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Quetiapine


Pronunciation

 (kwe TYE a peen)


U.S. Brand Names

 Seroquel®


Synonyms

 Quetiapine Fumarate


Generic Available

 No


Canadian Brand Names

 Seroquel®


Use

 Treatment of schizophrenia; treatment of acute manic episodes associated with bipolar disorder (as monotherapy or in combination with lithium or valproate)


Use - Unlabeled/Investigational

 Autism, psychosis (children)


Pregnancy Risk Factor

 C


Lactation

 Excretion in breast milk unknown/not recommended


Contraindications

 Hypersensitivity to quetiapine or any component of the formulation; severe CNS depression; bone marrow suppression; blood dyscrasias; severe hepatic disease, coma


Warnings/Precautions

 Has been noted to cause cataracts in animals, lens examination on initiation of therapy and every 6 months is recommended. May be sedating, use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; prior myocardial infarction or ischemic heart disease; hypercholesterolemia; thyroid disease; predisposition to seizures; subcortical brain damage; hepatic impairment; severe cardiac, renal, or respiratory disease. May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction - life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose). Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of pneumonia (ie, Alzheimer's disease).

May cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other antipsychotics, quetiapine has a moderate potency of cholinergic blockade. The risk of extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome in association with quetiapine is very low relative to other antipsychotics. May cause 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.


Adverse Reactions

>10%:

Central nervous system: Agitation, dizziness, headache, somnolence

Endocrine & metabolic: Cholesterol increased (11%), triglycerides increased (17%)

Gastrointestinal: Weight gain ( 7% body weight, dose related), xerostomia

1% to 10%:

Cardiovascular: Postural hypotension, tachycardia, palpitation, peripheral edema

Central nervous system: Anxiety, fever, pain

Dermatologic: Rash

Gastrointestinal: Abdominal pain (dose related), constipation, dyspepsia (dose related), anorexia, vomiting, gastroenteritis

Hematologic: Leukopenia

Hepatic: AST increased, ALT increased, GGT increased

Neuromuscular & skeletal: Dysarthria, back pain, weakness, tremor, hypertonia, dysarthria

Ocular: Amblyopia

Respiratory: Rhinitis, pharyngitis, cough, dyspnea

Miscellaneous: Diaphoresis, flu-like syndrome

<1% (Limited to important or life-threatening): Abnormal dreams, alkaline phosphatase increased, anemia, appetite increased, bradycardia, diabetes mellitus, epistaxis, hyperglycemia, hyperlipidemia, hypothyroidism, involuntary movements, leukocytosis, photosensitivity, QT prolongation, rash, salivation increased, tardive dyskinesia, vertigo

Postmarketing and/or case reports: Agranulocytosis, anaphylaxis, hyponatremia, rhabdomyolysis, SIADH, Stevens-Johnson syndrome


Drug Interactions

 Substrate of CYP2D6 (minor), 3A4 (major)

Antihypertensives: Concurrent use with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Azole antifungals (fluconazole, itraconazole, ketoconazole): Administration with ketoconazole increases serum concentration of quetiapine by 335%; use with caution.

Cimetidine: May decrease quetiapine's clearance by 20%; increasing serum concentrations.

CNS depressants: Quetiapine may enhance the sedative effects of other CNS depressants; includes antidepressants, benzodiazepines, barbiturates, ethanol, narcotic analgesics, and other sedative agents; monitor for increased effect.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of quetiapine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins. Higher maintenance doses of quetiapine may be required.

CYP3A4 inhibitors: May increase the levels/effects of quetiapine. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Divalproex: Concomitant use of quetiapine and divalproex increased the mean maximum plasma concentration of quetiapine at by 17% at steady state. The mean oral clearance of valproic acid was increased by 11%.

Levodopa: Quetiapine may inhibit the antiparkinsonian effect of levodopa; monitor.

Lorazepam: Metabolism of lorazepam may be reduced by quetiapine; clearance is reduced 20% in the presence of quetiapine; monitor for increased sedative effect.

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Phenytoin: Metabolism/clearance of quetiapine may be increased; fivefold changes have been noted. Higher maintenance doses of quetiapine may be required.

Thioridazine: May increase clearance of quetiapine, decreasing serum concentrations; clearance may be increased by 65%.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may cause excessive impairment in cognition/motor function).

Food: In healthy volunteers, administration of quetiapine with food resulted in an increase in the peak serum concentration and AUC (each by ~15%) compared to the fasting state.

Herb/Nutraceutical: St John's wort may decrease quetiapine levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).


Mechanism of Action

 Mechanism of action of quetiapine (dibenzothiazepine antipsychotic), as with other antipsychotic drugs, is unknown. However, 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.

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 with it. The drug's antagonism of adrenergic alpha1-receptors may explain the orthostatic hypotension observed with it.


Pharmacodynamics/Kinetics

Absorption: Rapidly absorbed following oral administration

Distribution: Vd: 10 ± 4 L/kg; Vdss: ~2 days

Protein binding, plasma: 83%

Metabolism: Primarily hepatic; via CYP3A4; forms two inactive metabolites

Bioavailability: 9% ± 4%; tablet is 100% bioavailable relative to solution

Half-life elimination: Mean: Terminal: ~6 hours

Time to peak, plasma: 1.5 hours

Excretion: Urine (73% as metabolites, <1% as unchanged drug); feces (20%)


Dosage

 Oral:

Children and Adolescents:

Autism (unlabeled use): 100-350 mg/day (1.6-5.2 mg/kg/day)

Psychosis and mania (unlabeled use): Initial: 25 mg twice daily; titrate as necessary to 450 mg/day

Adults:

Schizophrenia/psychoses: Initial: 25 mg twice daily; increase in increments of 25-50 mg 2-3 times/day on the second and third day, if tolerated, to a target dose of 300-400 mg 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 twice daily. Usual maintenance range: 300-800 mg/day

Mania: 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 of 200 mg/day. Usual dosage range: 400-800 mg/day

Note: Dose reductions should be attempted periodically to establish lowest effective dose in patients with psychosis or to establish need to continue treating agitated symptoms in demented older adults. Patients being restarted after 1 week of no drug need to be titrated as above.

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. See "Note" in Adults dosing.

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

Initial: 25 mg/day, increase dose by 25-50 mg/day to effective dose, based on clinical response and tolerability to patient


Monitoring Parameters

 Vital signs; fasting lipid profile and fasting blood glucose/Hgb A1c (prior to treatment, at 3 months, then annually); BMI, personal/family history of obesity, waist circumference; blood pressure; 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.


Dietary Considerations

 May be taken with or without food.


Patient Education

 Use exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results; do not discontinue without consulting prescriber. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. If diabetic, you may experience increased blood sugars. Monitor blood closely. You may experience excess drowsiness, restlessness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); mouth sores or GI upset (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); or postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing). Report persistent CNS effects (eg, somnolence, agitation, insomnia); severe dizziness; vision changes; respiratory difficulty; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.


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.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Child/Adolescent Considerations

 Six children with autistic disorder (mean age: 10.9 years) received 100-350 mg/day (1.6-5.2 mg/kg/day; Martin, 1999). Ten patients with DSM-IV chronic or intermittent psychotic disorders (12.3-15.9 years of age) received quetiapine twice daily starting at 25 mg and reaching 400 mg by day 20. The trial ended on day 23 (McConville, 2000). Thirty manic or mixed bipolar I adolescents (12-18 years of age) received quetiapine 25 mg twice daily with titration to 450 mg/day by day 7 (DelBello, 2001).

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.

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.


Dosage Forms

 Tablet, as fumarate: 25 mg, 100 mg, 200 mg, 300 mg [contains lactose]


References

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.

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.

Goldberg RJ, "Managing Psychosis-Related Behavioral Problems in the Elderly," Consult Pharm , 1997, 12(Suppl C):4-10.

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.

Shaw JA, Lewis JE, Pascal S, et al, "An Open Trial of Quetiapine in Adolescents With a Diagnosis of a Psychotic Disorder," Poster presented at NCDEU 41st Annual Meeting, Phoenix, AZ: May 28.


International Brand Names

 Alzen® (PT); Seroquel® (AR, AT, AU, BE, BR, CA, CH, CO, CZ, DE, DK, EC, ES, FI, GB, HR, HU, ID, IE, IL, IT, MX, NL, NO, NZ, PL, PT, RO, RU, SE, SG, SI, TH, TR, YU, ZA); Zyprexa® (SG)


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