of their baseline weight compared with 4% of those receiving placebo.

Increases from baseline in cholesterol and triglyceride concentrations of 11 and 17%, respectively, were reported in patients receiving quetiapine compared with slight decreases in patients receiving placebo in clinical studies in patients with schizophrenia. These changes were weakly related to increases in weight observed in patients receiving quetiapine. For additional information on metabolic effects, see Hyperglycemia and Diabetes Mellitus under Warnings/Precautions: Warnings, in Cautions.

Hepatic Effects

Asymptomatic, transient, and reversible increases in serum transaminases, principally ALT, have been reported in patients receiving quetiapine; these changes usually occurred within the first 3 weeks and resolved despite continued quetiapine therapy.

Priapism

Drugs possessing α-adrenergic blocking activity have been reported to cause priapism. One case of drug-induced priapism was reported in clinical studies of quetiapine. Severe priapism may require surgical intervention.

Body Temperature Regulation

Although not reported in clinical studies with quetiapine, disruption of the body's ability to reduce core body temperature has been associated with use of antipsychotic agents. 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).

GI Effects

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents. Use with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer's dementia).

Suicide

Attendant risk with bipolar disorder and psychotic illnesses; closely supervise high-risk patients. In clinical studies in patients with bipolar depression, the incidence of treatment-emergent suicidal ideation or suicide attempt in quetiapine-treated patients was low (1.7-2.6%) and similar to that observed with placebo (2%). Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Dispensing and Administration Precautions

Because of similarity in spelling between Seroquel (the trade name for quetiapine fumarate) and Serzone (the former trade name for nefazodone hydrochloride, an antidepressant agent; no longer commercially available in the US under this trade name), dispensing errors have been reported to the US Food and Drug Administration (FDA) and the manufacturer of Seroquel (AstraZeneca). According to the medication error reports, the overlapping strengths (100 and 200 mg), dosage forms (tablets), and dosing intervals (twice daily) and the fact that these 2 drugs were stored closely together in pharmacies also were critical in causing these errors. These medication errors may be associated with adverse CNS (e.g., mental status deterioration, hallucination, paranoia, muscle weakness, lethargy, dizziness) and GI effects (e.g., nausea, vomiting, diarrhea). As of November 2001, 4 patients had required emergency room visits and 3 patients reportedly had been hospitalized because of dispensing errors involving these 2 agents. One female patient 25 years of age experienced fever and respiratory arrest after mistakenly taking Seroquel for 3 days instead of taking Serzone, and eventually died, although a causal relationship has not been established. FDA also is concerned that several patients unintentionally ingested Serzone or Seroquel for a prolonged period of time before the error was discovered. Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Seroquel and Serzone. Although the Serzone brand was discontinued in June 2004, clinicians may continue to refer to nefazodone by the former brand name in prescribing. Some experts recommend that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these agents by spelling both the trade and generic names to prescribers, using computerized name alerts, attaching reminders to drug containers and pharmacy shelves, separating the drugs on pharmacy shelves, counseling patients).

Patients should be advised to question the dispensing pharmacist regarding any changes in the appearance of their prescription in terms of shape, color, or size of the tablets. Dispensing errors involving Seroquel (quetiapine) and Serzone (nefazodone) should be reported to the manufacturers or directly to the FDA MedWatch program by phone (800-FDA-1088), by fax (800-FDA-0178), by the Internet (http://www.fda.gov/Safety/MedWatch/default.htm), or by mail (FDA Safety Information and Adverse Event Reporting Program, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787).

Specific Populations

Pregnancy

Category C.

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment, while others have required intensive care unit support and prolonged hospitalization.

The effect of quetiapine on labor and delivery is unknown.

Lactation

Quetiapine appears to be distributed into human milk in relatively small amounts. The manufacturer recommends that women receiving quetiapine not breast-feed.

Pediatric Use

Safety and efficacy not established in children younger than 18 years of age.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants). However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

Carefully consider these findings when assessing potential benefits and risks of quetiapine in a child or adolescent for any clinical use.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

In clinical studies, approximately 7% of 3400 patients were 65 years of age or older. 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.(See Dosage and Administration: Special Populations and also see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Hepatic Impairment

Increased plasma concentrations expected in patients with hepatic impairment; dosage adjustment may be necessary.(See Dosage and Administration: Special Populations.)

Renal Impairment

Clearance may be decreased in patients with severe renal impairment, but dosage adjustment is not necessary.

Common Adverse Effects

The most common adverse effects reported in 5% or more of patients receiving quetiapine therapy for schizophrenia or bipolar disorder 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.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., erythromycin, fluconazole, itraconazole, ketoconazole): potential pharmacokinetic interaction (increased serum quetiapine concentrations). Use with caution.

Inducers of CYP3A4 (e.g., barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin): potential pharmacokinetic interaction (increased quetiapine metabolism and decreased serum quetiapine concentrations). Dosage adjustment may be necessary if these drugs are initiated or discontinued in patients receiving quetiapine.(See Drug Interactions: Phenytoin.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, CYP3A4, CYP2C9, CYP2C19, or CYP2D6: pharmacokinetic interaction unlikely.

Alcohol

Potential pharmacologic interaction (additive CNS effects). Avoid alcoholic beverages during quetiapine therapy.

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); use quetiapine with caution in patients concurrently receiving drugs with anticholinergic activity.(See Body Temperature Regulation under Warnings/Precautions: General Precautions, in Cautions.)

Cimetidine

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%. However, dosage adjustment of quetiapine is not necessary.

Divalproex

Potential pharmacokinetic interaction. Increased maximum plasma quetiapine concentrations, with no effect on extent of quetiapine absorption or mean clearance. Decreased maximum plasma valproic acid concentrations and extent of absorption (not clinically important).

Fluoxetine, Haloperidol, Imipramine, Risperidone

No effect on steady-state pharmacokinetics of quetiapine observed.

Hypotensive Agents

Potential pharmacologic interaction (additive hypotensive effects).

Levodopa and Dopamine Agonists

Potential pharmacologic interaction (antagonistic effects).

Lithium

No effect on steady-state lithium pharmacokinetics observed.

Lorazepam

Potential pharmacokinetic interaction (decreased clearance of lorazepam). 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.

Phenytoin

Concomitant use of quetiapine (250 mg 3 times daily) and phenytoin (100 mg 3 times daily) resulted in a fivefold increase in quetiapine clearance. An increase in quetiapine dosage may be required; caution advised if phenytoin is withdrawn and replaced with a noninducer of CYP3A4 (e.g., valproate).

Thioridazine

Potential pharmacokinetic interaction (increased oral clearance of quetiapine).

Other CNS Agents

Potential pharmacologic interaction (additive CNS effects). Use with caution.

Smoking

Smoking does not affect the oral clearance of quetiapine.