Quetiapine Fumarate

Pronunciation

Pronunciation: kwe-TYE-a-peen FUE-ma-rate
Class: Antipsychotic, Dibenzapine derivative

Trade Names

Seroquel
- Tablets 25 mg
- Tablets 50 mg
- Tablets 100 mg
- Tablets 200 mg
- Tablets 300 mg
- Tablets 400 mg

Seroquel XR
- Tablets, ER 50 mg
- Tablets, ER 150 mg
- Tablets, ER 200 mg
- Tablets, ER 300 mg
- Tablets, ER 400 mg

Pharmacology

Has antipsychotic effects, apparently caused by dopamine- and serotonin-receptor blockade in the CNS.

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Pharmacokinetics

Absorption

Rapid absorption. T max is 1.5 h (immediate-release) and 6 h (ER). Bioavailability is 100%. Food increases the immediate-release C max and AUC by 25% and 15%, respectively. High-fat meal increases the ER C max and AUC by as much as 52% and 22%, respectively; however, a light meal has no effect. Steady-state concentrations are expected within 2 days.

Distribution

Widely distributed throughout the body. Vd is approximately 10 L/kg. It is 83% bound to plasma proteins.

Metabolism

Highly metabolized by the liver via CYP3A4 isoenzyme. Major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to parent acid metabolite; both metabolites are inactive. Active metabolite is N-desalkyl quetiapine.

Elimination

Mainly via hepatic metabolism; less than 1% excreted as unchanged drug. Approximately 73% of dose recovered in urine and 20% in feces. The mean terminal half-life for immediate-release is 6 h, for ER is 7 h, and for N-desalkyl quetiapine is 12 h.

Special Populations

Renal Function Impairment

CrCl 10 to 30 mL/min had 25% lower Cl; dosage adjustment not needed.

Hepatic Function Impairment

30% lower Cl; AUC and C max is 3-fold higher. Dosage adjustments may be needed.

Elderly

Oral Cl reduced 40%. Dosage adjustments may be needed.

Gender

Gender has no effect on the pharmacokinetics of quetiapine.

Race

Race has no effect on the pharmacokinetics of quetiapine.

Smoking

No effect on the oral Cl of quetiapine.

Indications and Usage

Treatment of schizophrenia; treatment of acute manic or mixed episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; treatment of depressive episodes associated with bipolar I disorder; maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex; adjunctive treatment of major depressive disorders (ER only).

Unlabeled Uses

Alcohol dependence; obsessive-compulsive disorder; Tourette syndrome.

Contraindications

None well documented.

Dosage and Administration

Acute Bipolar Mania
Adults Immediate-release

PO 100 mg/day in 2 divided doses on day 1; increase to 400 mg/day on day 4 in increments of up to 100 mg/day in 2 divided doses. Further dosage adjustments of up to 800 mg/day by day 6 should be in increments of no more than 200 mg/day. Usual dosage ranges from 400 to 800 mg/day.

ER

PO 300 mg on day 1 and 600 mg on day 2. Administer dose once daily in the evening. Adjust dose between 400 and 800 mg beginning on day 3, depending on the response and tolerance of the patient.

Children 10 to 17 yr of age Immediate-release

PO 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), 300 mg (day 4) and 400 mg (day 5). After day 5, dose may be adjusted within the dosage range of 400 to 600 mg/day. Dosage adjustments should be in increments of no greater than 100 mg/day.

Depression Associated With Bipolar I Disorder
Adults Immediate-release

PO Start with 50 mg once daily at bedtime. Increase to 100 mg on day 2, 200 mg on day 3, and 300 mg on day 4. If indicated, the dose may be increased to 400 mg on day 5 and 600 mg on day 8.

ER

PO 50 mg (day 1); 100 mg (day 2); 200 mg (day 3); 300 mg (day 4). Administer once daily in the evening.

Maintenance in Bipolar I Disorder
Adults

PO Generally, in the maintenance phase patients are continued on the same dose on which they were stabilized during the dose-stabilization phase.

Major Depressive Disorder, Adjunct Therapy
Adults ER

PO Start with 50 mg once daily in the evening. On day 3, the dosage can be increased to 150 mg once daily. 150 to 300 mg/day was demonstrated to be effective as adjunctive therapy to antidepressants.

Schizophrenia
Adults Immediate-release

PO 25 mg twice daily initially; may increase in increments of 25 to 50 mg 2 or 3 times daily on days 2 and 3 to target range of 300 to 400 mg/day by day 4. Increase dose every 2 days by 25 to 50 mg twice daily as indicated. Therapeutic dosage range is 150 to 750 mg/day. Dosages of more than 800 mg/day have not been evaluated in clinical trials.

ER

PO Start with 300 mg once daily, preferably in the evening. Dose increases can be made at daily intervals in increments of up to 300 mg/day. Titrate within a dosage range of 400 to 800 mg/day, depending on the response and tolerance of the individual patient. Dosages above 800 mg/day have not been evaluated in clinical trials.

Children 13 to 17 yr of age Immediate-release

PO 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), 300 mg (day 4), and 400 mg (day 5). After day 5, dose may be adjusted within the recommended dose range of 400 to 800 mg/day. Dosage adjustments should be in increments of no greater than 100 mg/day.

Elderly/Hepatic Function Impairment
Adults ER

PO Start with 50 mg/day; increase in daily increments of 50 mg/day to an effective dose.

Hepatic Function Impairment
Adults Immediate-release

PO Start with 25 mg/day; increase in daily increments of 25 to 50 mg/day to an effective dose.

General Advice

  • Immediate-release tablets should be taken without regard to meals. Instruct patients to take with food if stomach upset occurs. Administer twice daily; however, may be administered 3 times daily where needed.
  • ER tablets should be swallowed whole and not split, chewed, or crushed. It may be taken without food or with a light meal (approximately 300 calories).
  • When restarting patients who have had an interval of less than 1 wk off quetiapine, resume maintenance dose. If the interval is more than 1 wk, follow initial titration schedule.
  • Schizophrenic patients currently treated with divided doses of the immediate-release formulation may be switched to equivalent total daily doses of the ER formulation taken once daily.
  • When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine therapy in place of the next scheduled injection.
  • Periodically reassess patients to determine the need for maintenance treatment and the appropriate dose for such treatment.
  • Avoid abrupt cessation because acute withdrawal symptoms may occur.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Alcohol, CNS-acting drugs

Possible additive CNS depressant effects; use with caution. Avoid alcohol.

Antihypertensive agents

Hypotensive effects may be enhanced. Use with caution.

Cimetidine

Quetiapine concentrations may be increased slightly; dosage adjustment does not appear to be needed.

Dopamine agonists (eg, pramipexole, ropinirole), levodopa

Quetiapine may antagonize therapeutic effects of dopamine agonists and levodopa. Monitor the response of the patient. If an interaction is suspected, it may be necessary to increase the levodopa or dopamine agonist dose.

Dopamine/Epinephrine

Do not use dopamine, epinephrine, or other sympathomimetics with beta-agonist activity for the treatment of quetiapine-induced hypotension.

Food

A high-fat meal was found to produce statistically significant increases in the quetiapine ER C max and AUC. In comparison, a light meal had no effect on the C max or AUC of quetiapine. It is recommended that quetiapine ER be taken without food or with a light meal.

Inducers of CYP3A (eg, barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin)

May decrease the effects of quetiapine; increased doses of quetiapine may be necessary to maintain control of psychotic symptoms. Quetiapine may increase the plasma concentrations of the active metabolite of carbamazepine, resulting in neurotoxicity. If neurotoxicity occurs, it may be necessary to discontinue one or both drugs.

Inhibitors of CYP3A (eg, erythromycin, fluconazole, fluvoxamine, itraconazole, ketoconazole, protease inhibitors, voriconazole)

May increase the effects of quetiapine; use with caution and adjust the quetiapine dose as needed.

Lorazepam

Quetiapine may increase the effects of lorazepam. Monitor the response of the patient. If an interaction is suspected, adjust the lorazepam dose as needed.

Thioridazine

May decrease the effects of quetiapine. Monitor the response of the patient and adjust the quetiapine dose as needed.

Valproic acid (eg, divalproex)

Coadministration may increase the mean C max of quetiapine. Monitor the response of the patient when starting, stopping, or changing the valproic acid dose. Be prepared to change the quetiapine dose as needed. In addition, the risk of leukopenia or neutropenia may be increased. If leukopenia or neutropenia occurs, stop one or both drugs.

Adverse Reactions

Cardiovascular

Tachycardia (8%); orthostatic/postural hypotension (7%); increased heart rate, palpitations (4%); hypotension (3%); syncope (2%); hypertension (1%); cardiomyopathy, myocarditis (postmarketing).

CNS

Somnolence/sedation (57%); headache (21%); agitation (20%); dizziness (18%); extrapyramidal effects (13%); fatigue (11%); insomnia (9%); parkinsonism (6%); akathisia, asthenia, dysarthria, lethargy (5%); dystonia, postural dizziness, tardive dyskinesia, tremor (less than 5%); anxiety, irritability (4%); abnormal dreams, hypersomnia, paresthesia (3%); aggression, balance disorder, confusional state, disorientation, disturbance in attention, hypoaesthesia, mental impairment, migraine, restless leg syndrome, restlessness, sluggishness (2%); dysgeusia (1%); nightmares.

Dermatologic

Rash (4%); acne, hyperhidrosis (2%); Stevens-Johnson syndrome (postmarketing).

EENT

Nasal congestion (5%); drooling (less than 5%); blurred vision, pharyngitis, rhinitis (4%); amblyopia, ear pain, epistaxis, seasonal allergy, sinus congestion, sinus headache, sinusitis (2%); dry throat (1%); rhinitis.

GI

Dry mouth (44%); constipation (10%); nausea, vomiting (8%); dyspepsia (7%); viral gastroenteritis (4%); toothache (3%); dysphagia, gastroenteritis, gastroesophageal reflux, stomach discomfort (2%); anorexia (at least 1%); abdominal distension, abdominal pain, tooth abscess (1%).

Genitourinary

Libido decreased, pollakiuria, urinary tract infection (2%).

Hematologic

Leukopenia (less than 5%); agranulocytosis, decreased platelets (postmarketing).

Hepatic

Increased ALT (5%); increased AST (3%).

Lab Tests

Increased triglycerides (22%); increased cholesterol (18%); decreased HDL cholesterol (10%); increased LDL cholesterol (8%); elevations in GGT (less than 5%); elevated serum creatine phosphokinase.

Metabolic-Nutritional

Weight gain (23%); hyperglycemia, increased appetite (12%); decreased appetite (2%); hyponatremia, peripheral edema, SIADH (postmarketing).

Musculoskeletal

Arthralgia (4%); back pain, muscle spasms (3%); musculoskeletal stiffness, myalgia, neck pain, pain in extremity (2%); rhabdomyolysis (postmarketing).

Respiratory

Upper respiratory tract infection (7%); cough (3%); dyspnea (at least 1%).

Miscellaneous

Pain (7%); fever, hypothyroidism (2%); flu-like syndrome (at least 1%); contusion (1%); hypersensitivity; NMS; anaphylactic reaction, galactorrhea (postmarketing).

Precautions

Warnings

Increased mortality in elderly patients

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Over the course of a 10-wk controlled trial, the rate of death in drug-treated patients was about 4.5% compared with 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Quetiapine is not approved for the treatment of patients with dementia-related psychosis.

Suicidality

Compared with placebo, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorders and other psychiatric disorders. Appropriately monitor patients of all ages who are started on antidepressant therapy and observe them closely for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the prescriber. Quetiapine ER is not approved for use in children. Quetiapine immediate-release is not approved for use in children younger than 10 yr of age.


Monitor

Monitor all patients for the emergence of agitation, irritability, clinical worsening, and other unusual changes in behavior, as well as the emergence of suicidality, especially during the initial few months of therapy or at times of dose changes. Monitor patients for symptoms of hyperglycemia. Perform fasting glucose testing in patients who develop hyperglycemia during treatment. Ensure that patients with risk factors for diabetes undergo fasting blood glucose testing at the start of therapy and periodically thereafter. Monitor patients with established diagnosis of diabetes mellitus regularly for worsening of glucose control. Perform eye exam at initiation of therapy to detect cataract formation and at 6-mo intervals during long-term treatment. Monitor patients requiring antipsychotic drug treatment after recovery from NMS for recurrence of NMS if quetiapine therapy is reintroduced. Baseline and periodic follow-up lipid evaluations are recommended for patients on quetiapine. Monitor WBC frequently during the first few months of therapy in patients with a preexisting low WBC or history of drug-induced leukopenia/neutropenia. Carefully monitor patients with neutropenia for fever or other symptoms or signs of infection. When treating children for any indication, assess weight gain against that expected for normal growth; measure BP at the beginning of therapy and periodically during therapy.


Pregnancy

Category C .

Lactation

Excreted.

Children

Safety and efficacy of ER not established; not approved for use in children. Safety and efficacy of immediate-release has been established in the treatment of bipolar mania in children 10 to 17 yr of age and in the treatment of schizophrenia in children 13 to 17 yr of age.

Elderly

May be more susceptible to effects. Consider lower starting dose, slower titration, and careful monitoring. May be at increased risk of tardive dyskinesia, especially elderly women.

Hepatic Function

Dosage adjustment may be needed.

Special Risk Patients

Consider lower starting dose, slower titration, and careful monitoring in debilitated patients and patients with predisposition to hypotensive reactions.

Body temperature regulation

Antipsychotics can disrupt the body's ability to reduce core temperature.

Cardiac effects

Orthostatic hypotension may occur, especially during the initial dose-titration period. Use with caution in patients with known CV disease (eg, conduction abnormalities, heart failure, history of MI, ischemic heart disease), cerebrovascular disease, or condition that would predispose patients to hypotension (eg, dehydration, hypovolemia, treatment with antihypertensive medications).

Cataracts

Lens changes have been observed in patients during long-term treatment.

Cognitive and motor performance

Mental and/or physical abilities may be impaired, especially during the first few days of therapy.

Dysphagia

Antipsychotics have been associated with esophageal dysmotility and aspiration. Use with caution in patients at risk for aspiration pneumonia.

Hematologic effects

Agranulocytosis (including fatal cases), leukopenia, and neutropenia have been reported during postmarketing experience.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, may occur.

Hyperlipidemia

Increased cholesterol and/or triglycerides may occur.

Hyperprolactinemia

Patients treated with antipsychotic agents often have elevation in prolactin levels.

Hypothyroidism

May occur.

NMS

Has occurred with antipsychotics and is potentially fatal.

Priapism

Has been reported.

Seizures

Use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold (eg, Alzheimer dementia).

Suicide

Closely supervise high-risk patients; prescribe small quantities.

Tardive dyskinesia

A potentially irreversible syndrome of involuntary body and facial movements may occur.

Transaminase elevations

Asymptomatic, transient, and reversible elevations in serum transaminases (mainly ALT) may occur.

Weight gain

Increases in weight have been observed.

Withdrawal

Acute withdrawal symptoms, including nausea, vomiting, and insomnia, have been reported rarely after abrupt cessation of therapy. Gradual withdrawal is advised.

Overdosage

Symptoms

Coma, death, drowsiness, first-degree heart block, hypokalemia, hypotension, QTc prolongation, sedation, tachycardia.

Patient Information

  • Advise patient to read Medication Guide before starting therapy and with each refill.
  • Explain risk of developing tardive dyskinesia and NMS to patient.
  • Instruct patient to take immediate-release dose 2 or 3 times daily as prescribed, without regard to meals. Advise patient to take ER dose once daily in the evening without food. Advise patient to take with a light meal if stomach upset occurs.
  • Advise patient that dose will be started low and then increased until max benefit is obtained.
  • Instruct patient not to stop taking quetiapine when feeling better.
  • Caution patient that if medication is stopped for more than 1 wk and then restarted, to follow the initial dose and titration schedule.
  • Instruct patients with diabetes to monitor blood glucose more frequently when drug is started or dose is changed, and to inform health care provider of significant changes in readings.
  • Tell patient to immediately report altered mental status, high fever, irregular or fast pulse, muscle rigidity, rash, seizures, or sweating to health care provider.
  • Advise patient to notify health care provider of the following: excessive drowsiness, excessive urination and thirst, involuntary body or facial movements, weight gain.
  • Advise patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Advise patient to avoid strenuous activity during periods of high temperature or humidity.
  • Advise patient and family to be alert for the emergence of agitation, irritability, and unusual changes in behavior, as well as the emergence of suicidality, and to report such symptoms immediately to the health care provider.
  • Instruct patient to avoid alcoholic beverages while taking quetiapine.
  • Instruct patient to rise slowly from lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patient to report dizziness with position changes to health care provider. Caution patient that hot tubs and hot showers or baths may make dizziness worse.
  • Advise patient taking antihypertensives to monitor BP at regular intervals.
  • Advise patient that drug may impair judgment, thinking, or motor skills, or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.

Copyright © 2009 Wolters Kluwer Health.

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