QUETIAPINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) ICI-204636
2) ZD-5077
3) ZM-204636
4) Molecular Formula: C42-H50-N6-O4-S2.C3-H4-O4
5) CAS 111974-69-7 (quetiapine)
6) CAS 111974-72-2 (quetiapine fumarate)
7) Quell (slang term)
8) Susie-Q (slang term)
9) Q-ball (combination of cocaine and quetiapine - slang term)
10) Baby heroin (slang term)

Available Forms Sources

1) Quetiapine fumarate is available as 25 mg (round, peach), 50 mg (round, white), 100 mg (round, yellow), 200 mg (round, white), 300 mg (capsule-shaped, white), and 400 mg (capsule-shaped, yellow) tablets (Prod Info SEROQUEL(R) oral tablets, 2008). It is present as the fumarate salt. However, all tablets strengths are expressed as milligrams of base, not as fumarate salt.
2) Quetiapine is also available as 50 mg, 150 mg, 200 mg, 300 mg, and 400 mg oral extended-release tablets (Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

1) It is an atypical antipsychotic, and is indicated for the management of depressive episodes associated with bipolar disorder; treatment of acute manic episodes associated with bipolar I disorder; schizophrenia, as either monotherapy or adjunct therapy to lithium or divalproex, and maintenance treatment of psychotic disorders, including schizophrenia (Prod Info SEROQUEL(R) oral tablets, 2008). Quetiapine has been tried as an antipsychotic in parkinsonism patients (S Sweetman , 2001).
2) POTENTIAL FOR ABUSE

a) There are reports in the literature of quetiapine being used in inmate populations where the drug has been widely abused for its sedative and anxiolytic effects. The tablets have been crushed and taken intranasally (Pierre et al, 2004). Single case reports of similar misuse have been reported in individuals with schizoaffective disorders (Morin, 2007).
b) Intravenous misuse of quetiapine and cocaine have also been reported in the literature and is referred to as "Q-ball". The sedative/anxiolytic effects of quetiapine may minimize the dysphoric effects of cocaine withdrawal as well as providing a hallucinogenic effect (Waters & Joshi, 2007).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Quetiapine is an atypical antipsychotic drug and is used in schizophrenia and bipolar disorders.
B) EPIDEMIOLOGY: Poisoning with quetiapine is common. Deaths are reported but are rare and usually due to a polypharmacy ingestion.
C) PHARMACOLOGY: Quetiapine is mainly an antagonist at the serotonin receptor 2 (5-HT2) and has only minor antagonist effects on dopamine receptors (D2). In overdose, quetiapine exhibits antimuscarinergic, antihistamine (H1), and antiadrenergic (alpha 1) effects.
D) TOXICOLOGY: Quetiapine overdose is mainly associated with CNS depression and anticholinergic effects. In most cases, sinus tachycardia is observed. Although quetiapine is associated with prolongation of the corrected QT interval (QTc), torsade de pointes (TdP) has not been documented to date.
E) WITH THERAPEUTIC USE

1) Somnolence, dizziness, sinus tachycardia, palpitations, and orthostatic hypotension can develop. Dry mouth, constipation, urinary retention, dyspepsia, elevated liver enzymes are also often reported.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Dry mouth, constipation, somnolence, dizziness, and mild sinus tachycardia may be observed.
2) SEVERE POISONING: Marked CNS depression, signs of anticholinergic poisoning, such as pronounced sinus tachycardia and urinary retention. Seizures and/or myoclonic jerks may be observed. Mild hypotension occurs but usually responds promptly to fluid resuscitation. Increased serum liver enzymes may also occur. QTc prolongation is often observed, although ventricular dysrhythmias have not been documented. Respiratory depression may occur following massive overdoses due to CNS depression.

0.2.20)

A) Quetiapine is classified as FDA pregnancy category C. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. Quetiapine is excreted into human breast milk. However, limited data on the safety of quetiapine in nursing infants demonstrates no evidence of toxicity. In male and female rats, quetiapine was shown to have adverse effects on mating and fertility.

0.2.21)

A) No tumorigenesis has been demonstrated with the class of drugs that increase prolactin release, including quetiapine, after chronic administration.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Primarily supportive care; activated charcoal may prevent or shorten the duration of symptoms in patients presenting shortly after ingestion of a significant amount of the drug.

B) MANAGEMENT OF SEVERE TOXICITY

1) Consider activated charcoal if a patient presents early after ingestion. If significant CNS depression occurs, perform orotracheal intubation for airway protection before giving charcoal. Administer benzodiazepines to treat seizures. Mild hypotension can be treated with normal saline. A Foley catheter may be necessary in case of urinary retention.

C) DECONTAMINATION

1) PREHOSPITAL: Decontamination is not recommended because of the potential for somnolence and seizures.
2) HOSPITAL: Consider activated charcoal after a recent substantial ingestion and if the patient is able to protect their airway. Quetiapine overdose is rarely life-threatening; gastric lavage is generally not indicated.

D) AIRWAY MANAGEMENT

1) Perform early orotracheal intubation in a patient with signs of severe intoxication (marked CNS depression, seizures).

E) ANTIDOTE

1) There is no antidote for quetiapine poisoning.

F) HYPOTENSION

1) Mild hypotension can be treated with IV NS at 10 to 20 mL/kg. Consider norepinephrine or phenylephrine, if hypotension persists.

G) DYSTONIA

1) ADULT: Benztropine 1 to 2 mg IV or diphenhydramine 1 mg/kg/dose IV over 2 minutes. CHILD: Diphenhydramine 1 mg/kg/dose IV over 2 minutes (maximum 5 mg/kg/day or 50 mg/m(2)/day).

H) FAT EMULSION

1) Limited data with quetiapine. Patients who develop significant cardiovascular toxicity may benefit from intravenous lipid therapy. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

I) PRIAPISM

1) Priapism may result following a quetiapine overdose due to alpha-adrenergic blockade. An immediate urological consult is necessary. Clinical history should include the use of other agents (ie, antihypertensives, antidepressants, illegal agents) that may also be contributing to priapism. In a patient with ischemic priapism the corpora cavernosa are often completely rigid and the patient complains of pain, while nonischemic priapism the corpora are typically tumescent, but not completely rigid and pain is not typical. Aspirate blood from the corpus cavernosum with a fine needle. Blood gas testing of the aspirated blood may be used to distinguish ischemic (typically PO2 less than 30 mmHg, PCO2 greater than 60 mmHg, and pH less than 7.25) and nonischemic priapism. Color duplex ultrasonography may also be useful. If priapism persists after aspiration, inject a sympathomimetic. PHENYLEPHRINE: Dose: Adult: For intracavernous injection, dilute phenylephrine with normal saline for a concentration of 100 to 500 mcg/mL and give 1 mL injections every 3 to 5 minutes for approximately 1 hour (before deciding that treatment is not successful). For children and patients with cardiovascular disease: Use lower concentrations in smaller volumes. NOTE: Treatment is less likely to be effective if done more than 48 hours after the development of priapism. Distal shunting (NOT first-line therapy) should only be considered after a trial of intracavernous injection of sympathomimetics.

J) ENHANCED ELIMINATION

1) There is no role for repeat-dose activated charcoal. Hemodialysis is not useful based on a large volume of distribution.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Children less than 12 years of age who are naive to quetiapine can be observed at home following an unintentional ingestion of 100 mg or less and are only experiencing mild sedation. All patients, 12 years of age or older, who are naive to quetiapine, can be observed at home following an unintentional ingestion of 125 mg or less and are experiencing only mild sedation. All patients who are taking quetiapine on a chronic basis can be observed at home if they have acutely ingested no more than 5 times their current single dose (not daily dose) of quetiapine.
2) OBSERVATION CRITERIA: Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility. Children less than 12 years of age who are naive to quetiapine should be referred to a healthcare facility following an unintentional ingestion of more than 100 mg. All patients, 12 years of age or older, who are naive to quetiapine should be referred to a healthcare facility following an unintentional ingestion of more than 125 mg. All patients who are taking quetiapine on a chronic basis should be referred to a healthcare facility following an acute ingestion of more than 5 times their current single dose (not daily dose) of quetiapine. Patients should be observed for 6 hours (or at least 12 hours after ingestion of extended-release formulations) and should be admitted if they remain symptomatic.
3) ADMISSION CRITERIA: Any patient with persistent hypotension, CNS depression, seizures, or myoclonus should be admitted to the hospital.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity (CNS depression, seizures) or in whom the diagnosis is not clear.

L) PHARMACOKINETICS

1) Bioavailability is only 9% because of extensive first pass metabolism. Maximal plasma concentrations are reached 90 minutes after ingestion of regular-release quetiapine and about 6 hours after ingestion of extended-release formulations. Protein binding is about 83%, volume of distribution is approximately 6 to 14 L/kg, elimination primarily occurs by hepatic metabolism (CYP 3A4). The elimination half-life is 6 to 7 hours. There are 2 active metabolites. Pharmacokinetic interaction may occur in individuals that are inducers or inhibitors of CYP 3A4.

M) TOXICOKINETICS

1) In mild to moderate overdose, elimination kinetics seem to be unchanged. However, in very large overdoses elimination may be delayed due to increased volume of distribution.

N) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis is wide given the nonspecific symptoms and signs in quetiapine overdose. Consider poisoning with other CNS depressants and CNS infection.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) Elevated body temperature has been reported with other antipsychotic agents and may occur as a result of quetiapine poisoning (Prod Info SEROQUEL(R) oral tablets, 2007).
2) CASE REPORT: A 61-year-old woman presented with an altered mental status after intentionally ingesting 9000 mg (60 tablets of 150 mg each) and developed a temperature up to 39.1 degrees Celsius. Laboratory studies revealed no obvious source of infection. She recovered following symptomatic care (Khan & Tham, 2008).

3.3.4)

A) WITH THERAPEUTIC USE

1) Orthostatic hypotension has been observed in approximately 7% of patients participating in quetiapine clinical trials (Prod Info Seroquel(R) Tablets, quetiapine, 1999).

B) WITH POISONING/EXPOSURE

1) Hypotension may occur in overdose (Bodmer et al, 2008; Prod Info SEROQUEL(R) oral tablets, 2007; Mowry et al, 1999).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Increased pulse rate is expected in overdose cases (Bodmer et al, 2008; Prod Info SEROQUEL(R) oral tablets, 2007; Harmon et al, 1998; Nudelman et al, 1998).

Acid-Base

3.11.2)

A) METABOLIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis (pH 7.32) was reported in a 61-year-old woman who presented with an altered mental status after intentionally ingesting 9000 mg (60 tablets of 150 mg each) of quetiapine. She recovered completely following symptomatic care (Khan & Tham, 2008).

B) RESPIRATORY ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 34-year-old woman with HIV, a history of drug abuse, and schizophrenia treated with extended-release quetiapine 600 mg/day developed respiratory acidosis (venous blood gas pH 7.26, PCO2 92 mmHg) after intentionally ingesting 36 g (120 300 mg tablets) of the extended-release quetiapine. She was found unconscious and was transported to the emergency department where she was intubated. With supportive therapy she was transferred out of critical care within 4 days and at a 4-month follow up she was maintaining therapy on extended-release quetiapine 300 mg/day in good condition (Capuano et al, 2011).

Hematologic

3.13.2)

A) HEMATOLOGY FINDING

1) WITH THERAPEUTIC USE

a) LACK OF EFFECT: Unlike clozapine, a structurally-related drug, quetiapine has not been shown in preclinical trials to cause significant leukopenia or agranulocytosis (Borison et al, 1996; Hirsch et al, 1996). However, clinical experience with this agent remains limited.

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 19-year-old man presented with confusion, agitation, impairment of short-term memory, and inability to move extremities due to pain approximately 2.5 days after ingesting 12,000 mg of quetiapine. Laboratory analysis showed a CPK of 47,663, myoglobin of 7267, a BUN of 68, a serum creatinine of 4.5, and elevated liver enzyme levels (AST 779 and ALT 274). The patient's serum quetiapine level was 68 nanograms/mL. A diagnosis of rhabdomyolysis was made. Five days later, hemodialysis was started after the patient's BUN and serum creatinine increased to 126 and 13.8, respectively. The patient's mental status and BUN and serum creatinine levels normalized 12 days after hospital admission, and there was no evidence of permanent renal or neurologic sequelae. The patient reported falling out of bed and laying unconscious on the floor for an unknown period of time after the overdose (Smith et al, 2004). Since rhabdomyolysis has not previously been reported with quetiapine overdose, it seems most likely that the rhabdomyolysis was secondary to prolonged immobilization, rather than a direct effect of quetiapine.

B) INCREASED CREATINE KINASE LEVEL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 61-year-old woman presented with an altered mental status after intentionally ingesting 9000 mg (60 tablets of 150 mg) and developed an elevated serum creatine kinase level of 4631 units/L (normal 0 to 200 units/L). Following symptomatic care, the patient's creatine kinase dropped to 157 units/L 48 hours after exposure. No permanent sequelae was observed (Khan & Tham, 2008).
b) CASE REPORT: A 29-year-old man with a history of schizophrenia reportedly ingested 12,000 mg of quetiapine, then slept for 32 hours and awoke in severe pain with muscle weakness and tenderness. Upon admission, he was noted to have bruising on the thighs and complained of pain; he was neurologically intact. Laboratory studies revealed an elevated creatine phosphokinase of 13353 units/L (normal up to 170 units/L), an elevated lactate dehydrogenase concentration (570 units/L; normal 247 units/L), along with an elevated WBC and C-reactive protein levels. Following aggressive hydration therapy the levels improved, and the patient was discharged to home on day 10. The authors could not determine if the effects were due directly to quetiapine toxicity or prolonged immobilization (Plesnicar et al, 2007).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) Pupils were reported to be 3 mm and sluggish in 1 patient following an overdose of 20 g (Harmon et al, 1998).
2) In a case series of 209 intentional overdoses, 2% were reported to have miosis (Mowry et al, 1999).
3) In an overdose case, a 40-year-old woman reported having diplopia but had normal eye movements and visual fields (Pollak & Zbuk, 2000).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Due to its alpha-1-receptor blockade properties, quetiapine has produced orthostasis, syncope, and reflex tachycardia in overdoses (Prod Info SEROQUEL(R) oral tablets, 2007; Hendrickson et al, 2001; Pollak & Zbuk, 2000; Dev & Raniwalla, 2000; King et al, 1998; Hirsch et al, 1996; Gajwani et al, 2000; Hustey, 1999).

a) INCIDENCE

1) In a retrospective chart review conducted by poison control centers from 2002 to 2006, 945 adult ingestions of quetiapine alone were identified; of those cases, hypotension was reported in 18% of patients (n=168; 95% CI, 16% to 20%) (Ngo et al, 2008).

b) CASE SERIES

1) In a case series of 209 intentional quetiapine overdoses, 6% experienced hypotension (Mowry et al, 1999). In another series of 18 patients with quetiapine overdose, 1 patient (6%) developed hypotension (Balit et al, 2003).

b) CASE REPORTS

1) The manufacturer has reported hypotension developing in patients taking overdoses ranging from 1200 mg to 9600 mg during clinical trials (Prod Info SEROQUEL(R) oral tablets, 2007; Prod Info Seroquel(R) Tablets, quetiapine, 1999).
2) Hypotension and tachycardia were reported in a 61-year-old woman after intentionally ingesting 9000 mg (60 tablets of 150 mg each) of quetiapine. She recovered following symptomatic care (Khan & Tham, 2008).
3) CASE REPORT: Following a 15 g quetiapine overdose, a 36-year-old woman developed obtundation, hypotension, tachycardia, and prolonged QT interval. The patient recovered (Hendrickson et al, 2001).
4) CASE REPORT: Transient mild hypotension (80 to 100 mmHg systolic BP) occurred in a 34-year-old woman who presented comatose (Glasgow Coma Scale score 5) and tachycardic (159 beats/min) 2 to 4 hours after ingesting approximately 24 g of quetiapine (Bodmer et al, 2008).

B) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Tachycardia is an expected overdose effect as a result of exaggeration of the drugs pharmacological effects, which includes alpha-1-receptor blockade causing orthostasis, syncope, and reflex tachycardia. Tachycardia may have a long duration following overdoses due to a long terminal elimination half-life (Isbister & Duffull, 2009; Bodmer et al, 2008; Prod Info SEROQUEL(R) oral tablets, 2007; Raja & Azzoni, 2002; Dev & Raniwalla, 2000; Gajwani et al, 2000; Pollak & Zbuk, 2000; Hustey, 1999; Lynch et al, 1999; Harmon et al, 1998; Small et al, 1997). Although the drug has minimal muscarinic activity, after a massive overdose it is possible that cholinergic blockade may contribute to tachycardia. In a series of 209 quetiapine ingestions, 25% developed tachycardia (Mowry et al, 1999).

b) INCIDENCE

1) In a cohort study of consecutive quetiapine overdose cases reported during January 2000 and May 2007, of the 137 adult ingestions of quetiapine alone, 100 patients (73%) developed tachycardia. No serious cardiac toxicity was observed. One patient died of respiratory failure and an asystolic cardiac arrest due to a confirmed 15 g ingestion of quetiapine (Isbister & Duffull, 2009).
2) In a retrospective chart review conducted by poison control centers from 2002 to 2006, 945 adult ingestions of quetiapine alone were identified; of those cases, tachycardia was reported in 532 patients (56% [95% CI, 53% to 59%]) (Ngo et al, 2008).

c) CASE REPORTS/SERIES

1) CASE SERIES: In a series of 18 patients with quetiapine overdose (confirmed by serum concentrations), 14 (78%) developed tachycardia (Balit et al, 2003).
2) CASE SERIES: In a case series involving 20 patients with quetiapine overdose, 4 developed different cardiac arrhythmias. One patient developed supraventricular tachycardia, another developed atrioventricular nodal re-entry tachycardia, and another patient developed multiple premature ventricular beats. Fatal ventricular tachycardia and treatment refractory cardiac arrest developed 50 hours after admission in another patient (Eyer et al, 2011).
3) CASE REPORT: A 34-year-old woman presented comatose (Glasgow Coma Scale score 5) and tachycardic (159 beats/min) 2 to 4 hours after ingesting approximately 24 g of quetiapine. An ECG revealed a sinus tachycardia of 143 beats/minute and a QT interval of 400 ms (QTc of 620 ms [normal less than 440 ms] corrected with Bazett's formula). She also experienced repetitive myoclonic jerks and 2 generalized tonic clonic seizures, which were successfully treated with lorazepam. She remained tachycardic for up to 40 hours after admission. Another ECG, 11 hours after presentation, revealed the QT interval of 360 ms and the QTc interval of 430 ms (Bodmer et al, 2008).
4) CASE REPORT: Coma and prolonged tachycardia occurred in a 38-year-old man after reportedly ingesting 20,000 mg of quetiapine in a suicide attempt (Raja & Azzoni, 2002).
5) CASE REPORT: Hypotension and tachycardia were reported in a 61-year-old woman after intentionally ingesting 9000 mg (60 tablets of 150 mg each) of quetiapine. She recovered following symptomatic care (Khan & Tham, 2008).
6) CASE REPORT: Sinus tachycardia (120 to 150 beats/min) with normal QRS complex persisting for 40 hours postingestion was reported in a 26-year-old woman following a 20 g overdose. The patient recovered and was transferred to psychiatric care (Harmon et al, 1998).
7) CASE REPORT: Approximately 1 hour after ingesting an overdose of 3000 mg of quetiapine, a 40-year-old woman presented to the emergency department with hypotension (90/55 mmHg) and tachycardia (120 beats/min). ECG revealed a sinus tachycardia (115 beats per minute) with nonspecific ST segment abnormalities. Management included fluid support. The patient continued to have tachycardia until 42 hours after the overdose, when her heart rate returned to normal (Pollak & Zbuk, 2000).
8) CASE REPORTS: Tachycardia was reported as an overdose effect in 6 patients with quetiapine overdoses ranging from 1200 mg to 9600 mg (Prod Info Seroquel(R) Tablets, quetiapine, 1999).

C) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) ECG changes, including QTc and QRS prolongation and PVCs, have been reported after overdoses (Bodmer et al, 2008; Ngo et al, 2008; Prod Info SEROQUEL(R) oral tablets, 2007; Hunfeld et al, 2006; Strachan & Benoff, 2006; Beelen et al, 2001; Hendrickson et al, 2001; Gajwani et al, 2000; Hustey, 1999) .

b) INCIDENCE

1) In a retrospective chart review conducted by poison control centers from 2002 to 2006, 945 adult ingestions of quetiapine alone were identified; of those cases, 10 patients with QRS prolongation were noted and 37 patients had QT prolongation. In most cases, documentation of QRS and QT intervals were not present. However, there were no reports of torsade de pointes or ventricular tachyarrhythmias (Ngo et al, 2008).

c) CASE REPORTS/SERIES

1) CASE SERIES: In a series of 14 cases of intentional quetiapine overdose, 3 patients had QTc interval prolongation with no signs of cardiac toxicity. The median ingestion was 2600 mg (range 1200 to 18,000 mg), with quetiapine as the sole ingestant in only 1 patient (Hunfeld et al, 2006).
2) CASE SERIES: In a series of 10 quetiapine overdose patients who did not have co-ingestants with known cardiac effects, 7 had a QTc interval of greater than 440 msec; however the mean QT interval (uncorrected for rate) was normal (Balit et al, 2003).
3) CASE SERIES: In a case series of 17 intentional ingestions in adults, 1 patient with a pure quetiapine ingestion was reported to have QRS prolongation on ECG (length not stated), and 2 other patients with pure quetiapine ingestions were reported to have PVCs (Lynch et al, 1999).
4) CASE REPORT: A 34-year-old woman presented comatose (Glasgow Coma Scale score 5) and tachycardic (159 beats/min) 2 to 4 hours after ingesting approximately 24 g of quetiapine. An ECG revealed a sinus tachycardia of 143 beats/min and a QT interval of 400 ms (QTc of 620 ms [normal less than 440 ms] corrected with Bazett's formula). She also experienced repetitive myoclonic jerks and 2 generalized tonic clonic seizures, which were successfully treated with lorazepam. She remained tachycardic for up to 40 hours after admission. Another ECG, 11 hours after presentation, revealed the QT interval of 360 ms and the QTc interval of 430 ms (Bodmer et al, 2008).
5) CASE REPORT: Following an estimated overdose of 9600 mg, a patient was reported to have hypokalemia and first-degree heart block (Prod Info SEROQUEL(R) oral tablets, 2007).
6) CASE REPORT: A prolonged QTc interval was reported in a 41-year-old man who was believed to have ingested 4500 mg of quetiapine. He presented with mental status changes, prolonged QTc interval, and myoclonus. ECG demonstrated a rate of 98 beats/min with left axis deviation, QRS of 140 msec, and a QTc interval of 684 msec. No structural heart abnormalities were seen. Tricyclic antidepressants and valproic acid (subtherapeutic level) were detected in serum. Quetiapine was detected by gas chromatography. The patient was discharged to psychiatric care after a 5-week hospital stay complicated by hypoxemia, ARDS, and septicemia (Strachan & Benoff, 2006).
7) CASE REPORT: A 14-year-old boy with a history of major depressive disorder with psychotic features, posttraumatic stress disorder, oppositional defiant disorder, and polysubstance abuse developed QTc prolongation (453 to 618 msec on the printout and 444 to 500 msec with manual calculation; baseline ECG, 411 to 416 msec) 1.5 hours after ingesting 1900 mg of quetiapine. Following supportive therapy, he recovered and was discharged without further sequelae (Kurth & Maguire, 2004).
8) CASE REPORT: Approximately 2 hours after an overdose of 2000 mg of quetiapine in an adult concurrently being treated with risperidone, an ECG revealed normal sinus rhythm with a corrected QTc interval of 537 msec (upper limit of normal, 440 msec). No episodes of ventricular tachycardia were seen on continuous ECG monitoring for the subsequent 18 hours. The patient made an uneventful recovery (Beelen et al, 2001).
9) CASE REPORT: QTc interval prolongation (581 msec) was reported about 2 hours postingestion of 48 tablets of quetiapine 200 mg (9600 mg) in a 19-year-old man. The patient was initially found comatose, hypotensive, and tachycardic. At 14 hours postingestion his QTc interval peaked at 710 msec, at which time magnesium supplementation was initiated. Following symptomatic therapy, all effects resolved by the third day (Gajwani et al, 2000; Hustey, 1999).

D) CARDIOVASCULAR FINDING

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 52-year-old man was found comatose and in acute respiratory distress several hours after a suicidal ingestion of quetiapine. The patient died despite resuscitative attempts by the paramedics. Autopsy revealed cardiomegaly, left ventricular hypertrophy, and bilateral pulmonary congestion. A postmortem serum quetiapine level was 18,300 nanograms/mL. It is estimated that the patient ingested approximately 10,800 mg of quetiapine (Fernandes & Marcil, 2002).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression may occur following massive overdoses, accompanying CNS depressive effects. Airway management with intubation should be instituted following massive overdoses. In a series of 209 patients with intentional quetiapine overdose, 2% developed respiratory depression (Mowry et al, 1999). One patient developed respiratory arrest.
b) INCIDENCE

1) In a retrospective chart review conducted by poison control centers from 2002 to 2006, 945 adult ingestions of quetiapine alone were identified; of those cases, respiratory depression developed in 49 patients (95% CI, 4% to 6%) (Ngo et al, 2008).
2) In a cohort study of consecutive quetiapine overdose cases reported during January 2000 and May 2007, of the 137 adult ingestions of quetiapine alone, 15 patients (11%) required intubation. Of the 38 occasions for mechanical ventilation, the median dose was 5000 mg (interquartile range: 2520 to 11,850 mg) and the probability of mechanical ventilation was found to be dose-dependent (Isbister & Duffull, 2009).

c) CASE REPORTS/CASE SERIES

1) CASE SERIES: In a series of 18 patients with quetiapine overdose, 4 (22%) required intubation and mechanical ventilation for respiratory and CNS depression (Balit et al, 2003).
2) CASE REPORT: A 34-year-old woman with HIV, a history of drug abuse, and schizophrenia intentionally ingested 120 tablets of quetiapine extended-release 300 mg (36 g). She was found unconscious and was transported to the emergency department. On admission her Glasgow Coma Scale score was 9, she was hypotensive, and her respiratory rate was 12 breaths/min. Venous blood gases indicated respiratory acidosis (pH 7.26, PCO2 92 mmHg) . Laboratory analyses showed a negative urine screen for opioids, cocaine, methadone and amphetamine. Blood screening was positive for quetiapine and ECG findings were normal. She was intubated and admitted to critical care with supportive therapy. Spontaneous breathing returned within 36 hours. She was treated with diazepam injections to manage psychotic symptoms and after 4 days of critical care was transferred to a separate facility where quetiapine was restarted. At a 4-month follow up she was maintaining therapy on extended-release quetiapine 300 mg/day in good condition (Capuano et al, 2011).
3) CASE REPORT: Following a massive overdose of 20 g, with no co-ingestants, a 26-year-old woman developed loss of consciousness with Glasgow Coma Score of 6. The patient was intubated for airway protection. A chest x-ray revealed bilateral infiltrates, but lungs were clear to auscultation. Arterial blood gas analysis showed pH 7.37, PCO2 38 mmHg, PO2 110 mmHg, and HCO3 24 at 95% O2 saturation on 40% FI02. The patient recovered and was discharged to psychiatric care 42 hours postingestion (Harmon et al, 1998).
4) CASE REPORT: A 52-year-old man was found comatose and in acute respiratory distress several hours after a suicidal ingestion of quetiapine. The patient died despite resuscitative attempts by the paramedics. Autopsy revealed cardiomegaly, left ventricular hypertrophy, and bilateral pulmonary congestion. A postmortem serum quetiapine level was 18,300 nanograms/mL. It is estimated that the patient ingested approximately 10,800 mg of quetiapine (Fernandes & Marcil, 2002).

B) HYPERVENTILATION

1) WITH THERAPEUTIC USE

a) An idiopathic adverse event of hyperventilation has been reported following the therapeutic use of quetiapine. A 69-year-old woman was noted to have hyperventilation shortly after taking quetiapine. She was admitted to the hospital and treated for tachypnea and acute respiratory alkalosis. It is suggested that quetiapine-induced hyperventilation may occur through a serotonin mediated peripheral mechanism. Symptoms improved after discontinuation of quetiapine (Shelton et al, 2000). This may also represent respiratory dyskinesia secondary to dopaminergic agents.

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Bilateral infiltrates consistent with ARDS were noted on chest x-ray in a 41-year-old man who was believed to have ingested 4500 mg of quetiapine. He presented with mental status changes, prolonged QTc interval, and myoclonus. Tricyclic antidepressants and valproic acid (subtherapeutic level) were detected in serum. Quetiapine was detected by gas chromatography. Within 24 hours from presentation, the patient developed progressive hypoxemia with an oxygen saturation as low as 62% and eventually became unresponsive to oxygen supplementation requiring intubation. High fraction oxygen and high levels of positive end-expiratory pressure were required to maintain oxygen saturation. The patient was discharged to psychiatric care after a 5 week hospital stay complicated by septicemia (Strachan & Benoff, 2006).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) The alpha-1-receptor blockade action of quetiapine is associated with orthostasis and syncope in overdoses. Also, quetiapine's affinity for H1 receptors may contribute to sedation and coma following massive overdoses. CNS depressive effects may include somnolence, drowsiness, slurred speech, ataxia, asthenia, dizziness, impaired judgement, and coma (Beelen et al, 2001; Pollak & Zbuk, 2000; Dev & Raniwalla, 2000; Mowry et al, 1999; Lynch et al, 1999; Anon, 1998; King et al, 1998; Small et al, 1997; Hirsch et al, 1996).

b) INCIDENCE

1) In a cohort study of consecutive quetiapine overdose cases reported during January 2000 and May 2007, of the 137 adult ingestions of quetiapine alone, 58 patients (42%) developed some degree of CNS depression (a Glasgow coma score (GCS) of less than 14) and 10 patients (7%) developed significant CNS depression (GCS of less than 9) (Isbister & Duffull, 2009).
2) In a retrospective chart review conducted by poison control centers from 2002 to 2006, 945 adult ingestions of quetiapine alone were identified, of those cases central nervous system effects including drowsiness were reported in 714 patients (76% [95% CI, 73% to 79%]) . Other events included: coma in 96 cases (10% [CI, 8% to 12%]), agitation in 56 cases (6% [95% CI, 4% to 8%]), and confusion in 22 cases (2% [95% CI, 1% to 3%]) (Ngo et al, 2008).
3) In a case series, 22% of patients with unintentional quetiapine exposures experienced drowsiness. Out of 209 suicidal ingestions, 46% reported drowsiness and 6% developed coma (Mowry et al, 1999).

c) CASE SERIES

1) In a series of 18 patients with quetiapine overdose, 8 (44%) developed a GCS of less than 15, and 3 (17%) developed a GCS of less than 9. Three patients developed delirium and 4 patients required mechanical ventilation for CNS and respiratory depression (Balit et al, 2003).

d) CASE REPORTS

1) A 34-year-old woman presented comatose (Glasgow Coma Scale [GCS] score 5) and tachycardic (159 beats/min) 2 to 4 hours after ingesting approximately 24 g of quetiapine. She experienced repetitive myoclonic jerks (forehead and abdominal wall) 1 hour after admission and 2 generalized tonic clonic seizures approximately 4 hours after admission (6 to 8 hours postingestion), which were successfully treated with lorazepam. Her GCS dropped to 3 two hours later, but following supportive care, her condition improved (GCS score of 8) and she was extubated 17 hours after admission (Bodmer et al, 2008).
2) Following a 20 g overdose, a 26-year-old woman lost consciousness and was reported to have Glasgow Coma Score (GCS) of 6 approximately 2.5 hours postingestion. Naloxone was administered with no response. The patient awoke simultaneously at 16 hours postingestion and was transferred to psychiatric care (Harmon et al, 1998).
3) The manufacturer reports 6 overdoses, ranging from 1200 mg to 9300 mg, during clinical trials. CNS depressive effects of drowsiness and sedation were reported in these patients (Prod Info Seroquel(R) Tablets, 1999).
4) Following an intentional ingestion of 9600 mg quetiapine, a 19-year-old man was reported to have coma (Glasgow Coma Scale of 6) which deteriorated to Glasgow Coma Scale of 3. Rapid improvement in neurological status occurred within 5.5 hours postingestion following symptomatic therapy (Gajwani et al, 2000; Hustey, 1999).
5) An overdose of 1300 mg in an 11-year-old girl resulted only in mental status changes of initial drowsiness followed by acute agitation, then prolonged somnolence after lorazepam treatment. Cardiotoxic or laboratory abnormalities were not seen (Juhl et al, 2002).
6) A 52-year-old man was found comatose and in acute respiratory distress several hours after a suicidal ingestion of quetiapine. The patient died despite resuscitative attempts by the paramedics. Autopsy revealed cardiomegaly, left ventricular hypertrophy, and bilateral pulmonary congestion. A post-mortem serum quetiapine level was 18,300 nanograms/mL. It is estimated that the patient ingested approximately 10,800 mg of quetiapine (Fernandes & Marcil, 2002).
7) A 38-year-old man became comatose, requiring mechanical ventilation, approximately 4 to 5 hours after reportedly ingesting 16,000 mg of valproate and 20,000 mg of quetiapine. The patient gradually regained consciousness following decontamination with activated charcoal and supportive care. A serum quetiapine level was not drawn (Raja & Azzoni, 2002).

B) DYSKINESIA

1) WITH THERAPEUTIC USE

a) Although not reported, some patients could develop dyskinetic movements following overdoses, especially elderly patients who may be more prone to dyskinesia syndromes (Prod Info SEROQUEL(R) oral tablets, 2007). Akathisia has been reported following therapeutic use of olanzapine, a related drug (Anon, 1998b).

2) WITH POISONING/EXPOSURE

C) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures have been reported in 0.5% (20 of 3490) of patients treated with quetiapine compared with 0.2% (2 of 954) on placebo and 0.7% (4 of 527) on active control drugs during clinical trials (Prod Info SEROQUEL(R) oral tablets, 2007). Patients with histories of seizures or conditions that lower the seizure threshold may be more prone to seizures following quetiapine therapy or overdose (Prod Info SEROQUEL(R) oral tablets, 2007; Anon, 1998).

2) WITH POISONING/EXPOSURE

a) SUMMARY

1) Seizures have been reported in premarketing clinical trials. Patients with histories of seizures or conditions that lower the seizure threshold may be more prone to seizures following quetiapine therapy or overdose (Prod Info SEROQUEL(R) oral tablets, 2007; Anon, 1998).

b) INCIDENCE

1) In retrospective chart review conducted by poison control centers from 2002 to 2006, 945 adult ingestions of quetiapine alone were identified, of those cases seizures occurred in 22 (2% [95% CI, 1% to 3%]) patients (Ngo et al, 2008). In a cohort study, seizures were more likely to occur following large ingestions along with the presence of co-ingestants (Isbister & Duffull, 2009).

c) CASE REPORTS/SERIES

1) CASE SERIES: In a retrospective case review involving 20 patients with quetiapine overdose, 4 experienced seizures (Eyer et al, 2011).
2) CASE REPORT: A 34-year-old woman presented comatose (Glasgow Coma Scale (GCS) score of 5) and tachycardic (159 beats/min) 2 to 4 hours after ingesting approximately 24 g of quetiapine. She experienced repetitive myoclonic jerks (forehead and abdominal wall) 1 hour after admission and 2 generalized tonic clonic seizures approximately 4 hours after admission (6 to 8 hours after ingestion), which were successfully treated with lorazepam. Her GCS dropped to 3 two hours later, but following supportive care, her condition improved (GCS score of 8) and she was extubated 17 hours after admission (Bodmer et al, 2008).
3) CASE REPORTS: Two cases with single seizures were reported in a case series of 209 patients taking intentional quetiapine overdoses (Mowry et al, 1999).
4) CASE SERIES: In a series of 18 patients with quetiapine overdose, 2 patients (11%) developed seizures (Balit et al, 2003).

d) DELAYED ONSET

1) CASE REPORT: A 27-year-old woman intentionally ingested 30 g of quetiapine and was initially somnolent but responsive to pain. She remained somnolent, and approximately 24 hours after ingestion she had 2 witnessed seizures. The patient was intubated and given lorazepam and diprovan (propofol), with no further seizures reported. Head CT and EEG were normal. Toxicology screening for drugs of abuse were negative. The patient gradually improved and was extubated by hospital day 4 and discharged by day 6 (Young et al, 2009).

D) MYOCLONUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Myoclonic jerks were reported in all extremities in a 41-year-old man who was believed to have ingested 4500 mg of quetiapine. He presented with mental status changes, prolonged QTc interval, and myoclonus. Startle myoclonus was also noted. Tricyclic antidepressants and valproic acid (subtherapeutic level) were detected in serum. Quetiapine was detected by gas chromatography. The patient was discharged to psychiatric care after a 5 week hospital stay complicated by hypoxemia, ARDS, and septicemia (Strachan & Benoff, 2006).
b) CASE REPORT: A 34-year-old woman presented comatose (Glasgow Coma Scale (GCS) score of 5) and tachycardic (159 beats/min) 2 to 4 hours after ingesting approximately 24 g of quetiapine. She experienced repetitive myoclonic jerks (forehead and abdominal wall) 1 hour after admission and 2 generalized tonic clonic seizures approximately 4 hours after admission (6 to 8 hours after ingestion), which were successfully treated with lorazepam. Her GCS dropped to 3 two hours later, but following supportive care, her condition improved (GCS score of 8) and she was extubated 17 hours after admission (Bodmer et al, 2008).

E) NEUROLEPTIC MALIGNANT SYNDROME

1) WITH THERAPEUTIC USE

a) Neuroleptic malignant syndrome (NMS) was reported in 2 patients (2 of 2387) during quetiapine clinical trials (Prod Info Seroquel(R) Tablets, quetiapine, 1999).

2) WITH POISONING/EXPOSURE

a) NMS has been reported in during quetiapine clinical trials. Although not reported in overdoses to date, it is important to recognize the clinical presentation, which may include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (Prod Info SEROQUEL(R) oral tablets, 2007). In 1 case, a 54-year-old patient who developed NMS following conventional antipsychotic medication (ie, haloperidol, chlorpromazine, and lorazepam) was challenged with quetiapine after discontinuation of his medications. He developed NMS on quetiapine challenge (Hatch et al, 2001).

F) FEELING AGITATED

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Agitation has been reported in a 34-year-old woman 39 hours after ingesting approximately 24 g of quetiapine. Initially, she presented comatose (Glasgow Coma Scale score of 5) and tachycardic (159 beats/min) 2 to 4 hours postingestion. She also experienced repetitive myoclonic jerks (forehead and abdominal wall), 2 generalized tonic clonic seizures, and prolonged QTc interval. Following supportive care, she recovered gradually over the next several hours (Bodmer et al, 2008).

G) LETHARGY

1) WITH POISONING/EXPOSURE

a) A 19-year-old female developed lethargy and transiently elevated liver enzyme levels following an intentional ingestion of 14 g of quetiapine. Continuous cardiac monitoring following the ingestion indicated no cardiac conduction abnormalities (Vivek, 2004).

Gastrointestinal

3.8.2)

A) PARASYMPATHOLYTIC POISONING

1) WITH THERAPEUTIC USE

a) Anticholinergic effects, consisting of constipation and dry mouth, are adverse effects of quetiapine therapy, with dry mouth occurring in 8% to 17% of schizophrenic patients in clinical trials (Small et al, 1997; Borison et al, 1996; Fulton & Goa, 1995). Constipation and dyspepsia occurred less commonly (Borison et al, 1996; Wetzel et al, 1995) . These effects are dose-related and may be anticipated following overdose.

2) WITH POISONING/EXPOSURE

a) An adult developed a dry mouth following an overdose of 3000 mg (Pollak & Zbuk, 2000).

B) BEZOAR

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In an observational study, 239 quetiapine extended-release overdoses were identified during the 2-year study period. Gastroscopic evaluation was performed in 19 cases due to suspicion of bezoar formation, delayed toxicity, and other potentially toxic coingestants. Of the 19 cases, 9 patients had gastric pharmacobezoars following the ingestion of large doses of extended-release quetiapine (ie, 10 to 61 tablets {6 to 24.4 g}). All patients except one ingested another agent but only 3 patients ingested another extended-release drug product (ie, venlafaxine, paliperidone). In each case, the bezoar was successfully removed followed by the oral administration of activated charcoal in 8 patients. Significant toxicity was not reported in any patient and the average length of stay was 1 to 2 days and up to 3 days in 2 patients (Rauber-Luthy et al, 2013).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Quetiapine therapy has been associated with asymptomatic elevations of serum transaminases and occasionally, serum bilirubin (approximately 15% of patients) (Dev & Raniwalla, 2000; Borison et al, 1996; Hirsch et al, 1996; Anon, 1995; Fabre et al, 1995a; Wetzel et al, 1995). In all patients, abnormalities have returned to normal after discontinuation of the drug. These effects appear to be dose- dependent.

2) WITH POISONING/EXPOSURE

a) Asymptomatic elevations of serum transaminases and serum bilirubin may occur following overdoses. These effects appear to be dose-dependent (Vivek, 2004; Dev & Raniwalla, 2000; Borison et al, 1996; Hirsch et al, 1996).

Genitourinary

3.10.2)

A) PRIAPISM

1) WITH POISONING/EXPOSURE

a) Priapism may result following a quetiapine overdose due to alpha-adrenergic blockade. Several hours following an overdose of 675 mg quetiapine, a 43-year-old man developed painful priapism. He reported to the emergency department after 18 hours of a painful erection. Resolution of the priapism was achieved with an intracavernosal phenylephrine injection followed by a cavernosal-glanular shunt (Pais & Ayvazian, 2001).

B) RETENTION OF URINE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 48-year-old woman reported urinary hesitancy 10 days after beginning quetiapine therapy 1800 mg daily and progressing to complete urinary retention after increasing the dose to 2400 mg daily. The patient was also taking diphenhydramine 100 mg daily. Ultrasound showed no signs of urinary obstruction and a lumbar MRI did not indicate impingement of the spinal cord. The patient recovered following urinary catheterization and a decrease in her quetiapine dosage regimen to 900 mg daily. Two months later, urinary hesitancy recurred after the patient increased the dosage of her quetiapine to 1800 mg daily, while taking diphenhydramine 75 mg daily. The patient again recovered after decreasing the quetiapine regimen to 900 mg daily (Sokolski et al, 2004). It is believed that the urinary retention is due to an anticholinergic effect potentiated by the coadministration of diphenhydramine and high-dose quetiapine therapy.

C) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute renal failure secondary to rhabdomyolysis occurred in a 19-year-old man following ingestion of 12,000 mg of quetiapine. Laboratory analysis performed 2.5 days postingestion showed a CPK level of 47,663, a myoglobin of 7267, a BUN of 68, and a serum creatinine level of 4.5. Five days after the patient was admitted the hospital, his BUN and serum creatinine levels increased to 126 and 13.8, respectively, prompting initiation of hemodialysis. The patient's BUN and serum creatinine levels normalized 7 days later, with no evidence of permanent renal sequelae reported (Smith et al, 2004).

Reproductive

3.20.1)

3.20.2)

A) CASE REPORT

1) THIRD TRIMESTER OVERDOSE

a) During an inpatient admission for psychosis, a 29-year-old gravida 3 woman attempted suicide at gestational week 37 by ingesting an unknown amount of quetiapine. She had intentionally minimized her food intake for several weeks to potentially harm the fetus. She had a witnessed seizure after exposure followed by a coma-like state and hypotension. The infant was delivered emergently via cesarean section and was underweight (1970 g (second percentile)) with an initial Apgar score of 7/7/7. Quetiapine levels in maternal serum was 1370 ng/mL and 1790 ng/mL (blood sample obtained immediately postpartum) in the infant. At birth the infant showed signs of respiratory insufficiency along with respiratory-metabolic acidosis. Following treatment the infant improved and was discharged on day 21 in good condition to a foster family (Paulzen et al, 2015).

B) CONGENITAL MALFORMATIONS

1) A systematic review of the literature found no significant correlation between first-trimester exposure to quetiapine and risk of congenital malformations. However, of 443 pregnancies with first-trimester exposure, 16 malformations were observed, resulting in a malformation rate of 3.6% (Ennis & Damkier, 2015).

C) LACK OF EFFECT

1) No major malformations were reported in infants who were born to 21 women exposed to quetiapine and other psychoactive medications during pregnancy in a prospective, observational study, or in 42 other infants (from 1 study in 36 women and 6 case reports) born to women who used quetiapine during pregnancy. However, with the limited published data on quetiapine exposure during pregnancy, the frequency or absence of adverse outcomes cannot be reliably established (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).
2) CASE REPORT: A 33-year-old woman was treated with fluvoxamine 200 mg/day and quetiapine 400 mg/day, during her second pregnancy, resulting in an uneventful pregnancy and the birth of a healthy female infant. The patient gained 9 kg with no symptoms of psychiatric instability. Routine biochemical tests were within the normal range and 5 echographic reports found no fetal abnormalities. The presence of an intrauterine myoma led to an elective caesarean-section. A healthy female infant weighing 2600 g and measuring 49 cm in length had Apgar scores of 9 and 10 at 1 minute and 5 minutes, respectively (Gentile, 2006).
3) One case report describes the maternal use of quetiapine 300 to 400 mg throughout gestation, and the subsequent birth of a healthy male infant without abnormality. At 6 months of age, the infant was developing normally (Tenyi et al, 2003).

D) ANIMAL STUDIES

1) RATS AND RABBITS: Pregnant rats and rabbits were treated with quetiapine up to 2.4 times the maximum recommended human dose (MRHD) of 800 mg/day for schizophrenia; no teratogenicity was observed. However, embryo/fetal toxicity (delays in skeletal ossification) was observed in rats and rabbits at doses approximately 1 and 2 times the MRHD and 1.2 to 2.4 times the MRHD, respectively. In both rats and rabbits, reduced fetal body weight was observed and there was an increased incidence of minor soft tissue anomaly (carpal/tarsal flexure) in rabbits at 2 times the MRHD (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

3.20.3)

A) PREGNANCY CATEGORY

1) Quetiapine is classified as FDA pregnancy category C (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).
2) A prospective, observational study of 54 women (mean age, 30.7 years) recruited from the Emory Women’s Mental Health program exposed to antipsychotic medication during pregnancy showed permeability of the placental barrier. Outcomes were determined by maternal and umbilical cord blood samples taken at delivery and though data collected from maternal reports and medical records. Placental passage showed a significant difference between antipsychotic medications, olanzapine 72.1% (95% confidence interval (CI), 46.8% to 97.5%) being the highest, followed by haloperidol 65.5% (95% CI, 40.3% to 90.7%), risperidone 49.2% (95% CI, 13.6% to 84.8%), and quetiapine 24.1% (95% CI, 18.7% to 29.5%), showing the lowest placental passage. In the quetiapine group (n=21), there was one case of preterm labor (less than 37 weeks gestation) and 2 infants that required neonatal intensive care admission. Seven neonates developed respiratory complications and 2 developed cardiovascular events. Low birth weight (less than 2500 g) occurred in 1 infant (Newport et al, 2007).

B) EXTRAPYRAMIDAL AND/OR WITHDRAWAL SYMPTOMS

1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

C) LACK OF EFFECT

1) In a retrospective cohort study, 2 cases of gestational diabetes mellitus in women taking quetiapine during pregnancy were reported. Both cases were uncomplicated by fetal or neonatal outcomes (Gentile, 2014).

D) ANIMAL STUDIES

1) Pregnant rats and rabbits were treated with quetiapine up to 2.4 times the maximum recommended human dose (MRHD) of 800 mg/day for schizophrenia. The high quetiapine dose in rats and all doses in rabbits produced maternal toxicity (ie, decreases in body weight gain and/or mortality) . In a perio/postnatal reproductive study in rats, no quetiapine-related effects were observed at 0.01, 0.12, and 0.2 times the MRHD. There were, however, increased fetal and pup death and decreased mean litter weights in rats at 3 times the MRHD (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

3.20.4)

A) BREAST MILK

1) Quetiapine is excreted in human breast milk. In published case reports, the level of quetiapine in breast milk was undetectable up to 170 mcg/L, with an estimated infant dose ranging from 0.09% to 0.43% of the maternal dose after adjusting for weight. The calculated infant daily doses based on a limited number of mother-infant pairs (n=8) range from less than 0.01 mg/kg (for a maternal dose up to 100 mg/day) to 0.1 mg/kg for a maternal dose of 400 mg/day (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

B) LACK OF EFFECT

1) CASE REPORT: A 26-year-old woman, prescribed quetiapine 400 mg daily, demonstrated a milk to plasma (M:P) ratio of 0.29 (an estimated relative infant dose of 0.09% of the maternal weight-adjusted dose) while breastfeeding her 3-month-old infant, suggesting a low level of exposure generally acceptable for breastfeeding. The infant's plasma contained quetiapine 1.4 mcg/L equivalent to 6% of the maternal plasma concentration. Upon clinical examination, the infant was healthy and his Denver age was the same as his chronological age (Rampono et al, 2007).
2) CASE REPORT: A 33-year-old woman was treated with fluvoxamine 200 mg/day and quetiapine 400 mg/day, during her second pregnancy, resulting in an uneventful pregnancy and the birth of a healthy female infant weighing 2600 g and measuring 49 cm in length with Apgar scores of 9 and 10 at 1 minute and 5 minutes, respectively. The patient chose to breastfeed; however, formula was required to supplement her breast milk due to insufficient milk production. In the 3 months that the infant received breast milk supplemented with formula, no adverse effects were detected and the infant continues to develop normally (Gentile, 2006).

3.20.5)

A) ANIMAL STUDIES

1) RATS: In male rats, the interval to mate and the number of matings required to produce pregnancy increased at quetiapine doses of 50 and 150 mg/kg (equivalent to 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 800 mg/day). After a 2-week period without quetiapine treatment, these effects continued at a dose of 150 mg/kg. The no-effect dose for mating and fertility impairment in male rats was 25 mg/kg (0.3 times the maximum human dose) (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).
2) RATS: In female rats, the interval to mate increased and the number of matings and the number of matings resulting in pregnancy decreased at a quetiapine dose of 50 mg/kg (approximately 1 time the maximum recommended human dose (MRHD) of 800 mg/day). At quetiapine doses of 10 and 50 mg/kg (0.1 and 1 times the MRHD, respectively), an increase in irregular estrus cycles was noted. The no-effect dose in female rats was 1 mg/kg (0.01 times the MRHD) (Prod Info SEROQUEL(R) oral tablets, 2013; Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

Carcinogenicity

3.21.2)

A) No tumorigenesis has been demonstrated with the class of drugs that increase prolactin release, including quetiapine, after chronic administration.

3.21.3)

A) LACK OF EFFECT

1) No tumorigenesis has been demonstrated with the class of drugs that increase prolactin release, including quetiapine, after chronic administration (Prod Info SEROQUEL(R) oral tablets, 2009; Prod Info SEROQUEL XR(R) extended-release oral tablets, 2009).

3.21.4)

A) THYROID CARCINOMA

1) Statistically significant increases in thyroid gland follicular adenomas were reported in male mice at doses of 250 mg/kg and 750 mg/kg (1.5 and 4.5 times the maximum human dose on mg/m(2) basis, respectively) when given as part of the diet for 2 years. Male rats also demonstrated an increased risk after a gavage dose of 250 mg/kg (3 times the maximum human dose on mg/m(2) basis) for 2 years (Prod Info SEROQUEL(R) oral tablets, 2009; Prod Info SEROQUEL XR(R) extended-release oral tablets, 2009).

B) MAMMARY GLAND ADENOCARCINOMA

1) Statistically significant increases in mammary gland adenocarcinomas were reported in female rats at doses of 25 mg/kg, 75 mg/kg and 250 mg/kg (0.3, 0.9, and 3 times the maximum human dose on mg/m(2) basis, respectively) when given by gavage for 2 years (Prod Info SEROQUEL(R) oral tablets, 2009; Prod Info SEROQUEL XR(R) extended-release oral tablets, 2009).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Quetiapine plasma levels are not rapidly available or clinically useful in the treatment of overdose.
C) No specific lab work is needed in most patients. Monitor creatinine phosphokinase levels in patients with prolonged CNS depression, myoclonus or seizures.
D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) LIVER FUNCTION: Reversible elevations of serum liver enzymes have been reported during quetiapine therapy and may develop in overdose (Prod Info SEROQUEL(R) oral tablets, 2009).

4.1.3)

A) ASSAY INTERFERENCE

1) Quetiapine can cause a false positive urine immunoassay for tricyclic antidepressants using the Microgenics(R) Tricyclic Serum Tox EIA Assay or the Syva(R) RapidTest d.a.u.. The Biosite Triage(R) Panel for Drugs of Abuse immunoassay was negative for samples with a concentration of quetiapine up to 1000 mcg/mL (Hendrickson & Morocco, 2003).
2) Chlordiazepoxide, norclobazam, and promethazine may interfere with quetiapine determination by high-performance liquid chromatography (Bodmer et al, 2008).
3) A blinded, in vitro study evaluated the degree to which quetiapine in therapeutic and supratherapeutic plasma levels may cross-react with quantitative (using TDx assay) and qualitative (using S TAD and Emit assays) plasma TCA immunoassays using commonly available autoanalyzers. The quantitative assay revealed concentration-related TCA cross-reactivity starting at quetiapine levels of 5 ng/mL and increasing with each subsequent sample. Using the Abbot TCA TDx Assay on the TDxFLx autoanalyzer, the quetiapine sample concentration of 640 ng/mL produced TCA results of 379 and 385 ng/mL in 2 separate laboratories (the Sylva Emit tox Serum TCA Assay on the AU 400 autoanalyzer and the S TAD Serum TCA Screen on the ACA-Star 300 autoanalyzer), respectively. The qualitative TCA assays were screened as positive with quetiapine sample concentrations of >/= 160 ng/mL and >/= 320 ng/mL for the S TAD and Emit assays, respectively (Caravati et al, 2005).

4.1.4)

A) OTHER

1) ECG

a) ECG: Continuous electrocardiogram monitoring is recommended following substantial overdoses, due to the potential for tachydysrhythmias and ECG changes (eg,, QTc prolongation) (Prod Info SEROQUEL(R) oral tablets, 2009; Beelen et al, 2001).

2) OTHER

a) Monitor pulse oximetry and/or arterial blood gases in symptomatic patients.

Methods

1) High-performance liquid chromatography has been used to determine quetiapine plasma concentrations; a limit of quantification and limit of detection were 0.020 mg/L and 0.010 mg/L, respectively (Bodmer et al, 2008).
2) Fabre et al (1995) used a validated high-pressure liquid chromatography method with fluorescence detection and a quantitation limit of 2 ng/mL to analyze plasma samples of quetiapine (Fabre et al, 1995).
3) Following an overdose, quetiapine plasma concentrations were measured using gas chromatography with a lower limit of quantitation of 5 ng/mL (Beelen et al, 2001).
4) Quetiapine was identified and quantitated in postmortem biological specimens using a basic liquid-liquid extraction and capillary gas chromatography with nitrogen phosphorus detection. The results were confirmed by full scan electron impact gas chromatography/mass spectrometry (Wise & Jenkins, 2005).
5) The following methods were also used: quantitation in human serum by C2 cartridge solid phase extraction and liquid chromatography with ultra-violet absorbance detection; n-butylchloride basic extraction with gas chromatograph (GC) (nitrogen phosphorus detection (NPD); GC-mass spectrometric confirmation; thin layer chromatography using the Ansys Diagnostics, Inc, Toxi-Lab A system with a limit of detection of 0.50 mcg/mL in urine (Wise & Jenkins, 2005).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any patient with persistent hypotension, CNS depression, seizures, or myoclonus should be admitted to the hospital.

6.3.1.2) HOME CRITERIA/ORAL

A) Children less than 12 years of age who are naive to quetiapine can be observed at home following an unintentional ingestion of 100 mg or less and are only experiencing mild sedation. All patients, 12 years of age or older, who are naive to quetiapine, can be observed at home following an unintentional ingestion of 125 mg or less and are experiencing only mild sedation. All patients who are taking quetiapine on a chronic basis can be observed at home if they have acutely ingested no more than 5 times their current single dose (not daily dose) of quetiapine (Cobaugh et al, 2007).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity (CNS depression, seizures) or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility. Children less than 12 years of age who are naive to quetiapine should be referred to a healthcare facility following an unintentional ingestion of more than 100 mg. All patients, 12 years of age or older, who are naive to quetiapine should be referred to a healthcare facility following an unintentional ingestion of more than 125 mg. All patients who are taking quetiapine on a chronic basis should be referred to a healthcare facility following an acute ingestion of more than 5 times their current single dose (not daily dose) of quetiapine (Cobaugh et al, 2007).
B) Patients should be observed for 6 hours (or at least 12 hours after ingestion of extended-release formulations) and should be admitted if they remain symptomatic

Monitoring

Oral Exposure

6.5.1)

A) ACTIVATED CHARCOAL

1) COHORT STUDY: In a cohort study of 176 consecutive quetiapine overdose patients observed on 286 occasions to evaluate the probability and duration of mechanical ventilation, single dose activated charcoal (SDAC) administered within 2 hours may be able to minimize the probability of intubation, but the findings only supported a modest benefit and did not alter the duration of mechanical ventilation. In addition, doses of activated charcoal given at any time or within 4 hours of exposure did not reduce the probability of intubation (Isbister & Duffull, 2009).
2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) Early administration of activated charcoal was associated with a modest decrease in the need for intubation in one study.

a) In a cohort study of 176 consecutive quetiapine overdose patients observed on 286 occasions to evaluate the probability and duration of mechanical ventilation, single dose activated charcoal (SDAC) administered within 2 hours of exposure was associated with a modest decrease in the need for intubation. SDAC administered within 2 hours of ingestions reduced the probability of intubation by 7% if the median dose of quetiapine ingested was 2 g, while there was a 17% reduction in intubation if the dose ingested was 10 g (Odds Ratio (OR) for the administration of charcoal versus no charcoal was 0.37 (93% probability that it is less than 1.0)).

2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

B) BEZOAR FORMATION

1) EXTENDED RELEASE FORMULATIONS: Extended release formulations have been associated with pharmacobezoar formation following acute exposure (Rauber-Luthy et al, 2013).
2) CASE SERIES: In an observational study, 239 quetiapine extended-release cases were identified during the 2 year study period. Gastroscopic evaluation was performed in 19 cases due to suspicion of bezoar formation, delayed toxicity, and other potentially toxic coingestants. Of the 19 cases, 9 patients had gastric pharmacobezoars following the ingestion of large doses of extended-release quetiapine (ie, 10 to 61 tablets {6 to 24.4 g}). All patients except one ingested another agent but only 3 patients ingested another extended-release drug product (ie, venlafaxine, paliperidone). In each case, the bezoar was successfully removed followed by the oral administration of activated charcoal in 8 patients. Significant toxicity was not reported in any patient and the average length of stay was 1 to 2 days and up to 3 days in 2 patients (Rauber-Luthy et al, 2013).

6.5.3)

A) SUPPORT

1) There is no specific antidote. Treatment is symptomatic and supportive. Patients should be monitored for respiratory and CNS depression, the possibility of seizures, and hypotension. The clinician should consider the possibility of multiple drug involvement in any quetiapine overdose.

B) AIRWAY MANAGEMENT

1) Establish and maintain an airway if needed for respiratory or CNS depression; ensure adequate oxygenation and ventilation. The risk for intubation appears to be dose-dependent.
2) RISK FOR INTUBATION

a) COHORT STUDY: In a cohort study of 176 consecutive quetiapine overdose patients observed on 286 occasions to evaluate the probability and duration of mechanical ventilation, single dose activated charcoal (SDAC) administered within 2 hours of exposure was associated with a modest decrease in the need for intubation. Of the patients (38 occasions) that required intubation, the median dose ingested was 5000 mg (Interquartile Range: 2520 to 11850 mg) with a median duration of ventilation of 21 hours. In this study, the probability of intubation was dose-dependent (eg, 10% after 2 g, 22% after 5 g, 37% after 10 g and 55% after 20 g) (Isbister & Duffull, 2009).

C) MONITORING OF PATIENT

1) Monitor patients for elevated liver enzymes, tachycardia, and antimuscarinic effects.
2) Quetiapine plasma levels are not rapidly available or clinically useful in the treatment of overdose.
3) No specific lab work is needed in most patients. Monitor creatinine phosphokinase levels in a patient with prolonged CNS depression, myoclonus or seizures.
4) Continuous cardiovascular monitoring, including continuous ECG monitoring to detect possible dysrhythmias, should be instituted in all symptomatic patients or following significant exposures. Avoid disopyramide, procainamide, and quinidine, which may worsen QT prolongation following a quetiapine overdose(Prod Info SEROQUEL(R) oral tablets, 2009).

D) HYPOTENSIVE EPISODE

1) Administer IV fluids and place in Trendelenburg position. In theory agents with beta adrenergic activity such as epinephrine or dopamine may worsen hypotension in the setting of quetiapine-induced alpha blockade. If hypotension is unresponsive to IV fluids, agents with alpha adrenergic effects such as norepinephrine or phenylephrine may be preferred. Agents with alpha adrenergic blocking properties, such as bretylium, should be avoided in quetiapine overdoses, since the hypotensive effects may be additive.
2) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

3) PHENYLEPHRINE: In order to rapidly raise blood pressure, a continuous intravenous infusion of 100 micrograms to 180 micrograms per minute should be started. If an initial pressor response is not attained, adjust the rate of flow upwards until a desired blood pressure level is obtained. Titrate down to a maintenance dose of 40 micrograms to 60 micrograms per minute when blood pressure stabilizes (Prod Info Neo-Synephrine(R), 1996).

E) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

F) DRUG-INDUCED DYSTONIA

1) ADULT

a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).

2) CHILDREN

a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).

G) PRIAPISM

1) SUMMARY

a) Priapism may result following a quetiapine overdose due to alpha-adrenergic blockade. A urology consult should be requested following a quetiapine overdose resulting in priapism. Initially, cavernosal aspiration followed by intracavernosal injections of epinephrine or phenylephrine may be administered. If unsuccessful, a cavernosal-glanular shunt may be performed (Pais & Ayvazian, 2001).

2) GUIDELINES ON THE MANAGEMENT OF PRIAPISM

a) The following American Urological Association Guideline has been developed to evaluate and treat priapism (Montague et al, 2003):

1) Ischemic priapism is characterized by little or no cavernous blood flow and abnormal cavernous blood gases (hypoxic, hypercarbic and acidotic).

a) CLINICAL HISTORY: A clear history can determine the most effective treatment and should include the following:

1) Duration of erection.
2) Degree of pain (ischemic priapism is painful; nonischemic is not painful).
3) Use of drug(s) associated with priapism (eg, antihypertensives, anticoagulants, antidepressants, illegal agents).
4) Underlying disease (eg, sickle cell) or trauma.

b) LABORATORY ANALYSIS: CBC, reticulocyte count, hemoglobin electrophoresis to rule out acute infection or underlying disease, psychoactive medication screening, and urine toxicology.
c) PHYSICAL EXAMINATION: In a patient with ischemic priapism the corpora cavernosa are often completely rigid and painful while nonischemic priapism the corpora are typically tumescent, but not completely rigid, and is usually not painful.
d) DIAGNOSTIC STUDIES: Blood gas testing and color duplex ultrasonography are the most reliable methods to distinguish between ischemic and nonischemic priapism.

1) Ischemic finding: Blood aspirated from the corpus cavernosum is hypoxic and appears dark, and on blood gas testing typically has a PO2 of less than 30 mmHg and a PCO2 of greater than 60 mmHg and a pH of less than 7.25.
2) Nonischemic finding: Blood is generally well oxygenated and appears bright red. Cavernosal blood gases are similar to normal arterial blood gas findings.
3) Color Duplex Ultrasonography: Ischemic patient: Little or no blood flow in the cavernosal arteries.
4) Penile Arteriography: An adjunctive study that has been mostly replaced by ultrasonography; it is often used only as part of an embolization procedure.

e) TREATMENT: Ischemic priapism: Initial treatment usually includes therapeutic aspiration (with or without irrigation) followed by intracavernous injection of sympathomimetics (agents frequently used: epinephrine, norepinephrine, phenylephrine, ephedrine and metaraminol) as needed. Of these agents, resolution of ischemic effects occurred in 81% treated with epinephrine, 70% with metaraminol, 43% with norepinephrine and 65% with phenylephrine. To minimize adverse events, phenylephrine is an alpha1-selective adrenergic agonist is often selected because it produces no indirect neurotransmitter releasing action. Repeat sympathomimetic injection prior to considering surgical intervention.

1) PHENYLEPHRINE: Dose: Adult: For intracavernous injection, dilute phenylephrine with normal saline for a concentration of 100 to 500 mcg/mL and 1 mL injections every 3 to 5 minutes for approximately 1 hour (before deciding that treatment is not successful). For children and patients with cardiovascular disease: Use lower concentrations in smaller volumes. NOTE: Treatment is less likely to be effective if done more than 48 hours after the development of priapism.
2) DISTAL SHUNTING (NOT first -line therapy): Inserting a surgical shunt should ONLY be considered after a trial of intracavernous injection of sympathomimetics. A caveroglanular (corporoglanular) shunt is the preferred method to avoid complications.

H) EXPERIMENTAL THERAPY

1) INTRAVENOUS LIPID EMULSION THERAPY

a) CASE REPORT: A 29-year-old woman was found comatose by her family with empty packs of quetiapine, escitalopram, ibuprofen, and amoxicillin found nearby. The estimated dosages were as follows: 9 g quetiapine, 4 g ibuprofen, 280 mg escitalopram and 5 g amoxicillin. Upon admission, she was disoriented and responded to painful stimuli only and was found to be hypotensive (BP 90/55 mm Hg) and tachycardic (110 beats/min). She was immediately intubated and ventilated and received 2 L of isotonic IV fluids with little clinical improvement. One hour after admission, an intravenous lipid (20%) infusion was started due to the lipophilic properties of quetiapine with a total bolus dose of 3 mg/kg given in 2 equal doses at 15 minute intervals; an infusion was not needed. Approximately 30 minutes following the second bolus dose, BP increased to 115/70 mm Hg and heart rate decreased to 95 beats/min and the patient opened her eyes spontaneously. Within 3 hours she was successfully extubated. She continued to improve and required no additional therapies or medications and was discharged to home the next day with psychiatric outpatient follow-up (Arslan et al, 2013).
b) CASE REPORT: An adult was admitted comatose approximately 3.5 hours after intentionally ingesting 4.3 grams of quetiapine and 3.1 grams of sertraline. Initially, the patient was hypotensive (88/64 mmHg) and in normal sinus rhythm (heart rate 80 beats per minute) with spontaneous respirations. Glasgow Coma Score (GCS) was 3 on admission. Based on his clinical symptoms and the lipophilic nature of the ingested drugs, the patient was started on a 20% lipid emulsion at an initial bolus dose of 1.5 mL/kg (100 mL), which was followed by an infusion of 6 mL/kg (400 mL) over the next hour. The patient rapidly regained consciousness within 15 minutes and was able to protect his airway. The patient continued to neurologically improve and remained hemodynamically stable. Quetiapine and sertraline serum concentrations could not be obtained; a benzodiazepine level was negative. Nineteen hours after exposure the patient had a GCS of 12, and was transferred a few hours later to a psychiatric care setting with a GCS of 15 (Finn et al, 2009).
c) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
d) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):

1) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
2) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
3) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
4) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

2) EXTRACORPOREAL LIFE SUPPORT

a) CASE REPORT: A 40 year-old woman, with a history of schizophrenia, was admitted with decreased consciousness following a suspected overdose and had a complicated clinical course that was successfully treated with extracorporeal circulatory support (ECCS). Her admission vital signs were as follows: immeasurable blood pressure, irregular bradycardia, hypothermia and Glasgow Coma Scale (GCS) of 8. An ECG showed a slow wave irregular rhythm at a rate of 30 beats/min and widened QRS complexes. Intravenous fluid replacement was started. Spontaneous breathing was present with oxygen supplementation via mask. Severe metabolic acidosis (pH 7.18, base excess -18, pCO2 2.9 kPa, pO2 40.2 kPa and a lactate of 7.5 mmol/L) developed shortly after admission. The patient was intubated and ventilated. An echocardiogram showed abnormal myocardial contractility along with decreased stroke volume and cardiac output. Mean arterial blood pressure remained low (below 60 mm Hg) despite volume replacement. Continuous renal replacement therapy (CRRT/CVVHF-D) was initiated due to ongoing severe metabolic acidosis, an unknown ingestant and to improve hemodynamic function. However, clinical improvement was only temporary and worsening metabolic acidosis and hypotension (MAP below 50 mm Hg) were observed. The patient was transferred to another hospital to receive ECCS and gradually circulation began to improve along with successful weaning of vasopressor support. ECCS was needed for approximately 48 hours. The patient was successfully extubated by the end of this period. She slowly became more alert and was hemodynamically stable. The patient was transferred to a medical floor on day 4 and was discharged to home on day 10 fully recovered. Laboratory analysis obtained 24 hours after admission was positive for quetiapine (715 ng/mL) only; it decreased to 124 ng/mL by the following day (Lannemyr & Knudsen, 2012).

Enhanced Elimination

1) Methods such as forced diuresis, hemodialysis, hemoperfusion, and exchange transfusion are NOT LIKELY to be of benefit in treating quetiapine overdose due to extensive protein binding (83%) and a volume of distribution of approximately 10 (+/- 4) L/kg (Prod Info SEROQUEL(R) oral tablets, 2009).

Abstracts

Case Reports

1) An acute quetiapine overdose of 20,000 mg resulted in loss of consciousness at 2.5 hours postingestion, with no response to naloxone, in a 26-year-old woman. Pupils were 3 mm and sluggish. Heart rate was recorded at 135 beats/min. At 5 hours postingestion, the patient was reported with a Glasgow Coma Score of 6. The patient was paralyzed and intubated prior to air transport to a medical facility. On arrival at a medical facility, the patient had a heart rate of 136 beats/min, blood pressure of 147/90 mmHg, oxygen saturation of 98%, and respiratory rate of 12 beats/min. Chest x-ray revealed bilateral pulmonary infiltrates. At 16 hours postingestion, the patient was awake and agitated. Metoprolol was started to control persistent sinus tachycardia. ECG at 18 hours postingestion revealed sinus tachycardia (120 to 150). This lasted approximately 40 hours postingestion. At 42 hours postingestion an ECG was normal for her pretherapy baseline heart rate of 100 to 110 beats/min. The patient was transferred to a psychiatric hospital (Harmon et al, 1998).
2) An acute quetiapine overdose of 9600 mg in a 19-year-old man resulted in tachycardia, hypotension, rapidly progressive coma, and prolonged QTc, which peaked at 710 msec 14 hours postingestion on ECG. The patient recovered following symptomatic therapy (Hustey, 1999; Gajwani et al, 2000).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) BIPOLAR DISORDER, DEPRESSION

1) REGULAR-RELEASE TABLETS: Usual initial dose is 50 mg once daily at bedtime followed with titration to 300 mg once daily (Prod Info SEROQUEL(R) oral tablets, 2013).
2) EXTENDED-RELEASE TABLETS: Usual initial dose is 50 mg once daily, preferably in the evening, followed with titration to 300 mg/day as a single dose (Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

B) BIPOLAR DISORDER, MANIA

1) REGULAR-RELEASE TABLETS: Usual initial dose is 50 mg twice daily followed with titration to 400 mg/day to 800 mg/day, divided and given twice daily (Prod Info SEROQUEL(R) oral tablets, 2013).
2) EXTENDED-RELEASE TABLETS: Usual initial dose for mania or mixed episode of bipolar disorder is 300 mg once daily, preferably in the evening, followed with titration to 400 mg/day to 800 mg/day as a single dose (Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

C) BIPOLAR DISORDER, MAINTENANCE

1) REGULAR-RELEASE TABLETS: 400 mg/day to 800 mg/day, divided and given twice daily; maximum dose is 800 mg/day (Prod Info SEROQUEL(R) oral tablets, 2013).
2) EXTENDED-RELEASE TABLETS: 400 mg/day to 800 mg/day given as a single dose, preferably in the evening; maximum dose is 800 mg/day(Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

D) MAJOR DEPRESSIVE DISORDER, ADJUNCT

1) EXTENDED-RELEASE TABLETS: Usual initial dose is 50 mg once daily in the evening followed with titration to 150 mg/day to 300 mg/day as a single dose. The MAXIMUM dose is 300 mg/day (Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

E) SCHIZOPHRENIA

1) REGULAR-RELEASE TABLETS: Usual initial dose is 25 mg twice daily followed with titration to 150 mg/day to 750 mg/day, divided and given as 2 or 3 doses per day. The maintenance dose is 400 mg/day to 800 mg/day, and the maximum dose is 800 mg/day (Prod Info SEROQUEL(R) oral tablets, 2013).
2) EXTENDED-RELEASE TABLETS: Usual initial dose is 300 mg once daily, preferably in the evening, followed with titration to 400 mg/day to 800 mg/day (maintenance) as a single dose. The MAXIMUM dose is 800 mg/day (Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

7.2.2)

A) BIPOLAR DISORDER, MANIA

1) REGULAR-RELEASE TABLETS: CHILDREN AND ADOLESCENTS 10 to 17 YEARS OLD: Usual initial dose is 25 mg twice daily followed with titration to 400 mg/day to 600 mg/day, divided and given as 2 or 3 doses per day; MAXIMUM dose is 600 mg/day (Prod Info SEROQUEL(R) oral tablets, 2013).
2) CHILDREN AND ADOLESCENTS 10 to 17 YEARS OLD, EXTENDED-RELEASE TABLETS: Usual initial dose is 50 mg once daily followed with titration to 400 mg/day to 600 mg/day as a sing dose; MAXIMUM dose is 600 mg/day (Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

B) SCHIZOPHRENIA

1) REGULAR-RELEASE TABLETS: ADOLESCENTS 13 to 17 YEARS OLD: Usual initial dose is 25 mg twice daily followed with titration to 400 mg/day to 800 mg/day, divided and given as 2 or 3 doses per day; the MAXIMUM dose is 800 mg/day (Prod Info SEROQUEL(R) oral tablets, 2013).
2) ADOLESCENTS 13 to 17 YEARS OLD, EXTENDED-RELEASE TABLETS: Usual initial dose is 50 mg once daily followed with titration to 400 mg/day to 800 mg/day as a sing dose; MAXIMUM dose is 800 mg/day (Prod Info SEROQUEL XR(R) oral extended-release tablets, 2013).

Minimum Lethal Exposure

1) An adult developed respiratory failure and died of an asystolic cardiac arrest 8 hours after ingesting 15 g of quetiapine. The ingestion of quetiapine was confirmed on postmortem evaluation (Isbister & Duffull, 2009).
2) A 52-year-old man developed acute respiratory distress, became comatose, and subsequently died following an estimated overdose ingestion of approximately 10,8 g of quetiapine (Fernandes & Marcil, 2002).

Maximum Tolerated Exposure

1) A dose of more than 100 mg is potentially toxic in a drug naive child less than 12 years old. A dose of more than 125 mg is potentially toxic in a drug naive child aged 12 years or greater. In children on chronic quetiapine therapy an acute ingestion of more than 5 times their current single dose (not daily dose) is potentially toxic (Cobaugh et al, 2007).

1) SUMMARY

a) RESPIRATORY AND CNS DEPRESSION: Adults have developed coma and respiratory depression after ingesting quetiapine doses between 9.6 g and 39 g. Ingestions between 3 g and 14 g have resulted in mild to moderate CNS depression (Capuano et al, 2011; Vivek, 2004; Gajwani et al, 2000; Pollak & Zbuk, 2000; Hustey, 1999). Seizures have also been reported at doses between 24 g and 30 g (Young et al, 2009; Bodmer et al, 2008).
b) ACUTE MOVEMENT DISORDERS: Acute dyskinesia, myoclonus, and akathisia developed in a 13-year-old boy that intentionally abused quetiapine via insufflation. Forty-eight hours prior to admission, the patient reported insufflation of quetiapine by crushing 2 tablets (500 mg each) on 4 separate occasions. He recovered completely within 24 hours after being treated with diphenhydramine (George et al, 2013).

2) CASE REPORTS

a) A 34-year-old woman with a history of schizophrenia became unconscious (Glasgow Coma Scale score of 9) and presented to the emergency department after intentionally ingesting 36 g of extended release quetiapine. Upon presentation, the patient was also bradypneic (12 breaths/min) and later developed respiratory acidosis. She was intubated and received supportive therapy. Spontaneous breathing returned within 36 hours and she was discharged from critical care 4 days after the event. The patient developed no permanent sequelae from the overdose(Capuano et al, 2011).
b) A 27-year-old woman intentionally ingested 30 g of quetiapine and was initially somnolent, but responsive to pain. She remained somnolent, and approximately 24 hours after ingestion, she had 2 witnessed seizures. The patient was intubated and given lorazepam and diprovan (propofol) with no further seizures reported. Head CT and EEG were normal. Toxicology screening for drugs of abuse were negative. The patient gradually improved and was extubated by hospital day 4 and discharged on day 6 (Young et al, 2009).
c) A woman presented comatose and tachycardic 2 to 4 hours after ingesting approximately 24 g of quetiapine. She also experienced repetitive myoclonic jerks (forehead and abdominal wall), 2 generalized tonic clonic seizures, and prolonged QTc interval. Following supportive care, she recovered gradually over the next several hours (Bodmer et al, 2008).
d) A 19-year-old woman developed lethargy and transiently elevated liver enzyme levels following an intentional ingestion of 14 g of quetiapine. Continuous cardiac monitoring following the ingestion indicated no cardiac conduction abnormalities (Vivek, 2004).
e) An acute quetiapine overdose of 9.6 g in a 19-year-old man resulted in tachycardia, hypotension, rapidly progressive coma, and prolonged QTc on ECG. The patient recovered following symptomatic therapy (Hustey, 1999; Gajwani et al, 2000).
f) Following an overdose of 3 g quetiapine, a 40-year-old woman developed persistent tachycardia which lasted up to 42 hours. All symptoms (lethargy, somnolence and dry mouth) resolved after 48 hours with symptomatic therapy (Pollak & Zbuk, 2000).

3) PEDIATRIC

a) CASE REPORT: A 13-year-old boy, with a history of mood disorder, was admitted with acute movement disorders (ie, complaints of frequent eye blinking, recurring episodes of abnormal movements and feeling restless with a constant need to move). Forty-eight hours prior to admission the patient reported insufflation of quetiapine by crushing 2 tablets (500 mg each) on 4 separate occasions. Quetiapine (500 mg daily) had been prescribed about a week prior to admission. A single dose of lorazepam worsened his restlessness and he was successfully treated with diphenhydramine 50 mg IV. A toxicology screen was negative. Within 24 hours, the patient was stable and he was referred for substance abuse counseling (George et al, 2013).
b) CASE REPORT: An 11-year-old girl developed lethargy within 1 hour of a quetiapine overdose of 1300 mg. Three hours after ingestion, agitation and combativeness followed. Extended somnolence was reported after treatment with lorazepam. Return of normal mental status was reported 16 hours after ingestion. No cardiotoxic or laboratory abnormalities occurred (Juhl et al, 2002).

4) CASE SERIES

a) In a series of 18 patients with quetiapine overdose confirmed by serum levels, the reported range was 0.5 to 24 g. No fatalities occurred. The 19-year-old patient who ingested 24 g developed mental status depression (GCS 5), required mechanical ventilation, had tachycardia, a single self limited seizure and transient hypotension. She did well with supportive care, was extubated 25 hours after ingestion and discharged from the hospital 40 hours after ingestion (Balit et al, 2003).
b) Severe symptoms, consisting of coma, seizures and respiratory depression occurred in 11 patients who ingested more than 2.5 g of quetiapine (Eyer et al, 2011).
c) In a series of 14 patients with intentional quetiapine overdose, the median dose ingested was 2600 mg (range: 1200 to 18000 mg). Tachycardia and somnolence were the most frequently reported clinical events. Quetiapine was the sole ingestant in only one patient in this series. Six patients required ICU admission for CNS depression and intubation with one respiratory arrest reported. Seizures were not reported. All patients recovered in approximately 2 days with no permanent sequelae reported (Hunfeld et al, 2006).
d) Acute adult overdose of 9600 mg resulted in hypokalemia and first degree heart block (Prod Info Seroquel(R) Tablets, quetiapine, 1999).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) ADULT

a) Plasma quetiapine levels are unlikely to be clinically useful due to the variability in individual symptomatic responses. Peak serum concentrations of up to 365 ng/mL have been reported following 75 mg oral doses (Fabre et al, 1995a). In another study, mean steady-state plasma levels of 43.9 and 91.1 ng/mL were reported with therapeutic dosages of 300 mg and 600 mg, respectively (Nudelman et al, 1998).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) POSTMORTEM: In a review of 21 medical examiner cases, quetiapine concentrations indicative of toxicity were estimated to be greater than 1 mg/L in peripheral and central blood, and greater than 5 mg/kg in the liver. It was determined that in cases in which quetiapine had a significant role in death, postmortem liver concentrations were greater than 5 mg/kg; cases that were considered incidental or noncontributory to the individual's death had liver concentrations of 2 mg/kg or less (Parker & McIntyre, 2005).
2) CASE REPORTS

a) A 27-year-old woman intentionally ingested 30 g of quetiapine and had an initial serum concentration of 8.67 mg/L (8670 ng/mL) on day one and 3.28 mg/L (3280 ng/mL) on day three. She remained sedated, and approximately 24 hours after ingestion, the patient had two witnessed seizures, but recovered with intensive supportive care. These levels were consistent with previously reported postmortem levels (Young et al, 2009).
b) A quetiapine plasma level of 180 ng/mL was reported 60 hours following a quetiapine overdose of 4700 mg in a 21-year-old man (Nudelman et al, 1998).
c) A quetiapine serum level of 12,700 ng/mL was reported following ingestion of 20,000 mg (20 g) in a 26-year-old female (Harmon et al, 1998).
d) Quetiapine plasma concentrations were 1800 and 160 ng/mL at 2 and 18 hours, respectively, postingestion of 2000 mg in an adult (Beelen et al, 2001).
e) The following serum quetiapine levels were reported in a 40-year-old woman after a 3000 mg overdose (Pollak & Zbuk, 2000):

1) 1824 ng/mL at 2.5 hr postingestion
2) 963 ng/mL at 8 hr postingestion
3) 5 ng/mL at 48 hr postingestion

f) The postmortem serum quetiapine level of a 52-year-old male was 18,300 ng/mL following a suicidal overdose ingestion of approximately 10,800 mg (Fernandes & Marcil, 2002).
g) A quetiapine serum level of 68 ng/mL was reported 2.5 days after a 19-year-old male ingested 12,000 mg of quetiapine (Smith et al, 2004).
h) One study reported 13 postmortem cases in which quetiapine was measured in multiple biological specimens. Overall, heart blood quetiapine levels ranged from 0.07 to 18.37 mg/L (mean +/- SD 3.42 +/- 5.67; n=12) and femoral blood levels ranged from 0.06 to 19.25 mg/L (mean +/- SD 3.89 +/-6.12, n=10). Heart blood quetiapine levels ranged from 0.07 to 0.51 mg/L (mean 0.3 mg/L, n=5) in patients where quetiapine was not considered a factor in the cause of death. These levels were within the reported therapeutic levels. In three cases, quetiapine toxicity (heart blood levels range 0.72 to 18.37 mg/L) was determined to be the cause of death. Quetiapine levels in heart blood tended to be greater than in femoral blood (7 out of 11 cases for which both concentrations available), suggesting that quetiapine undergoes post mortem redistribution (Wise & Jenkins, 2005).

1) In 2 cases, the following fluid and tissue quetiapine levels were determined (cause of death case 1: accidental quetiapine intoxication, case 4: polysubstance overdose including ibuprofen, tricyclic antidepressants and verapamil):

SPECIMEN	QUETIAPINE LEVEL MG/L OR MG/KG CASE 1	CASE 4
Heart blood	0.72	11.2
Femoral blood	0.28	7.35
CSF	1.92	QNS
Urine	3.06	N/A
Vitreous humor	QNS	QNS
Bile	12.07	86
Gastric contents	625	220
Brain	1.24	11.26
Heart tissue	5.29	10.02
Kidney	4.2	20.64
Liver	3.9	8.09
Lung	1.88	9.1
Muscle	5.89	3.69
Spleen	2.28	10.22
Bone	NEG	NEG
Hospital blood	N/A	5.36
NEG = Negative; N/A = Not available; QNS = Quantity not sufficient.

Pharmacology Toxicology

Pharmacologic Mechanism

1) Compared to clozapine, affinities of quetiapine for all receptor types are lower, notably, the binding affinities of quetiapine for 5-HT2 and alpha-2 adrenergic receptors are 11 times and 7 times lower, respectively, than affinities for clozapine (Saller & Salama, 1993). Quetiapine has essentially no affinity for benzodiazepine receptors (Saller & Salama, 1993), but demonstrates some affinity for muscarinic receptor types (Fulton & Goa, 1995).
2) Antagonism of histamine H1 and adrenergic alpha1 receptors may be responsible for drowsiness and orthostatic hypotension, respectively, associated with quetiapine use.

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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