Quetiapine

383.51

383.51

601-143-7

BGL0JSY5SI

758918

DTXSID9023546

C61917

Solid

N05AH04|N - Nervous system

2934999090

73.6

3.17 (est)

Solid

1.27±0.1 g/cm3(Predicted)

172-173 °C

556.5±60.0 °C(Predicted)

9.7 deg C (49.5 deg F) - closed cup

1.653

H2O: moderately soluble

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 deg C

5.39X10-14 mm Hg at 25 deg C (est)

7.06None

Henry's Law constant = 7.45X10-18 atm-cu m/mol at 25 °C (est)

7.06|pKa1 = 2.78 (imine); pKa2 = 7.46 (amine) (est)

192.9 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|191.5 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]|191.1 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]

Crystals from ethanol, MW 883.09. MP 172-173 °C /Quetiapine hemifumarate/|Hydroxyl radical reaction rate constant = 1.79X10-10 cu cm/molec-sec at 25 °C (est)

Stable under recommended storage conditions.

P264, P270, P301+P312, P330, P501

H302

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Incompatible materials: Acids, Oxidizing agents, Alkali metals, Strong oxidizing agents, Strong acids, Acid chlorides, Acid anhydrides, Reducing agents, Strong reducing agents, Phosphorus halides

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including quetiapine fumarate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Quetiapine fumarate/

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P273, P280, P301+P312, P304+P340, P305+P351+P338, P310, P312, P330, P391, P403+P233, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H225: Highly Flammable liquid and vapor [Danger Flammable liquids]|P210, P233, P240, P241, P242, P243, P260, P261, P264, P270, P271, P273, P280, P301+P310, P302+P352, P303+P361+P353, P304+P340, P307+P311, P311, P312, P321, P322, P330, P361, P363, P370+P378, P403+P233, P403+P235, P405, and P501

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Skin protection: Handle with gloves.|Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. Use water spray to cool unopened containers.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.; Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Use explosion-proof equipment.Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge.

The oral LD50 if quetiapine in rats is 2000 mg/kg. **Overdose information** Some signs and symptoms of a quetiapine overdose include sedation, drowsiness, tachycardia, and hypotension. Clinical trials demonstrate that overdoses of up to 30 grams of quetiapine did not result in death. A lethal outcome was reported in a clinical trial after an overdose of 13.6 grams of quetiapine. In the case of an acute overdose, ensure to maintain an airway and provide adequate ventilation and oxygenation. Gastric lavage following intubation (if necessary) along with activated charcoal and a laxative may be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiac monitoring should also take place. **A note on QT-interval prolongation in an overdose** Postmarketing reports reveal increases in the cardiac QT interval in cases of quetiapine overdose, concomitant illness, and in those taking drugs that increase QT interval or affect electrolyte levels. Note that disopyramide, procainamide, and quinidine may exert additive QT-prolonging effects when administered in patients who have overdosed with quetiapine, and should be avoided.|IDENTIFICATION AND USE: Quetiapine fumarate is used for the symptomatic management of psychotic disorders. Short-term efficacy of quetiapine for the management of schizophrenia has been established by placebo-controlled studies of 6 weeks' duration principally in hospitalized patients with schizophrenia. Quetiapine is used alone or in conjunction with lithium or divalproex sodium for the management of acute manic episodes associated with bipolar I disorder. Quetiapine also is used for the treatment of depressive episodes associated with bipolar disorder. HUMAN EXPOSURE AND TOXICITY: The most common adverse effects reported in 5% or more of patients receiving quetiapine therapy for schizophrenia or bipolar disorder and at a frequency twice that reported among patients receiving placebo in clinical trials include somnolence, sedation, asthenia, lethargy, dizziness, dry mouth, constipation, increased ALT, weight gain, dyspepsia, abdominal pain, postural hypotension, and pharyngitis. The development of cataracts in association with quetiapine was observed in animal studies. Lens changes also have been reported in some patients receiving long-term quetiapine therapy, although a causal relationship has not been established. Seizures occurred in 0.6% of patients receiving quetiapine in controlled clinical trials. Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric patients with major depressive disorder and other psychiatric disorders, whether or not they are taking antidepressants. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including quetiapine. Contact dermatitis, maculopapular rash, and photosensitivity reactions were reported infrequently during clinical trials. Anaphylaxis and Stevens-Johnson syndrome have been reported during postmarketing surveillance. Quetiapine appears to be distributed into human milk in relatively small amounts. The effect of quetiapine on labor and delivery is unknown. Safety and efficacy of quetiapine in pediatric patients younger than 18 years of age with bipolar depression have not been established. Quetiapine overdose causes central nervous system depression and sinus tachycardia. In large overdoses, patients may require intubation and ventilation for associated respiratory depression. Although a prolonged QTc occurs, its clinical significance is unclear because it is most likely caused by an overcorrection caused by the tachycardia. No evidence of clastogenic potential was obtained in an in vitro chromosomal aberration assay in cultured human lymphocytes. ANIMAL STUDIES: Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in a mouse 2 year carcinogenicity study. Doses were 75-750 mg/kg. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown. In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta-8-cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. The teratogenic potential of quetiapine was studied in rats and rabbits dosed during the period of organogenesis. No evidence of a teratogenic effect was detected in rats at doses of 25 to 200 mg/kg or in rabbits at 25 to 100 mg/kg. There was, however, evidence of embryo/fetal toxicity. Delays in skeletal ossification were detected in rat fetuses at doses of 50 and 200 mg/ kg and in rabbits at 50 and 100 mg/kg. Fetal body weight was reduced in rat fetuses at 200 mg/kg and rabbit fetuses at 100 mg/kg. There was an increased incidence of a minor soft tissue anomaly (carpal/tarsal flexure) in rabbit fetuses at a dose of 100 mg/kg. Evidence of maternal toxicity (i.e., decreases in body weight gain and/or death) was observed at the high dose in the rat study and at all doses in the rabbit study. In a peri/ postnatal reproductive study in rats, no drug-related effects were observed at doses of 1, 10, and 20 mg/kg. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 150 mg/kg. The mutagenic potential of quetiapine was tested in six in vitro bacterial gene mutation assays and in an in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. However, sufficiently high concentrations of quetiapine may not have been used for all tester strains. Quetiapine did produce a reproducible increase in mutations in one Salmonella typhimurium tester strain in the presence of metabolic activation. No evidence of clastogenic potential was obtained in the in vivo micronucleus assay in rats.

Liver test abnormalities may occur in up to 30% of patients on long term therapy with quetiapine, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Instances of clinically apparent acute liver injury have been reported due to quetiapine, but they are rare. The onset of jaundice is within 1 to 4 weeks of starting the drug, and the pattern of serum enzyme elevations is typically hepatocellular. Signs of immunoallergic manifestations (fever, rash and eosinophilia) are rare, as are autoantibodies. Most cases are mild to moderate in severity and self-limited in course. Instances of acute liver failure have been reported but not vanishing bile duct syndrome or chronic liver injury.

Coadministration of quetiapine (250 mg) and phenytoin (100 mg) increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (e.g., carbamazepine, barbiturates, rifampin, glucocorticoids). Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate)|Coadministration of quetiapine (150 mg) and divalproex (500 mg) increased the mean maximum plasma concentration of quetiapine at steady state by 17% without affecting the extent of absorption or mean oral clearance.|Thioridazine (200 mg) increased the oral clearance of quetiapine (300 mg) by 65%.|Administration of multiple daily doses of cimetidine (400 mg) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg).|For more Interactions (Complete) data for QUETIAPINE (10 total), please visit the HSDB record page.

Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Analyses of 17 placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., quetiapine, aripiprazole, olanzapine, risperidone) compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. The manufacturer states that quetiapine is not approved for the treatment of dementia-related psychosis.|Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders.

The protein binding of quetiapine is 83%.

Quetiapine's production and administration as an antipsychotic(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3.2X10+4(SRC), determined from a structure estimation method(2), indicates that quetiapine is expected to be immobile in soil(SRC). The estimated pKa values of quetiapine are 2.78 and 7.46(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of quetiapine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.5X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Quetiapine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.4X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3.2X10+4(SRC), determined from a structure estimation method(2), indicates that quetiapine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.5X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 31(SRC), from an estimated log Kow of 3.17(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2015).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), quetiapine, which has an estimated vapor pressure of 5.4X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase quetiapine may be removed from the air by wet and dry deposition(SRC). Quetiapine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may to be susceptible to direct photolysis by sunlight(SRC).

Quetiapine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Quetiapine contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 31 was calculated in fish for quetiapine(SRC), using an estimated log Kow of 3.17(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of quetiapine can be estimated to be 3.2X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that quetiapine is expected to be immobile in soil. The estimated pKa values of quetiapine are 2.78 and 7.46(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

The Henry's Law constant for quetiapine is estimated as 7.5X10-18 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that quetiapine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Quetiapine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.4X10-14 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to quetiapine were not located(SRC, 2015), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

Quetiapine appears to be distributed into milk in humans in relatively small amounts.|EXPERIMENTAL: Quetiapine is distributed into milk in animals. Not known whether quetiapine is distributed into milk in humans.

Occupational exposure to quetiapine may occur through inhalation and dermal contact with this compound at workplaces where quetiapine is produced or used. Exposure to quetiapine among the general population may be limited to those administered the drug, an antipsychotic. (SRC)

... The quetiapine mean and range of concentrations found in each tissue are as follows: peripheral blood, 7.7 mg/L (0.14-37 mg/L, n = 17); heart blood, 23.63 mg/L (0.53-76 mg/L, n = 4); liver, 91 mg/Kg (1.1-510 mg/Kg, n = 19); bile, 44 mg/L (6.0-96 mg/L, n = 4); urine, 15 mg/L (1.9-37 mg/L, n = 8); gastric, 897 mg total (3.5-3960 mg, n = 7); and vitreous, 1.4 mg/L (0.2-3.2 mg/L, n = 5). The average of all blood concentrations in 18 cases in which quetiapine contributed to the cause of death was 7.95 mg/L (0.4-76 mg/L). The manner of death in 13 of those cases was suicide, two were undetermined, and three were accidents. In two cases in which quetiapine was an incidental finding, the blood concentrations were 0.14 and 1.0 mg/L. ...

Quetiapine is used in the symptomatic treatment of schizophrenia. In addition, it may be used for the management of acute manic or mixed episodes in patients with bipolar I disorder, as a monotherapy or combined with other drugs. It may be used to manage depressive episodes in bipolar disorder. In addition to the above indications, quetiapine is used in combination with antidepressant drugs for the treatment of major depression. Some off-label uses for this drug include the management of post-traumatic stress disorder (PTSD), generalized anxiety disorder, and psychosis associated with Parkinson's disease.|FDA Label

Quetiapine is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder. Use of quetiapine has been associated with serum aminotransferase elevations and in rare instances with clinically apparent acute liver injury.

Antipsychotic Agents

Antipsychotic Agents|Quetiapine also is used for the treatment of depressive episodes associated with bipolar disorder.|Quetiapine is used alone or in conjunction with lithium or divalproex sodium for the management of acute manic episodes associated with bipolar I disorder.|Short-term efficacy of quetiapine for the management of schizophrenia has been established by placebo-controlled studies of 6 weeks' duration principally in hospitalized patients with schizophrenia.|Quetiapine fumarate is used for the symptomatic management of psychotic disorders (e.g., schizophrenia).

/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA- RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Quetiapine is not approved for the treatment of patients with dementia-related psychosis. Suicidal Thoughts and Behaviors: Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. Quetiapine is not approved for use in pediatric patients under ten years of age.|Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Analyses of 17 placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., quetiapine, aripiprazole, olanzapine, risperidone) compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. The manufacturer states that quetiapine is not approved for the treatment of dementia-related psychosis.|Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of quetiapine or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Quetiapine is not approved for use in pediatric patients.|Pooled analyses of short-term (4 to 16 weeks) placebo- controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.|For more Drug Warnings (Complete) data for QUETIAPINE (31 total), please visit the HSDB record page.

While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine, e.g., development of tolerance, increases in dose, drug-seeking behavior.

Quetiapine improves the positive and negative symptoms of schizophrenia and major depression by acting on various neurotransmitter receptors, such as the serotonin and dopamine receptors. In bipolar disorder, it improves both depressive and manic symptoms. **A note on suicidality in young patients and administration in the elderly** Quetiapine can cause suicidal thinking or behavior in children and adolescents and should not be given to children under 10 years of age. It is important to monitor for suicidality if this drug is given to younger patients. In addition, this drug is not indicated for the treatment of psychosis related to dementia due to an increased death rate in elderly patients taking this drug.

Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems. (See all compounds classified as Antidepressive Agents.)|Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)

Quetiapine is rapidly and well absorbed after administration of an oral dose. Steady-state is achieved within 48 hours Peak plasma concentrations are achieved within 1.5 hours. The bioavailability of a tablet is 100%. The steady-state Cmax of quetiapine in Han Chinese patients with schizophrenia after a 300 mg oral dose of the extended released formulation was approximately 467 ng/mL and the AUC at steady-state was 5094 ng·h/mL. Absorption of quetiapine is affected by food, with Cmax increased by 25% and AUC increased by 15%.|After an oral dose of radiolabeled quetiapine, less than 1% of unchanged drug was detected in the urine, suggesting that quetiapine is heavily metabolized. About 73% of a dose was detected in the urine, and about 20% in the feces.|Quetiapine distributes throughout body tissues. The apparent volume of distribution of this drug is about 10±4 L/kg.|The clearance of quetiapine healthy volunteers in the fasted state during a clinical study was 101.04±39.11 L/h. Elderly patients may require lower doses of quetiapine, as clearance in these patients may be reduced by up to 50%. Those with liver dysfunction may also require lower doses.|Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with Cmax and AUC values increased by 25% and 15%, respectively.|Steady state concentrations are expected to be achieved within two days of dosing.|Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10 +/-4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations.|Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In two of the 8 hepatically impaired patients, AUC and C max were 3-times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population...|For more Absorption, Distribution and Excretion (Complete) data for QUETIAPINE (8 total), please visit the HSDB record page.

The metabolism of quetiapine occurs mainly in the liver. Sulfoxidation and oxidation are the main metabolic pathways of this drug. According to in vitro studies, cytochrome P450 3A4 metabolizes quetiapine to an inactive sulfoxide metabolite and also participates in the metabolism of its active metabolite, N-desalkyl quetiapine. CYP2D6 also regulates the metabolism of quetiapine. In one study, three metabolites of N-desalkylquetiapine were identified. Two of the metabolites were identified as N-desalkylquetiapine sulfoxide and 7-hydroxy-N-desalkylquetiapine. CYP2D6 has been found to be responsible for metabolism of quetiapine to 7-hydroxy-N-desalkylquetiapine, a pharmacologically active metabolite. Individual differences in CYP2D6 metabolism may be present, which may affect the concentrations of the active metabolite.|Quetiapine is extensively metabolized in the liver principally via sulfoxidation and oxidation to inactive metabolites. In vitro studies suggest that the cytochrome P-450 (CYP) 3A4 isoenzyme is involved in the metabolism of quetiapine to the inactive sulfoxide metabolite, which is the principal metabolite. ... Based on in vitro studies, quetiapine and 9 of its metabolites do not appear likely to inhibit CYP isoenzymes 1A2, 3A4, 2C9, 2C19, or 2D6.|Quetiapine has known human metabolites that include 7-Hydroxy Quetiapine and Quetiapine Sulfoxide.

The average terminal half-life of quetiapine is about 6-7 hours.|The mean terminal half-life of quetiapine is about 6 hours.

Although the mechanism of action of quetiapine is not fully understood, several proposed mechanisms exist. In schizophrenia, its actions could occur from the antagonism of dopamine type 2 (D2) and serotonin 2A (5HT2A) receptors. In bipolar depression and major depression, quetiapine's actions may be attributed to the binding of this drug or its metabolite to the norepinephrine transporter. Additional effects of quetiapine, including somnolence, orthostatic hypotension, and anticholinergic effects, may result from the antagonism of H1 receptors, adrenergic α1 receptors, and muscarinic M1 receptors, respectively.|The therapeutic effects of antipsychotic drugs are thought to be mediated by dopaminergic blockade in the mesolimbic and mesocortical areas of the CNS, while antidopaminergic effects in the neostriatum appear to be associated with extrapyramidal effects. The apparently low incidence of extrapyramidal effects associated with quetiapine therapy suggests that the drug is more active in the mesolimbic than in the neostriatal dopaminergic system. In contrast to typical antipsychotic agents (e.g., chlorpromazine) but like other atypical antipsychotic drugs (e.g., clozapine), quetiapine does not cause sustained elevations in serum prolactin concentrations and therefore is unlikely to produce adverse effects such as amenorrhea, galactorrhea, and impotence.|The exact mechanism of antipsychotic action of quetiapine has not been fully elucidated but may involve antagonism at serotonin type 1 (5-hydroxytryptamine [5- HT1A]) and type 2 (5-HT2A, 5-HT2C) receptors, and at dopamine (D1, D2) receptors. Current evidence suggests that the clinical potency and antipsychotic efficacy of both typical and atypical antipsychotic drugs generally are related to their affinity for and blockade of central dopamine D2 receptors; however, antagonism at dopamine D2 receptors does not appear to account fully for the antipsychotic effects of quetiapine. Results of in vivo and in vitro studies indicate that quetiapine is a comparatively weak antagonist at dopamine D2 receptors. Receptor binding studies show quetiapine is a weak antagonist at D1 receptors. Although their role in eliciting the pharmacologic effects of antipsychotic agents remains to be fully elucidated, dopamine D3, D4, and D5 receptors also have been identified; quetiapine possesses no affinity for the dopamine D4 receptor.|Quetiapine exhibits alpha1- and alpha2-adrenergic blocking activity; blockade of alpha1-adrenergic receptors may explain the occasional orthostatic hypotension associated with the drug. Quetiapine also blocks histamine H1 receptors, which may explain the sedative effects associated with the drug. Quetiapine possesses little or no affinity for beta-adrenergic, gamma-aminobutyric acid (GABA), benzodiazepine, or muscarinic receptors.|Recent neuroimaging and postmortem studies have reported abnormalities in white matter of schizophrenic brains, suggesting the involvement of oligodendrocytes in the etiopathology of schizophrenia. This view is being supported by gene microarray studies showing the downregulation of genes related to oligodendrocyte function and myelination in schizophrenic brain compared to control subjects. However, there is currently little information available on the response of oligodendrocytes to antipsychotic drugs (APDs), which could be invaluable for corroborating the oligodendrocyte hypothesis. In this study we found: (1) quetiapine (QUE, an atypical APD) treatment in conjunction with addition of growth factors increased the proliferation of neural progenitors isolated from the cerebral cortex of embryonic rats; (2) QUE directed the differentiation of neural progenitors to oligodendrocyte lineage through extracellular signal-related kinases; (3) addition of QUE increased the synthesis of myelin basic protein and facilitated myelination in rat embryonic cortical aggregate cultures; (4) chronic administration of QUE to C57BL/6 mice prevented cortical demyelination and concomitant spatial working memory impairment induced by cuprizone, a neurotoxin. These findings suggest a new neural mechanism of antipsychotic action of QUE, and help to establish a role for oligodendrocytes in the etiopathology and treatment of schizophrenia.

Emergency and supportive measures: 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. 2. Treat coma, seizures, hypotension, and hyperthermia if they occur. 3. Monitor vital signs ECG for at least 6 hours and admit the patient for at least 24 hours if there are signs of significant intoxication. Children with antipsychotic intoxication should be evaluated for possible intentional abuse. /Antipsychotic drugs/|Specific drugs and antidotes. There is no specific antidote.1. Dystonic reactions. Give diphenhydramine ... or benztropine ... . 2. QRS interval prolongation: treat quinidine-like cardiotoxic effects with bicarbonate ... . 3. Hypotension from these drugs probably involves vasodilation caused by alpha-1 receptor blockade. Treat with iv fluids and, if needed a vasoconstrictor such as norepinephrine or phenylephrine. Theoretically, drugs with beta-2 activity (eg, epinephrine, isoproterenol) may worsen hypotension. 4. QT prolongation and torsade may respond to magnesium infusion or overdrive pacing. /Antipsychotic drugs/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antipsychotic drugs/|Enhanced elimination. Owing to extensive tissue distribution, these drugs are not effectively removed by dialysis or hemoperfusion. Repeat-dose activated charcoal has not been evaluated. /Antipsychotic drugs/|For more Antidote and Emergency Treatment (Complete) data for QUETIAPINE (7 total), please visit the HSDB record page.

/HUMAN EXPOSURE STUDIES/ Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Analyses of 17 placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., quetiapine, aripiprazole, olanzapine, risperidone) compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. The manufacturer states that quetiapine is not approved for the treatment of dementia-related psychosis.|/SIGNS AND SYMPTOMS/ Experience with quetiapine fumarate in acute overdosage was limited in the clinical trial database (6 reports) with estimated doses ranging from 1200 mg to 9600 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects i.e. drowsiness and sedation, tachycardia and hypotension. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there have been ... reports of overdose of quetiapine alone resulting in death, coma, or QTc prolongation.|/SIGNS AND SYMPTOMS/ Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving certain atypical antipsychotic agents, including quetiapine. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., quetiapine, clozapine, olanzapine, risperidone).|/SIGNS AND SYMPTOMS/ Adverse events reported since market introduction, which were temporally related to quetiapine therapy, but not necessarily causally related, include the following: agranulocytosis, anaphylaxis, hyponatremia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and Steven Johnson syndrome (SJS).|For more Human Toxicity Excerpts (Complete) data for QUETIAPINE (26 total), please visit the HSDB record page.

2-(2-(4-dibenzo(b,f)(1,4)thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol

Table: Quetiapine Fumarate Preparations [Table#7274]

HPLC and GC/MS determination in plasma.|Analyte: quetiapine; matrix: blood (plasma); procedure: reversed-phase high-performance liquid chromatography with ultraviolet (at 225 nm) and electrochemical detection; limit of quantitation: 2.5 ng/mL|Analyte: quetiapine; matrix: blood (serum); procedure: high-performance liquid chromatography with ultraviolet detection at 230 nm; limit of quantitation: 5 ng/mL

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