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Special Alerts
Antipsychotics: Newborn Extrapyramidal and Withdrawal Symptoms with Third Trimester Exposure (Update)
June 2011
The U.S. Food and Drug Administration (FDA) and Health Canada have updated or are in the process of updating the pregnancy sections of their respective prescribing information for antipsychotics to contain detailed information about nonteratogenic effects following maternal use during pregnancy. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms; EPS) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects vary in severity and may be self-limiting (subsiding within hours or days) or require hospitalization. In the cases reported to the FDA, concomitant use of other medications (known to precipitate withdrawal symptoms) may have contributed to the effects, although in some cases, antipsychotic medication use was the only contributing factor for the EPS and withdrawal symptoms.
Women who are taking antipsychotics should not stop them if they become pregnant (abrupt discontinuation is not recommended), but should notify their healthcare provider. Women taking antipsychotics who intend to become pregnant should discuss treatment concerns with their healthcare provider. Any adverse effects noted in newborns should be reported in the U.S. to the FDA's Medwatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm) or in Canada to Health Canada's Canada Vigilance Program (1-866-234-2345 or http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php).
For additional information, please refer to:
U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm#aihp
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_78-eng.php
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(kwe TYE a peen)
Generic Available (U.S.)
Yes: Excludes extended relase tablet
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Seroquel®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089126.pdf
Seroquel XR®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM194582.pdf
REMS Components
Seroquel®, Seroquel XR®: Released from REMS requirement 11/9/2011
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of schizophrenia; treatment of acute manic or mixed episodes associated with bipolar I disorder (as monotherapy or in combination with lithium or divalproex); maintenance treatment of bipolar I disorder (in combination with lithium or divalproex); treatment of acute depressive episodes associated with bipolar disorder; adjunctive treatment of major depressive disorder
Use: Unlabeled
Autism; delirium in the critically-ill patient; psychosis/agitation related to Alzheimer's dementia
Pregnancy Risk Factor
C
Pregnancy Considerations
Quetiapine was embryo and fetal toxic, but not teratogenic in animal reproduction studies. Congenital malformations have not been observed in humans (based on limited data). The long term effects of in utero exposure on infant development and behavior are not known. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy. Healthcare providers are encouraged to enroll women 18-45 years of age exposed to quetiapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388).
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Based on information from 8 mother/infant pairs, concentrations of quetiapine in breast milk have been reported as 0-170 μg/L. The estimated exposure to the breast-feeding infant would be up to 1 mg/kg/day (relative infant dose up to 0.43% based on a weight adjusted maternal dose of 400 mg/day).
Contraindications
There are no contraindications listed in manufacturers labeling.
Canadian labeling: Hypersensitivity to quetiapine or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Dementia: See “Disease-related concerns” below.
•Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• Suicidal thinking/behavior: [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor all patients for clinical worsening, suicidality, or unusual changes in behavior; particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increased or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants (for any indication) should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.
• Anticholinergic effects: May cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Relative to other antipsychotics, quetiapine has a moderate potency of cholinergic blockade.
• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, pre-existing low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1000/mm3.
• Cataracts: Use has been noted to cause cataracts in animals; lens changes have been observed in humans during long-term treatment. Lens examination on initiation of therapy and every 6 months is recommended.
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of aspiration pneumonia (ie, Alzheimer's disease).
• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients.
• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control.
• Hyperlipidemia: Increases in cholesterol and triglycerides have been noted. Use with caution in patients with pre-existing abnormal lipid profile.
• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
• Hypothyroidism: May cause dose-related decreases in thyroid levels, including cases requiring thyroid replacement therapy. Reversal of thyroid effects occurred in almost all cases following discontinuation.
• Neuroleptic malignant syndrome (NMS): Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability. This risk in association with quetiapine is very low relative to other antipsychotics.
• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Priapism: Rare cases of priapism have been reported.
• QT prolongation: Use has been associated with QT prolongation; postmarketing reports have occurred in patients with concomitant illness, quetiapine overdose, or who were receiving concomitant therapy known to affect QT interval or cause electrolyte imbalance. Avoid use in patients at increased risk of torsade de pointes/sudden death (eg, hypokalemia, hypomagnesemia, history of cardiac arrhythmias, congenital prolongation of QT interval, concomitant medications with QTc interval-prolonging properties). Use with caution in patients at increased risk of QT prolongation (eg, cardiovascular disease, heart failure, cardiac hypertrophy, elderly, family history of QT prolongation).
• Sedation: May be sedating; use with caution in disorders where CNS depression is a feature. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with severe cardiac disease, hemodynamic instability, prior myocardial infarction, ischemic heart disease, or hypercholesterolemia.
• Dementia: [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Quetiapine is not approved for the treatment of dementia-related psychosis.
• Hepatic impairment: Use with caution in patients with hepatic disease or impairment; may increase transaminases (primarily ALT; transient, reversible). Substantial hepatic metabolism via CYP3A4; may require dose adjustment.
• Mania/hypomania: May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Quetiapine is FDA approved for the treatment of bipolar depression.
• Parkinson's disease: Use with caution in patients with Parkinson's disease.
• Renal impairment: Use with caution in patients with renal disease; experience is limited.
• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.
• Thyroid disease: Use with caution in patients with thyroid disease.
Dosage form specific issues:
• Patients using immediate release tablets may be switched to extended release tablets at the same total daily dose taken once daily. Dosage adjustments may be necessary based on response and tolerability.
Other warnings/precautions:
• Withdrawal syndrome: Use caution when withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Abrupt cessation may cause (rarely) acute withdrawal symptoms (eg, nausea, vomiting, or insomnia).
Adverse Reactions
Actual frequency may be dependent upon dose and/or indication. Unless otherwise noted, frequency of adverse effects is reported for adult patients; spectrum and incidence of adverse effects similar in children (with significant exceptions noted).
>10%:
Cardiovascular: Diastolic blood pressure increased (children and adolescents, 41%), systolic blood pressure increased (children and adolescents, 15%)
Central nervous system: Somnolence (18% to 57%), headache (7% to 21%), agitation (5% to 20%), dizziness (1% to 18%), fatigue (3% to 14%), extrapyramidal symptoms (1% to 13%)
Endocrine & metabolic: Triglycerides increased (≥200 mg/dL, 8% to 22%), HDL cholesterol decreased (≤40 mg/dL, 6% to 19%), total cholesterol increased (≥240 mg/dL, 7% to 18%), LDL cholesterol increased (≥160 mg/dL, 4% to 17%), hyperglycemia (≥200 mg/dL post glucose challenge or fasting glucose ≥126 mg/dL, 2% to 12%)
Gastrointestinal: Xerostomia (9% to 44%), weight gain (dose related; 3% to 23%), appetite increased (2% to 12%), constipation (6% to 11%)
1% to 10%:
Cardiovascular: Orthostatic hypotension (2% to 7%; children and adolescents <1%), tachycardia (1% to 6%), syncope (<5%), palpitation (4%), peripheral edema (4%), hypotension (3%), hypertension (1% to 2%)
Central nervous system: Insomnia (9%), akathisia (≤8%), pain (1% to 7%), dystonia (≤6%), lethargy (1% to 5%), tardive dyskinesia (<5%), anxiety (2% to 4%), irritability (1% to 4%), parkinsonism (≤4%), abnormal dreams (2% to 3%), depression (1% to 3%), hypersomnia (1% to 3%), abnormal thinking (2%), ataxia (2%), attention disturbance (2%), coordination impaired (2%), disorientation (2%), hypoesthesia (2%), mental impairment (2%), migraine (2%), sluggishness (2%), vertigo (2%), confusion (1% to 2%), restlessness (1% to 2%), fever (1% to 2%), chills (1%)
Dermatologic: Rash (4%), hyperhidrosis (2%)
Endocrine & metabolic: Hyperprolactinemia (4%), libido decreased (≤2%), hypothyroidism (≤2%), female lactation (1%)
Gastrointestinal: Nausea (7% to 8%), abdominal pain (dose related; 4% to 7%), dyspepsia (dose related; 2% to 7%), vomiting (1% to 6%), drooling (<5%), gastroenteritis (2% to 4%), toothache (2% to 3%), appetite decreased (2%), dysphagia (2%), flatulence (2%), GERD (2%), anorexia (≥1%), abnormal taste (1%), abdominal distension (≤1%)
Genitourinary: Pollakiuria (2%), urinary tract infection (2%), impotence (1%)
Hematologic: Neutropenia (≤2%), leukopenia (≥1%), hemorrhage (1%)
Hepatic: Transaminases increased (1% to 6%), GGT increased (1%)
Neuromuscular & skeletal: Weakness (2% to 10%), tremor (2% to 8%), back pain (3% to 5%), dysarthria (1% to 5%), hypertonia (4%), twitching (4%), dyskinesia (≤4%), arthralgia (1% to 4%), paresthesia (3%), muscle spasm (1% to 3%), limb pain (2%), myalgia (2%), neck pain (2%), neck rigidity (1%)
Ocular: Blurred vision (1% to 4%), amblyopia (2% to 3%)
Otic: Ear pain (1% to 2%)
Respiratory: Pharyngitis (4% to 6%), nasal congestion (5%), rhinitis (3% to 4%), upper respiratory tract infection (2% to 3%), sinus congestion (2%), sinus headache (2%), sinusitis (2%), cough (3%), dyspnea (≥1%), dry throat (1%)
Miscellaneous: Diaphoresis (2%), restless legs syndrome (2%), flu-like syndrome (1% to 2%), lymphadenopathy (1%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Acute renal failure, agranulocytosis, alkaline phosphatase increased, amnesia, anaphylactic reaction, anaphylaxis, anemia, angina, asthma, atrial arrhythmia, AV block, bradycardia, bundle branch block, cardiomyopathy, cataract formation, cerebral ischemia, cerebrovascular accident, HF, CPK increased, creatinine increased, dehydration, diabetes mellitus, dysuria, eosinophilia, epistaxis, exfoliative dermatitis, galactorrhea, hallucinations, hematemesis, hypersensitivity, hypoglycemia, hypokalemia, hyponatremia, hypothermia, intestinal obstruction, involuntary movements, leukocytosis, myocarditis, neuroleptic malignant syndrome, nightmares, palpitation, pancreatitis, pneumonia, priapism, QRS duration increased, QT prolongation, rectal bleeding, rhabdomyolysis, seizure, SIADH, sleepwalking, Stevens-Johnson syndrome, ST segment elevation, suicidal ideation, suicide attempt, thrombocytopenia, tinnitus, T-wave abnormal, T-wave inversion, urinary retention
Metabolism/Transport Effects
Substrate of CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Amphetamines: Antipsychotics may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Anti-Parkinson's Agents (Dopamine Agonist): Antipsychotics (Atypical) may diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk D: Consider therapy modification
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Fosphenytoin: May decrease the serum concentration of QUEtiapine. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Indacaterol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Lithium formulations: May enhance the neurotoxic effect of Antipsychotics. Lithium formulations may decrease the serum concentration of Antipsychotics. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Methylphenidate: Antipsychotics may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotics. Risk X: Avoid combination
Metyrosine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Mifepristone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Management: Avoid use of mifepristone for treatment of hyperglycemia in Cushing's syndrome in patients receiving QT interval prolonging agents. Avoid initiation of QT prolonging agents for 2 weeks following mifepristone discontinuation. Risk X: Avoid combination
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of QUEtiapine. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
QTc-Prolonging Agents: QUEtiapine may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
Quinagolide: Antipsychotics may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Serotonin Modulators: Antipsychotics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vemurafenib: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Vemurafenib. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: In healthy volunteers, administration of quetiapine (immediate release) with food resulted in an increase in the peak serum concentration and AUC by 25% and 15%, respectively, compared to the fasting state. Administration of the extended release formulation with a high-fat meal (~800-1000 calories) resulted in an increase in peak serum concentration by 44% to 52% and AUC by 20% to 22% for the 50 mg and 300 mg tablets; administration with a light meal (≤300 calories) had no significant effect on the Cmax or AUC.
Herb/Nutraceutical: St John's wort may decrease quetiapine levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Store at controlled room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Quetiapine is a dibenzothiazepine atypical antipsychotic. It has been proposed that this drug's antipsychotic activity is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonism. It is an antagonist at multiple neurotransmitter receptors in the brain: Serotonin 5-HT1A and 5-HT2, dopamine D1 and D2, histamine H1, and adrenergic alpha1- and alpha2- receptors; but appears to have no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors. Norquetiapine, an active metabolite, differs from its parent molecule by exhibiting high affinity for muscarinic M1 receptors.
Antagonism at receptors other than dopamine and 5-HT2 with similar receptor affinities may explain some of the other effects of quetiapine. The drug's antagonism of histamine H1-receptors may explain the somnolence observed. The drug's antagonism of adrenergic alpha1-receptors may explain the orthostatic hypotension observed.
Pharmacodynamics/Kinetics
Absorption: Rapidly absorbed following oral administration
Distribution: Vd: 6-14 L/kg
Protein binding, plasma: 83%
Metabolism: Primarily hepatic; via CYP3A4; forms the metabolite N-desalkyl quetiapine (active) and two inactive metabolites
Bioavailability: 100% (relative to oral solution)
Half-life elimination:
Mean: Terminal: Quetiapine: ~6 hours; Extended release: ~7 hours
Metabolite: N-desalkyl quetiapine: 9-12 hours
Time to peak, plasma: Immediate release: 1.5 hours; Extended release: 6 hours
Excretion: Urine (73% as metabolites, <1% of total dose as unchanged drug); feces (20%)
Dosage
Oral:
Children ≥10 years: Note: Total daily doses may also be divided into 3 doses per day.
Bipolar disorder:
Mania: Immediate release tablet: Initial: 25 mg twice daily on day 1; increase to 50 mg twice daily on day 2, further increasing by 100 mg/day each day until a target dose of 400 mg/day is reached on day 5. May increase up to 600 mg/day at increments ≤100 mg/day; however, no additional benefit seen with 600 mg/day. Usual dosage range: 400-600 mg/day.
Maintenance therapy: Immediate release tablet: Continue therapy at lowest dose needed to maintain remission; periodically assess maintenance treatment needs.
Autism (unlabeled use): 100-350 mg/day (1.6-5.2 mg/kg/day) (Martin, 1999)
Adolescents ≥13 years: Note: Total daily doses may also be divided into 3 doses per day: Schizophrenia: Immediate release tablet: Initial: 25 mg twice daily on day 1; increase to 50 mg twice daily on day 2, further increasing by 100 mg/day each day until a target dose of 400 mg/day is reached on day 5. May increase up to 800 mg/day at increments ≤100 mg/day; however, no additional benefit seen with 800 mg/day. Usual dosage range: 400-800 mg/day; periodically assess maintenance treatment needs.
Adults:
Bipolar disorder:
Depression:
Immediate release tablet: Initial: 50 mg once daily the first day; increase to 100 mg once daily on day 2, further increasing by 100 mg/day each day until a target dose of 300 mg once daily is reached by day 4. Further increases up to 600 mg once daily by day 8 have been evaluated in clinical trials, but no additional antidepressant efficacy was noted.
Extended release tablet: Initial: 50 mg/day the first day; increase to 100 mg on day 2, further increasing by 100 mg/day each day until a target dose of 300 mg/day is reached by day 4.
Mania:
Immediate release tablet: Initial: 50 mg twice daily on day 1, increase dose in increments of 100 mg/day to 200 mg twice daily on day 4; may increase to a target dose of 800 mg/day by day 6 at increments ≤200 mg/day. Usual dosage range: 400-800 mg/day.
Extended release tablet: Initial: 300 mg on day 1; increase to 600 mg on day 2 and adjust dose to 400-800 mg once daily on day 3, depending on response and tolerance.
Maintenance therapy: Immediate release tablet: 200-400 mg twice daily with lithium or divalproex; Note: Average time of stabilization was 15 weeks in clinical trials.
Major depressive disorder (adjunct to antidepressants): Extended release tablet: Initial: 50 mg once daily; may be increased to 150 mg on day 3. Usual dosage range: 150-300 mg/day
Schizophrenia/psychoses:
Immediate release tablet: Initial: 25 mg twice daily; followed by increases in the total daily dose on the second and third day in increments of 25-50 mg divided 2-3 times/day, if tolerated, to a target dose of 300-400 mg/day in 2-3 divided doses by day 4. Make further adjustments as needed at intervals of at least 2 days in adjustments of 25-50 mg divided twice daily. Usual maintenance range: 300-800 mg/day.
Extended release tablet: Initial: 300 mg once daily; increase in increments of up to 300 mg/day (in intervals of ≥1 day). Usual maintenance range: 400-800 mg/day.
Note: Dose reductions should be attempted periodically to establish lowest effective dose in patients with psychosis. Patients being restarted after 1 week of no drug need to be titrated as above.
ICU delirium: Initial: 50 mg twice daily; may increase as necessary on a daily basis in increments of 50 mg twice daily to a maximum dose of 400 mg/day (Devlin, 2010)
Elderly: 40% lower mean oral clearance of quetiapine in adults >65 years of age; higher plasma levels expected and, therefore, dosage adjustment may be needed; elderly patients usually require 50-200 mg/day of immediate release tablets or 50 mg/day of extended release tablets with a slower titration schedule. Increase immediate release dose by 25-50 mg/day or extended release dose by 50 mg/day to effective dose, based on clinical response and tolerability. If initiated with immediate release tablets, patient may transition to extended release formulation (at equivalent total daily dose) when effective dose has been reached. See “Note” in adult dosing.
Psychosis/agitation related to Alzheimer's dementia (unlabeled use): Initial: 12.5-50 mg/day; if necessary, gradually increase as tolerated not to exceed 200-300 mg/day (Rabins, 2007)
Dosing comments in renal insufficiency: 25% lower mean oral clearance of quetiapine than normal subjects; however, plasma concentrations similar to normal subjects receiving the same dose; no dosage adjustment required
Dosing comments in hepatic insufficiency: 30% lower mean oral clearance of quetiapine than normal subjects; higher plasma levels expected in hepatically impaired subjects; dosage adjustment may be needed
Immediate release tablet: Initial: 25 mg/day, increase dose by 25-50 mg/day to effective dose, based on clinical response and tolerability to patient. If initiated with immediate-release formulation, patient may transition to extended-release formulation (at equivalent total daily dose) when effective dose has been reached.
Extended release tablet: Initial: 50 mg/day; increase dose by 50 mg/day to effective dose, based on clinical response and tolerability to patient.
Administration: Oral
Immediate release tablet: May be administered with or without food.
Extended release tablet: Administer without food or with a light meal (≤300 calories), preferably in the evening. Swallow tablet whole; do not break, crush, or chew.
Administration: Other
Nasogastric/enteral tube (unlabeled route): Hold tube feeds for 30 minutes before administration; flush with 25 mL of sterile water. Crush dose using immediate-release formulation, mix in 10 mL water and administer via NG/enteral tube; follow with a 50 mL flush of sterile water (Devlin, 2010).
Monitoring Parameters
Vital signs; fasting lipid profile and fasting blood glucose/Hgb A1c (prior to treatment, at 3 months, then annually); CBC frequently during first few months of therapy in patients with pre-existing low WBC or a history of drug-induced leukopenia/neutropenia; BMI, personal/family history of obesity, waist circumference; mental status, abnormal involuntary movement scale (AIMS). Weight should be assessed prior to treatment, at 4 weeks, 8 weeks, 12 weeks, and then at quarterly intervals. Consider titrating to a different antipsychotic agent for a weight gain ≥5% of the initial weight. Patients should have eyes checked for cataracts every 6 months while on this medication. Observe for new or worsening depression, anxiety, irritability, aggression, or other symptoms of unusual behavior, mood, or suicide ideation (especially at the beginning of therapy or when doses are increased or decreased).
Test Interactions
May interfere with urine detection of methadone (false-positives); may cause false-positive serum TCA screen
Dietary Considerations
Immediate-release tablet may be taken without regard to meals. Extended release tablet should be taken without food or with a light meal (≤300 calories).
Patient Education
It may take 2-3 weeks to achieve desired results. Avoid alcohol. Maintain adequate hydration. If you have diabetes, you may experience increased blood sugars; monitor closely. Avoid overeating and/or dehydration. You may experience excess drowsiness, restlessness, dizziness, urinary retention, or blurred vision; mouth sores, dry mouth, or GI upset; weight gain; constipation; or postural hypotension. Report persistent CNS effects (eg, somnolence, agitation, insomnia), anormal involuntary movements, suicide ideation, severe dizziness, vision changes, respiratory difficulty, muscle stiffness, high fever, or worsening of condition.
Geriatric Considerations
Any changes in disease status in any organ system can result in behavior changes. Evaluation of disease status should be done before initiating psychotropic drug therapy for behavior changes.
Extrapyramidal syndrome symptoms occur less often than with traditional antipsychotics from the phenothiazine and butyrophenone classes. Many elderly patients receive antipsychotic medications for inappropriate nonpsychotic behavior. Before initiating antipsychotic medication, the clinician should investigate any possible reversible cause; any stress or stress from any disease can cause acute “confusion” or worsening of baseline nonpsychotic behavior. Most commonly acute changes in behavior are due to increases in drug dose or addition of new drug to regimen, fluid electrolyte loss, infections, and changes in environment.
In the treatment of agitated, demented elderly patients, authors of meta-analyses of controlled trials of the response to the traditional antipsychotics (eg, phenothiazines, butyrophenones) in controlling agitation, have concluded that the use of neuroleptics results in a response rate of 18%. Clearly neuroleptic therapy for behavior control should be limited with frequent attempts to withdraw the agent given for behavior control. In light of significant risks and adverse effects in the elderly population compared with limited data demonstrating efficacy in the treatment of dementia related psychosis, aggression, and agitation, an extensive risk:benefit analysis should be performed prior to use.
Anesthesia and Critical Care Concerns/Other Considerations
Quetiapine has a very low incidence of extrapyramidal symptoms such as restlessness and abnormal movement, and is at least as effective as conventional antipsychotics. For patients who have been off quetiapine for more than 1 week, dose titration is necessary when restarting the medication.
Delirium in the Critically Ill Patient: The use of quetiapine for the treatment of delirium in the critically ill patient was evaluated in a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study (Devlin, 2010). Thirty-six patients diagnosed with delirium while in the ICU (mostly medical ICU patients) were randomized to receive either an initial dose of quetiapine 50 mg every 12 hours or placebo. Of note, patients in either arm were allowed to receive I.V. haloperidol (1-10 mg) up to every 2 hours as needed to control delirium. The dose of quetiapine was escalated on a daily basis if the patient received more than one dose of haloperidol for breakthrough delirium in the prior 24 hours. Use was discontinued if the delirium subsided, therapy ≥10 days, or the patient was discharged from the ICU. Important exclusions were primary neurologic condition/injury, hepatic encephalopathy, and alcohol withdrawal. The primary outcome, time to first resolution of delirium, was achieved at a faster rate in the patients who received quetiapine compared to those receiving placebo (median: 1 vs. 4.5 days, p=0.001). Patients receiving quetiapine also experienced a reduced duration of delirium (36 vs. 120 hours, p=0.006) and less agitation (Sedation-Agitation Scale [SAS]] score ≥5) (6 vs. 36 hours, p=0.02). The use of I.V. haloperidol was less in the quetiapine group but this was not significantly different between the two groups. Although not statistically significant, the number of patients experiencing somnolence was higher in the quetiapine group. The authors concluded that quetiapine, when added to an as-needed haloperidol regimen, achieves faster delirium resolution, less agitation, and a higher rate of transfer to home or rehabilitation. Future clinical trials with larger numbers of patients are necessary to determine whether or not quetiapine is safe and effective in a more generalized ICU population.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Quetiapine is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Quetiapine is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Quetiapine is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Mental Health: Child/Adolescent Considerations
Metabolic side effects are frequently more severe in children and adolescents compared to adults; therefore, the risk:benefit of using quetiapine in this population must be carefully considered.
Correll CU, Manu P, Olshanskiy V, et al, "Cardiometabolic Risk of Second-Generation Antipsychotic Medications During First-Time Use in Children and Adolescents," JAMA, 2009, 302(16):1765-73.
Kowatch R, "RCT of Atypical Antipsychotics for Bipolar Disorder in Youth Ages 10-17 Years," Current Psych, 2009, 8(11):19-33.
Mental Health: Comment
Quetiapine is an antipsychotic agent of a class often referred to as atypical. It should be noted that the definition of the term “atypical” is not universally agreed upon. Some prefer to describe antipsychotics based on their pharmacological properties. A common feature of all definitions used to describe “atypical” antipsychotics is the lack of significant acute or subacute EPS, at dosages generally associated with antipsychotic actions. Other experts have included definitions of atypicality that include a) failure to increase serum prolactin levels; b) superior efficacy for positive, negative, and cognitive symptoms; and c) lack of evidence of tardive dyskinesia or dystonia following chronic administration.
Clinically, the dosage range for quetiapine is large and depends on what is being targeted. The general dose range for GAD and depression is low (50-300 mg/day), bipolar mania and depression is 300-600 mg/day, while dosages for schizophrenia can range from 300-1200 mg/day.
Tardive dyskinesia (TD) secondary to typical antipsychotics has an estimated incidence of 3% to 5% per year for the first 5 years of treatment. The incidence of TD associated with the atypical antipsychotics is estimated to be 0.5% to 1%. It is not clear if this estimate represents a risk associated with mental illness or to what extent drug therapy can be implicated. Atypical antipsychotics appear less likely to cause tardive dyskinesia than typical antipsychotics (fluphenazine, haloperidol).
Coadministration of two or more antipsychotics does not generally improve clinical response and may increase the potential for adverse effects.
In 2008, the FDA issued a warning regarding increased mortality risk with typical and atypical antipsychotic drugs when used in elderly patients with dementia-related psychosis.
Nursing: Physical Assessment/Monitoring
Assess mental status for depression and suicide ideation and observe for abnormal involuntary movements. Evaluate for cataracts before initiating treatment and every 6 months during chronic treatment. Monitor weight prior to initiating therapy and at least monthly. Consider titrating to a different antipsychotic agent for weight gain ≥5% of initial weight. Initiate at lower doses and taper dosage slowly when discontinuing.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg
SEROquel®: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg
Tablet, extended release, oral:
SEROquel XR®: 50 mg, 150 mg, 200 mg, 300 mg, 400 mg
Pricing: U.S. (www.drugstore.com)
Tablet, 24-hour (SEROquel XR)
50 mg (60): $337.99
150 mg (60): $597.99
200 mg (60): $673.96
300 mg (60): $880.02
400 mg (60): $1022.95
Tablets (SEROquel)
25 mg (60): $212.09
50 mg (100): $625.00
100 mg (60): $396.98
200 mg (60): $715.99
300 mg (60): $969.96
400 mg (30): $575.97
References
American College of Obstetricians and Gynecologists, ACOG Practice Bulletin: Clinical Management Guidelines for Obstetricians-Gynecologists No. 92 April 2008 (Replaces Practice Bulletin Number 87, November 2007), “Use of Psychiatric Medications During Pregnancy and Lactation,” Obstet Gynecol, 2008, 111(4):1001-20.
American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity, “Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes,” Diabetes Care, 2004, 27(2):596-601.
Bauer M, Pretorius HW, Constant EL, et al, “Extended-Release Quetiapine as Adjunct to an Antidepressant in Patients with Major Depressive Disorder: Results of a Randomized, Placebo-Controlled, Double-Blind Study,” J Clin Psychiatry, 2009, 70(4):540-9.
Davis JM, Chen N, and Glick ID, “A Meta-analysis of the Efficacy of Second-Generation Antipsychotics,” Arch Gen Psychiatry, 2003, 60(6):553-64.
DelBello MP, Schwiers ML, Rosenberg HL, et al, “Quetiapine as Adjunctive Treatment for Adolescent Mania,” Poster presented at Fourth International Conference on Bipolar Disorder, Pittsburgh, PA: Jun 14.
Devlin JW, Roberts RJ, Fong JJ, et al, “Efficacy and Safety of Quetiapine in Critically Ill Patients With Delirium: A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Pilot Study,” Crit Care Med, 2010, 38(2):419-27.
Dixon L, Perkins D, and Calmes C, Guideline Watch (September 2009): Practice Guideline for the Treatment of Schizophrenia, Arlington, Va: American Psychiatric Association, 2009. Available at http://www.psychiatryonline.com/content.aspx?aid=501001
Gentile S, "Infant Safety With Antipsychotic Therapy in Breast-Feeding: A Systematic Review," J Clin Psychiatry, 2008, 69(4):666-73.
Gill SS, Bronskill SE, Normand SL, et al, “Antipsychotic Drug Use and Mortality in Older Adults With Dementia,” Ann Intern Med, 2007, 146(11):775-86.
Goldberg RJ, “Managing Psychosis-Related Behavioral Problems in the Elderly,” Consult Pharm, 1997, 12(Suppl C):4-10.
Hendrickson RG and Morocco AP, “Quetiapine Cross-Reactivity Among Three Tricyclic Antidepressant Immunoassays,” Clin Toxicol, 2003, 41(2):105-8.
Martin A, Koenig K, Scahill L, et al, “Open-Label Quetiapine in the Treatment of Children and Adolescents With Autistic Disorder,” J Child Adolesc Psychopharmacol, 1999, 9(2):99-107.
McConville BJ, Arvanitis LA, Thyrum PT, et al, “Pharmacokinetics, Tolerability, and Clinical Effectiveness of Quetiapine Fumarate: An Open-Label Trial in Adolescents With Psychotic Disorders,” J Clin Psychiatry, 2000, 61(4):252-60.
Moore TA, “Schizophrenia Treatment Guidelines in the United States,” Clin Schizophr Relat Psychoses, 2011, 5(1):40-9.
National Institute for Health and Clinical Excellence (NICE), National Collaborating Centre for Mental Health , “Schizophrenia. Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care (Updated),” National Clinical Practice Guideline Number 82, 2009:1-399. Available at www.nice.org.uk/cg082
Rabins PV, Blacker D, Rovner BW, et al, “Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Second Edition,” Am J Psychiatry, 2007, 164(12 Suppl):5-56.
Schneeweiss S, Setoguchi S, Brookhart A, et al, “Risk of Death Associated With the Use of Conventional Versus Atypical Antipsychotic Drugs Among Elderly Patients,” CMAJ, 2007, 176(5): 627-32.
Schneider LS, Tariot PN, Dagerman KS, et al, “Effectiveness of Atypical Antipsychotic Drugs in Patients With Alzheimer's Disease,” N Engl J Med, 2006, 355(15):1525-38.
Shaw JA, Lewis JE, Pascal S, et al, “An Open Trial of Quetiapine in Adolescents With a Diagnosis of a Psychotic Disorder” [poster NCDEU 41st Annual Meeting, Phoenix, AZ: May 28.
Suppes T, Dennehy EB, Hirschfeld RMA, et al, “The Texas Implementation of Medication Algorithms: Update to the Algorithms for the Treatment of Bipolar I Disorder,” J Clin Psychiatry, 2005, 66(7):870-86.
Widschwendter CG, Zernig G, and Hofer A, “Quetiapine Cross Reactivity with Urine Methadone Immunoassays,” Am J Psychiatry, 2007, 164(1):172.
Yonkers KA, Wisner KL, Stewart DE, et al, “The Management of Depression During Pregnancy: A Report From the American Psychiatric Association and the American College of Obstetricians and Gynecologists,” Obstet Gynecol, 2009, 114(3):703-13.
International Brand Names
Lexi-Comp.com
Last full review/revision April 2012
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