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QUEtiapine

Class: Atypical Antipsychotics
VA Class: CN709
Chemical Name: (E)-2-Butenedioate-2-[2-(4-dibenzo[b,f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol (2:1) (salt)
Molecular Formula: (C21H25N3O2S)2C4H4O4
CAS Number: 111974-72-2
Brands: SEROquel

Medically reviewed by Drugs.com on Mar 22, 2021. Written by ASHP.

Warning

    Increased Mortality in Geriatric Patients
  • Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis receiving atypical antipsychotic agents (e.g., quetiapine, aripiprazole, olanzapine, risperidone) compared with those receiving placebo (2.6%).

  • Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).

  • Atypical antipsychotics are not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

    Suicidality
  • Antidepressants increased risk of suicidal thinking and behavior (suicidality) compared with placebo in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need. (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.

  • Appropriately monitor and closely observe all patients who are started on quetiapine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process. (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Atypical or second-generation antipsychotic agent.

Uses for QUEtiapine

Schizophrenia

Symptomatic management of schizophrenia.

Bipolar Disorder

Management (alone or in combination with lithium or divalproex sodium) of acute manic episodes associated with bipolar I disorder.

QUEtiapine Dosage and Administration

General

  • Monitor 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 Cautions.)

Administration

Oral Administration

Administer orally, generally 2–3 times daily without regard to meals.

When switching from other antipsychotic agents to quetiapine, abrupt discontinuance of previous agent may be acceptable for some patients with schizophrenia, but gradual discontinuance may be appropriate for others. In all cases, minimize period of overlapping antipsychotic administration.

In patients being switched from long-acting (depot) parenteral antipsychotic therapy to oral quetiapine therapy, administer first oral dose in place of next scheduled depot injection of the long-acting preparation.

Periodically reevaluate need for continuing any existing drug therapy for symptomatic relief of adverse extrapyramidal effects.

Dosage

Available as quetiapine fumarate; dosage is expressed in terms of quetiapine.

Reinitiating therapy: In patients previously treated with quetiapine, dosage titration is not necessary if reinitiated after a drug-free period <1 week; if reinitiated after a drug-free period >1 week, generally titrate dosage as with initial therapy.

Adults

Schizophrenia
Oral

Initially, 25 mg twice daily.

Increase dosage 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.

Make subsequent dosage adjustments at intervals of not less than 2 days, usually in increments or decrements of 25–50 mg twice daily.

Dosages ranging from 150–750 mg daily were effective in clinical trials. Dosages >300 mg daily usually do not result in greater efficacy, but dosages of 400–500 mg daily have been required in some patients.

Optimum duration of therapy currently not known, but efficacy of maintenance therapy with antipsychotics is well established. Continue therapy in responsive patients as long as clinically necessary and tolerated but at lowest possible effective dosage; reassess need for continued therapy and optimal dosage periodically (e.g., at least annually).

If discontinuance is considered, precautions include slow, gradual dose reduction over many months, more frequent clinician visits, and use of early intervention strategies.

Bipolar Disorder
Acute Mania
Oral

Initially, 100 mg daily in 2 divided doses. Increase dosage (in increments of ≤100 mg daily in 2 divided doses) to 400 mg daily on the fourth day of therapy. Make subsequent adjustments in increments of ≤200 mg daily to reach a dosage of up to 800 mg daily by the sixth day of therapy.

Majority of patients respond to 400–800 mg daily.

Optimum duration not established; efficacy has been demonstrated in two 12-week monotherapy trials and one 3-week adjunct therapy trial. If used for extended periods, periodically reevaluate long-term risks and benefits for the individual patient.

Prescribing Limits

Adults

Schizophrenia
Oral

Safety of dosages >800 mg daily not established.

Bipolar Disorder
Acute Mania
Oral

Safety of dosages >800 mg daily not established.

Special Populations

Hepatic Impairment

Initially, 25 mg daily; increase dosage by 25–50 mg daily according to clinical response and tolerability until an effective dosage is reached.

Renal Impairment

No dosage adjustment necessary.

Patients at Risk of Orthostatic Hypotension

Consider a slower rate of dosage titration and a lower target dosage in geriatric patients and in patients who are debilitated or have a predisposition to hypotensive reactions. Adjust dosage with caution.

Initially, 25 mg twice daily to minimize risk of orthostatic hypotension and associated syncope. If hypotension occurs during dosage titration, return to previous dosage in titration schedule.

Cautions for QUEtiapine

Contraindications

  • Known hypersensitivity to quetiapine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis. (See Boxed Warning and see Geriatric Use under Cautions.)

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs. (See Boxed Warning and also see Pediatric Use under Cautions.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

Appropriately monitor and closely observe patients receiving quetiapine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality. Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, reported rarely.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported infrequently. Consider discontinuance of quetiapine.

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents, including quetiapine. Closely monitor patients with preexisting diabetes mellitus for worsening of glucose control and perform fasting glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes). If manifestations of hyperglycemia occur in any patient, test for diabetes mellitus.

General Precautions

Orthostatic Hypotension

Orthostatic hypotension reported. Use with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy). (See Patients at Risk of Orthostatic Hypotension under Dosage and Administration.)

Ocular Effects

Possible lenticular changes; ophthalmologic examination of the lens by methods adequate to detect cataract formation (e.g., slit lamp exam) recommended at initiation of therapy, or shortly thereafter, and at 6-month intervals during chronic therapy.

Nervous System Effects

Possible risk of seizures; 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).

Disruption of ability to reduce core body temperature possible; use with caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).

Somnolence reported. Potential impairment of judgment, thinking, or motor skills.

Endocrine Effects

Hypothyroidism possible.

Elevated prolactin concentrations reported with some atypical antipsychotic agents; not observed in clinical trials with quetiapine but reported in animals.

Metabolic Effects

Weight gain possible.

Increases in cholesterol and triglyceride concentrations possible; weakly related to weight gain.

Hepatic Effects

Asymptomatic, transient, and reversible increases in serum transaminases (principally ALT) reported; usually occurred within first 3 weeks and resolved despite continued quetiapine therapy.

Sexual Dysfunction

Priapism possible.

GI Effects

Esophageal dysmotility and aspiration possible; use with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer’s dementia).

Possible Prescribing and Dispensing Precautions

Ensure accuracy of prescription; similarity in spelling of Seroquel (quetiapine) and Serzone (former trade name for nefazodone hydrochloride, an antidepressant agent) may result in errors associated with adverse CNS (e.g., mental status deterioration, hallucination, paranoia, muscle weakness, lethargy, dizziness) and GI (e.g., nausea, vomiting, diarrhea) effects.

Specific Populations

Pregnancy

Category C.

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

Lactation

Distributes into human milk in relatively small amounts. Women receiving quetiapine should not breast-feed.

Pediatric Use

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

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the 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 based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants). However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <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 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 Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

No substantial differences in safety relative to younger adults, but factors that decrease pharmacokinetic clearance, increase the pharmacodynamic response, or cause poorer tolerance or orthostasis may be present. (See Patients at Risk of Orthostatic Hypotension under Dosage and Administration.)

Possible increased risk of death in geriatric patients with dementia-related psychosis. Substantial (1.6- to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) for treatment of behavioral disorders; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis. (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo. (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Hepatic Impairment

Increased plasma concentrations expected in patients with hepatic impairment; dosage adjustment may be necessary.

Renal Impairment

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

Common Adverse Effects

Somnolence, dizziness, dry mouth, constipation, increased ALT, weight gain, dyspepsia.

Interactions for QUEtiapine

Metabolized principally by CYP3A4. Does not appear to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro; pharmacokinetic interaction with substrates of these isoenzymes unlikely.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4; potential pharmacokinetic interaction (altered quetiapine metabolism).

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potentiation of cognitive and motor effects of alcohol

Avoid alcohol during therapy with quetiapine

Antifungals, azole (e.g., fluconazole, itraconazole, ketoconazole)

Substantial decrease in quetiapine clearance with concomitant use of ketoconazole, resulting in increased peak plasma quetiapine concentrations

Use concomitantly with caution; dosage adjustment of quetiapine may be necessary

Barbiturates

Possible increased quetiapine clearance

Increased quetiapine dosage may be required

Carbamazepine

Possible increased quetiapine clearance

Increased quetiapine dosage may be required

Cimetidine

Decreased quetiapine mean clearance

No dosage adjustment of quetiapine required

CNS agents

Possible additive CNS effects

Use with caution

Divalproex sodium

Increased peak plasma quetiapine concentrations, with no effect on extent of absorption or mean quetiapine clearance; decreased peak plasma valproic acid concentrations and extent of absorption, but not significant

Dopamine agonists

Antagonistic effects

Erythromycin

Decreased quetiapine clearance

Use concomitantly with caution

Fluoxetine

No effect on quetiapine pharmacokinetics

Glucocorticoids

Possible increased quetiapine clearance

Increased quetiapine dosage may be required

Haloperidol

No effect on quetiapine pharmacokinetics

Hypotensive agents

Additive hypotensive effects

Imipramine

No effect on quetiapine pharmacokinetics

Levodopa

Antagonistic effects

Lithium

No effect on lithium pharmacokinetics

Lorazepam

Decreased lorazepam clearance

Phenytoin

Substantially increased quetiapine clearance

Increased quetiapine dosage may be required; caution advised if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate)

Rifampin

Possible increased quetiapine clearance

Increased quetiapine dosage may be required

Risperidone

No effect on quetiapine pharmacokinetics

Thioridazine

Substantially increased quetiapine clearance

QUEtiapine Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed after oral administration, with peak plasma concentrations attained within 1.5 hours. Bioavailability of tablet formulation is 100% relative to an oral solution (not commercially available in US).

Food

Bioavailability is marginally affected by food.

Distribution

Extent

Widely distributed throughout the body.

Distributed into milk in relatively small amounts.

Plasma Protein Binding

83%.

Elimination

Metabolism

Extensively metabolized to inactive metabolites, principally via CYP3A4.

Elimination Route

Excreted in urine (73%) and feces (20%), with <1% of the drug excreted unchanged.

Half-life

Approximately 6 hours.

Special Populations

In patients with hepatic impairment, clearance is 30% lower and AUC and peak plasma concentrations are 3 times higher than those of healthy individuals.

In patients with severe renal impairment (Clcr 10–30 mL/minute), clearance may be reduced by 25% compared with healthy individuals; however, plasma concentrations in patients with renal impairment were within the range of those seen in healthy patients.

In geriatric patients, clearance is decreased by about 40% compared with younger patients.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

  • Exact mechanism of antipsychotic action is not known; may involve antagonism at serotonin type 1 (5-hydroxytryptamine [5-HT1A]), type 2 (5-HT2A, 5-HT2C), and type 6 (5-HT6) receptors, and at dopamine receptors.

  • Antagonism at other receptors (e.g., α1-adrenergic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).

Advice to Patients

  • Importance of providing written patient information (medication guide) each time quetiapine is dispensed.

  • Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. Inform patients and caregivers that quetiapine is not approved for treating geriatric patients with dementia-related psychosis.

  • Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.

  • Risk of orthostatic hypotension, especially during initial dosage titration and at times of re-initiation of therapy or increases in dosage.

  • Risk of somnolence and impairment of judgment, thinking, or motor skills; avoid driving, operating machinery, or performing hazardous tasks until effects on the individual are known.

  • Importance of avoiding alcohol during quetiapine therapy.

  • Importance of avoiding overheating or dehydration.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., diabetes mellitus, seizures, dementia).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions). Importance of advising patients not to stop taking quetiapine if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications. Importance of advising patients not to breast-feed during therapy.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

QUEtiapine Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

25 mg (of quetiapine)

SEROquel (with povidone)

AstraZeneca

50 mg (of quetiapine)

SEROquel (with povidone)

AstraZeneca

100 mg (of quetiapine)

SEROquel (with povidone)

AstraZeneca

200 mg (of quetiapine)

SEROquel (with povidone)

AstraZeneca

300 mg (of quetiapine)

SEROquel (with povidone)

AstraZeneca

400 mg (of quetiapine)

SEROquel (with povidone)

AstraZeneca

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 30, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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