Quetiapine Fumarate

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)₂^•C₄H₄O₄
CAS Number: 111974-72-2
Brands: Seroquel

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

[Posted 05/02/2007] FDA notified healthcare professionals that the Agency proposed that makers of all antidepressant medications update the existing black box warning on the prescribing information for their products to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment. The proposed labeling changes also state that scientific data did not show this increased risk in adults older than 24 years of age and that adults 65 years of age and older taking antidepressants have a decreased risk of suicidality. The proposed updates apply to the entire category of antidepressants. Individuals currently taking prescribed antidepressant medications should not stop taking them and should notify their healthcare professional if they have concerns. Manufacturers of antidepressant medications will have 30 days to submit their revised product labeling and revised Medication Guides to FDA for review. See the FDA press release for the list of products affected by the proposed antidepressant product labeling changes. For more information visit the FDA website at: , and .

REMS:

FDA approved a REMS for quetiapine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of quetiapine and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

• 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%).^{a 97 98}

  
  


• 
  

  Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{a 97 98}

  
  


• 
  

  Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{a 97 98} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

  
  

Introduction

Atypical or second-generation antipsychotic agent.^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 21 22 23 26 27 28}

Uses for Quetiapine Fumarate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Symptomatic management of schizophrenia.^{1 2 3 4 5 6 18 22 23 26}

Bipolar Disorder

Management (alone or in combination with lithium or divalproex sodium) of acute manic episodes associated with bipolar I disorder.^{1 a}

Quetiapine Fumarate Dosage and Administration

Administration

Oral Administration

Administer orally, generally 2–3 times daily without regard to meals.^{1 25}

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.¹ In all cases, minimize period of overlapping antipsychotic administration.¹

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.¹

Periodically reevaluate need for continuing any existing drug therapy for symptomatic relief of adverse extrapyramidal effects.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as quetiapine fumarate; dosage is expressed in terms of quetiapine.¹

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

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Oral

Initially, 25 mg twice daily.^{1 23}

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.^{1 23}

Make subsequent dosage adjustments at intervals of not less than 2 days, usually in increments or decrements of 25–50 mg twice daily.^{1 20}

Dosages ranging from 150–750 mg daily were effective in clinical trials.^{1 4 5 6 7 8 11 18 22} Dosages >300 mg daily usually do not result in greater efficacy, but dosages of 400–500 mg daily have been required in some patients.¹

Optimum duration of therapy currently not known, but efficacy of maintenance therapy with antipsychotics is well established.^{1 22} 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).^{1 22}

If discontinuance is considered, precautions include slow, gradual dose reduction over many months, more frequent clinician visits, and use of early intervention strategies.²²

Bipolar Disorder

Acute Mania

Oral

Initially, 100 mg daily in 2 divided doses.¹ Increase dosage (in increments of ≤100 mg daily in 2 divided doses) to 400 mg daily on the fourth day of therapy.¹ 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.¹

Majority of patients respond to 400–800 mg daily.¹

Optimum duration not established; efficacy has been demonstrated in two 12-week monotherapy trials and one 3-week adjunct therapy trial.^a If used for extended periods, periodically reevaluate long-term risks and benefits for the individual patient.^{1 a}

Prescribing Limits

Adults

Schizophrenia

Oral

Safety of dosages >800 mg daily not established.¹

Bipolar Disorder

Acute Mania

Oral

Safety of dosages >800 mg daily not established.¹

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.¹

Renal Impairment

No dosage adjustment necessary.¹

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.¹ Adjust dosage with caution.¹

Initially, 25 mg twice daily to minimize risk of orthostatic hypotension and associated syncope.¹ If hypotension occurs during dosage titration, return to previous dosage in titration schedule.¹

Cautions for Quetiapine Fumarate

Contraindications

• 
  

  Known hypersensitivity to quetiapine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.^{a 97 98}

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{a 97 98} (See Boxed Warning and see Geriatric Use under Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, reported rarely.¹

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported infrequently.¹ Consider discontinuance of quetiapine.¹

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents, including quetiapine.^{1 34 35 36 37 38 39 40 41 42 43 44 45 47 60 61 62 63 67 87} 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).^{1 34 35 36 37 38 39 40 41 42 43 44 45} If manifestations of hyperglycemia occur in any patient, test for diabetes mellitus.^{1 34 35 36 37 38 39 40 41 42 43 44 45}

General Precautions

Orthostatic Hypotension

Orthostatic hypotension reported.¹ 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).¹ (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.¹

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).¹

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).¹

Somnolence reported.¹ Potential impairment of judgment, thinking, or motor skills.¹

Endocrine Effects

Hypothyroidism possible.¹

Elevated prolactin concentrations reported with some atypical antipsychotic agents; not observed in clinical trials with quetiapine but reported in animals.¹

Metabolic Effects

Weight gain possible.¹

Increases in cholesterol and triglyceride concentrations possible; weakly related to weight gain.¹

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.¹

Sexual Dysfunction

Priapism possible.¹

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).¹

Suicide

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Attendant risk with psychotic illnesses; closely supervise high-risk patients.¹ Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.¹

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.^{29 30 31}

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.¹

Lactation

Distributed into milk in animals; not known whether distributed into human milk.¹ Women receiving quetiapine should not breast-feed.¹

Pediatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Safety and efficacy not established in children <18 years of age.¹

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.¹ (See Patients at Risk of Orthostatic Hypotension under Dosage and Administration.)

Possible increased risk of death in geriatric patients with dementia-related psychosis.^{a 97 98} 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).^{a 97 98}

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{a 97 98} (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Increased plasma concentrations expected in patients with hepatic impairment; dosage adjustment may be necessary.¹

Renal Impairment

Clearance may be decreased in severe renal impairment, but dosage adjustment not necessary.¹

Common Adverse Effects

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

Interactions for Quetiapine Fumarate

Metabolized principally by CYP3A4.^{1 b} Does not appear to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro; pharmacokinetic interaction with substrates of these isoenzymes unlikely.^{1 b}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4; potential pharmacokinetic interaction (altered quetiapine metabolism).^{1 b}

Specific Drugs

Drug	Interaction	Comments
Alcohol	Potentiation of cognitive and motor effects of alcohol1	Avoid alcohol during therapy with quetiapine1
Antifungals, azole (e.g., fluconazole, itraconazole, ketoconazole)	Substantial decrease in quetiapine clearance with concomitant use of ketoconazole, resulting in increased peak plasma quetiapine concentrations1	Use concomitantly with caution; dosage adjustment of quetiapine may be necessary1
Barbiturates	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Carbamazepine	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Cimetidine	Decreased quetiapine mean clearance1	No dosage adjustment of quetiapine required1
CNS agents	Possible additive CNS effects1	Use with caution1
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 significant1
Dopamine agonists	Antagonistic effects1
Erythromycin	Decreased quetiapine clearance1	Use concomitantly with caution1
Fluoxetine	No effect on quetiapine pharmacokinetics1
Glucocorticoids	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Haloperidol	No effect on quetiapine pharmacokinetics1
Hypotensive agents	Additive hypotensive effects1
Imipramine	No effect on quetiapine pharmacokinetics1
Levodopa	Antagonistic effects1
Lithium	No effect on lithium pharmacokinetics1
Lorazepam	Decreased lorazepam clearance1
Phenytoin	Substantially increased quetiapine clearance1	Increased quetiapine dosage may be required;1 23 caution advised if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate)1
Rifampin	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Risperidone	No effect on quetiapine pharmacokinetics1
Thioridazine	Substantially increased quetiapine clearance1

Quetiapine Fumarate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed after oral administration, with peak plasma concentrations attained within 1.5 hours.^{1 b} Bioavailability of tablet formulation is 100% relative to an oral solution (not commercially available in US).^{1 b}

Food

Bioavailability is marginally affected by food.^{1 b}

Distribution

Extent

Widely distributed throughout the body.¹

Distributed into milk in animals; not known whether distributed into human milk.¹

Plasma Protein Binding

83%.^{1 b}

Elimination

Metabolism

Extensively metabolized to inactive metabolites, principally via CYP3A4.^{1 b}

Elimination Route

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

Half-life

Approximately 6 hours.^{1 b}

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.¹

In patients with severe renal impairment (Cl_cr 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.¹

In geriatric patients, clearance is decreased by about 40% compared with younger patients.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• 
  

  Exact mechanism of antipsychotic action is not known; may involve antagonism at serotonin type 1 (5-hydroxytryptamine [5-HT_1A]),^{1 6 7 15 17} type 2 (5-HT_2A, 5-HT_2C),^{1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 23} and type 6 (5-HT₆) receptors,¹⁷ and at dopamine receptors.^{1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 26 28}

  
  


• 
  

  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).¹

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Risk of orthostatic hypotension, especially during initial dosage titration and at times of re-initiation of therapy or increases in dosage.¹

  
  


• 
  

  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.¹

  
  


• 
  

  Importance of avoiding alcohol during quetiapine therapy.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of avoiding overheating or dehydration.¹

  
  


• 
  

  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).¹

  
  


• 
  

  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.

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

SEROquel 100MG Tablets (ASTRAZENECA): 60/$364.98 or 180/$1,063.93

SEROquel 200MG Tablets (ASTRAZENECA): 60/$683.97 or 180/$2,012.08

SEROquel 25MG Tablets (ASTRAZENECA): 60/$212.09 or 180/$607.90

SEROquel 300MG Tablets (ASTRAZENECA): 60/$902.01 or 180/$2,652.93

SEROquel 400MG Tablets (ASTRAZENECA): 30/$551.01 or 90/$1,506.89

SEROquel 50MG Tablets (ASTRAZENECA): 100/$584.01 or 300/$1,709.97

SEROquel XR 150MG 24-hr Tablets (ASTRAZENECA): 60/$597.99 or 180/$1,685.97

SEROquel XR 200MG 24-hr Tablets (ASTRAZENECA): 60/$673.96 or 180/$1,980.98

SEROquel XR 400MG 24-hr Tablets (ASTRAZENECA): 60/$983.96 or 180/$2,893.85

SEROquel XR 50MG 24-hr Tablets (ASTRAZENECA): 60/$337.99 or 180/$953.01

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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35. Novartis Pharmaceuticals. Clozaril (clozapine) prescribing information. East Hanover, NJ; 2003 Dec.

36. Eli Lilly and Company. Zyprexa (olanzapine) tablets and Zyprexa Zydis (olanzapine) orally disintegrating tablets prescribing information. Indianapolis, IN; 2004 Sep 22.

37. Janssen Pharmaceutica. Risperdal (risperidone) tablets and oral solution prescribing information. Titusville, NJ; 2003 Oct.

38. Pfizer Inc. Geodon (ziprasidone) prescribing information. New York, NY; 2004 Aug.

39. Lewis-Hall F. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Princeton, NJ: Briston-Myers Squibb Company; 2004 Mar 25. From FDA website.

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41. Eli Lilly and Company. Lilly announces FDA notification of class labeling for atypical antipsychotics regarding hyperglycemia and diabetes. Indianapolis, IN; 2003 Sep 17. Press release.

42. Eisenberg P. Dear health care professional letter regarding safety data on Zyprexa (olanzapine) – hyperglycemia and diabetes. Indianapolis, IN: Eli Lilly and Company; 2004 Mar 1. From the FDA website.

43. Macfadden W. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Wilmington, DE: AstraZeneca Pharmaceuticals; 2004 Apr 22. From the FDA website.

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