Side Effects of Seroquel (quetiapine)

Seroquel (quetiapine) is an oral atypical antipsychotic drug used alone or in combination with other drugs to treat schizophrenia and bipolar disorder. It also is used for treating major depression in combination with antidepressants.

Common side effects of Seroquel include

• headache,
• agitation,
• dizziness,
• drowsiness/tiredness,
• weight gain, and
• stomach upset.

Serious side effects of Seroquel include

• suicidality,
• worsening of depression,
• extrapyramidal symptoms,
• tardive dyskinesia,
• serious allergic reactions,
• seizures,
• stroke,
• prolonged erection (priapism),
• hypothyroidism, and
• neuroleptic malignant syndrome (symptoms of NMS include high fevers, muscle rigidity, altered mental status, irregular pulse or blood pressure, rapid heart rate, excessive sweating, and heart arrhythmias).

Drug interactions of Seroquel include phenytoin and thioridazine, which markedly decrease the amount of Seroquel absorbed from the intestine, reducing its effectiveness.

Seroquel and can cause low blood pressure (hypotension) and may increase the blood pressure lowering effects of antihypertensive drugs, resulting in lower blood pressure.

Seroquel can add to the sedating effects of other drugs that sedate, such as

• narcotic pain relievers,
• barbiturates,
• sedatives,
• ethanol, and blood pressure drugs that can cause orthostatic hypotension, such as prazosin and terazosin.

Seroquel is eliminated from the body by an enzyme in the liver called cytochrome P450 3A.

Drugs that strongly interfere with the enzyme may cause elevated and toxic levels of quetiapine, for example,

• ketoconazole,
• itraconazole,
• fluconazole,
• erythromycin,
• clarithromycin,
• nefazodone,
• verapamil,
• diltiazem,
• St. John's wort,
• carbamazepine, and
• rifampin.

There are no adequate studies of Seroquel in pregnant women. Seroquel should be used in pregnancy only if the physician feels it is necessary and the potential benefits justify the unknown risks. It is not known if Seroquel is excreted in human milk; it is recommended that women taking Seroquel not breastfeed.

Warning for people with high or low blood pressure and Seroquel or Seroquel XR

Seroquel or Seroquel XR can cause orthostatic hypotension (a drop in blood pressure upon standing that can lead to dizziness or fainting) especially during the first 3-5 day period of treatment, when it is restarted after temporary discontinuation, and after an increase in the dose.

The risk of orthostatic hypotension is about 1 in 100 (one of every hundred patients who take quetiapine).

As with other antipsychotics, long-term use of quetiapine may lead to irreversible tardive dyskinesia, a neurologic disease which consists of involuntary movements of the jaw, lips, and tongue.

Warning for people with cataracts taking Seroquel or Seroquel XR

In animals, quetiapine has been associated with the development of cataracts, and cataracts have been reported in patients using quetiapine for prolonged periods.

Although it is not clear if quetiapine was responsible for the cataracts seen in humans, eye examinations by slit-lamp (to identify cataracts before they impair vision) are recommended at the beginning of treatment and every six months during treatment. If cataracts form, treatment should be discontinued.

Warning for people with high triglycerides or cholesterol taking Seroquel or Seroquel XR

Quetiapine may increase blood concentrations of cholesterol and triglycerides by 11% and 17%, respectively.

Warning for people with diabetes taking quetiapine taking Seroquel or Seroquel XR

There is an increased risk of hyperglycemia (high blood glucose) and diabetes-related events in patients taking atypical antipsychotics, including quetiapine. Patients should be tested during treatment for elevated blood-sugars.

Additionally, persons with risk factors for diabetes, including obesity or a family history of diabetes, should have their fasting levels of blood sugar tested before starting treatment and periodically throughout treatment to detect the onset of diabetes. Any patient developing symptoms that suggest diabetes during treatment should be tested for diabetes.

Common side effects

• The most common side effects of Seroquel or Seroquel XR are
  • headache,
  • agitation,
  • dizziness,
  • drowsiness,
  • weight gain, and
  • and stomach upset.
• Possible serious side effects include
  • suicidality,
  • worsening of depression,
  • extrapyramidal symptoms,
  • tarkive dykinesia,
  • serious allergic reactions,
  • seizures,
  • stroke, and
  • priapism.
• Other important side effects include a potentially fatal complex referred to as neuroleptic malignant syndrome (NMS), in which patients may have
  • high fevers,
  • muscle rigidity,
  • altered mental status,
  • irregular pulse or blood pressure,
  • rapid heart rate,
  • excessive sweating, and
  • heart arrhythmias.
• Quetiapine frequently causes tiredness (1 in 5 patients), especially during the first 3-5 days of treatment. Because of this tiredness, care should be exercised in any activity requiring mental alertness such as operating a motor vehicle or hazardous machinery.
• Less common side effects include seizures (1 in 125 patients) and hypothyroidism (1 in 250 patients).

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis
• Suicidal thoughts and behaviors in adolescents and young adults
• Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis
• Neuroleptic Malignant Syndrome (NMS)
• Metabolic changes (hyperglycemia, dyslipidemia, weight gain)
• Tardive dyskinesia
• Hypotension
• Falls
• Increases in blood pressure (children and adolescents)
• Leukopenia, neutropenia and agranulocytosis
• Cataracts
• QT Prolongation
• Seizures
• Hypothyroidism
• Hyperprolactinemia
• Potential for cognitive and motor impairment
• Body temperature regulation
• Dysphagia
• Discontinuation Syndrome
• Anticholinergic (antimuscarinic) Effects

Clinical Study Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adults

The information below is derived from a clinical trial database for Seroquel consisting of over 4300 patients.

• This database includes
  • 698 patients exposed to Seroquel for the treatment of bipolar depression,
  • 405 patients exposed to Seroquel for the treatment of acute bipolar mania (monotherapy and adjunct therapy),
  • 646 patients exposed to Seroquel for the maintenance treatment of bipolar I disorder as adjunct therapy, and
  • approximately 2600 patients and/or normal subjects exposed to 1 or more doses of Seroquel for the treatment of schizophrenia.
• Of these approximately 4,300 subjects, approximately 4000 (2300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2400 patient-years.
• The conditions and duration of treatment with Seroquel varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure.
• Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.
• The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed.

Adverse Reactions Associated With Discontinuation Of Treatment In Short-Term, Placebo-Controlled Trials

Schizophrenia

• Overall, there was little difference in the incidence of discontinuation due to adverse reactions (4% for Seroquel vs. 3% for placebo) in a pool of controlled trials.
• However, discontinuations due to somnolence (0.8% Seroquel vs. 0% placebo) and hypotension (0.4% Seroquel vs. 0% placebo) were considered to be drug related.

Bipolar Disorder

Mania

• Overall, discontinuations due to adverse reactions were 5.7% for Seroquel vs. 5.1% for placebo in monotherapy and 3.6% for Seroquel vs. 5.9% for placebo in adjunct therapy.

Depression

• Overall, discontinuations due to adverse reactions were 12.3% for Seroquel 300 mg vs. 19.0% for Seroquel 600 mg and 5.2% for placebo.

Commonly Observed Adverse Reactions In Short-Term, Placebo-Controlled Trials

In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials, the most commonly observed adverse reactions associated with the use of Seroquel monotherapy (incidence of 5% or greater) and observed at a rate on Seroquel at least twice that of placebo were

• somnolence (18%),
• dizziness (11%),
• dry mouth (9%),
• constipation (8%),
• ALT increased (5%),
• weight gain (5%), and
• dyspepsia (5%).

Adverse Reactions Occurring At An Incidence Of 2% Or More Among Seroquel Treated Patients In Short-Term, Placebo-Controlled Trials

• The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials.
• Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.
• The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence in the population studied.
• Table 9 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 2% or more of patients treated with Seroquel (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with Seroquel was greater than the incidence in placebo-treated patients.

Table 9: Adverse Reaction Incidence in 3-to 12-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy)

In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies, the most commonly observed adverse reactions associated with the use of Seroquel (incidence of 5% or greater) and observed at a rate on Seroquel at least twice that of placebo were

• somnolence (34%),
• dry mouth (19%),
• asthenia (10%),
• constipation (10%),
• abdominal pain (7%),
• postural hypotension (7%),
• pharyngitis (6%), and
• weight gain (6%).

Table 10 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 2% or more of patients treated with Seroquel (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with Seroquel was greater than the incidence in placebo-treated patients.

Table 10: Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy)

In bipolar depression studies (up to 8 weeks), the most commonly observed adverse reactions associated with the use of Seroquel (incidence of 5% or greater) and observed at a rate on Seroquel at least twice that of placebo were

• somnolence (57%),
• dry mouth (44%),
• dizziness (18%),
• constipation (10%), and
• lethargy (5%).

Table 11 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 2% or more of patients treated with Seroquel (doses of 300 and 600 mg/day) where the incidence in patients treated with Seroquel was greater than the incidence in placebo-treated patients.

Table 11: Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression

Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors.

Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials

Dose-related Adverse Reactions

• Spontaneously elicited adverse reaction data from a study of schizophrenia comparing five fixed doses of Seroquel (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse reactions.
• Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse reactions: dyspepsia, abdominal pain, and weight gain.

Adverse Reactions In Clinical Trials With Quetiapine And Not Listed Elsewhere In The Label

The following adverse reactions have also been reported with quetiapine:

• nightmares,
• hypersensitivity, and elevations in serum creatine phosphokinase (not associated with NMS),
• galactorrhea,
• bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/or syncope),
• decreased platelets,
• somnambulism (and other related events),
• elevations in gamma-GT levels,
• hypothermia,
• dyspnea,
• eosinophilia,
• urinary retention,
• intestinal obstruction and
• priapism.

Extrapyramidal Symptoms (EPS)

Dystonia

Class Effect

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include:

• spasm of the neck muscles, sometimes progressing to tightness of the throat,
• swallowing difficulty,
• difficulty breathing, and/or
• protrusion of the tongue.

While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Four methods were used to measure EPS:

• (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia,
• (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score,
• (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and
• (4) use of anticholinergic medications to treat EPS.

Adults

Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of Seroquel (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with Seroquel treatment.

Three methods were used to measure EPS:

• (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia,
• (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and
• (3) use of anticholinergic medications to EPS.

In Table 12, dystonic event included

• nuchal rigidity,
• hypertonia,
• dystonia,
• muscle rigidity,
• oculogyration;
• parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia;
• akathisia included akathisia, psychomotor agitation;
• dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and
• other extrapyramidal event included restlessness,
• extrapyramidal disorder,
• movement disorder.

Table 12: Adverse Reactions Associated with EPS in a Short-Term, Placebo-Controlled Multiple Fixed-Dose Phase III Schizophrenia Trial (6 weeks duration)

Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75, 150, 300, 600, 750 mg/day) were: -0.6; -1.0, -1.2; -1.6; -1.8, and -1.8. The rate of anticholinergic medication use to treat EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12%, and 11%.

In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of Seroquel, there were no differences between the Seroquel and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS.

In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of Seroquel, the incidence of adverse reactions potentially related to EPS was 12% in both dose groups and 6% in the placebo group.

In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity, and muscle rigidity) were generally low and did not exceed 4% in any treatment group.

The 3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment. The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups.

Children And Adolescents

The information below is derived from a clinical trial database for Seroquel consisting of over 1000 pediatric patients. This database includes 677 patients exposed to Seroquel for the treatment of schizophrenia and 393 children and adolescents (10-17 years old) exposed to Seroquel for the treatment of acute bipolar mania.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials

Schizophrenia

The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on Seroquel and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo).

Bipolar I Mania

The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse reactions leading to discontinuation in 2% or more of patients on Seroquel and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0).

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials

In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%).

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were

• somnolence (53%),
• dizziness (18%),
• fatigue (11%),
• increased appetite (9%),
• nausea (8%),
• vomiting (8%),
• tachycardia (7%),
• dry mouth (7%), and
• weight increased (6%).

In an acute (8-week) Seroquel XR trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of Seroquel XR (incidence of 5% or greater and at least twice that for placebo) were

• dizziness 7%,
• diarrhea 5%,
• fatigue 5%, and
• nausea 5%.

Adverse Reactions Occurring at an Incidence of ≥ 2% among Seroquel Treated Patients in Short-Term, Placebo-Controlled Trials

Schizophrenia (Adolescents, 13-17 Years Old)

The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.

Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with Seroquel (doses of 400 or 800 mg/day) where the incidence in patients treated with Seroquel was at least twice the incidence in placebo-treated patients.

Adverse reactions that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included

• dizziness (8% vs. 15%),
• dry mouth (4% vs. 10%), and
• tachycardia (6% vs. 11%).

Table 13: Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients

Bipolar I Mania (Children And Adolescents 10-17 Years Old)

The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.

Commonly Observed Adverse Reactions

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were

• somnolence (53%),
• dizziness (18%),
• fatigue (11%),
• increased appetite (9%),
• nausea (8%),
• vomiting (8%),
• tachycardia (7%),
• dry mouth (7%), and
• weight increased (6%).

Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with Seroquel (doses of 400 or 600 mg/day) where the incidence in patients treated with Seroquel was greater than the incidence in placebo-treated patients.

Adverse reactions that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included

• somnolence (50% vs. 57%),
• nausea (6% vs. 10%), and
• tachycardia (6% vs. 9%).

Table 14: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients

Extrapyramidal Symptoms

In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for Seroquel and 5.3% (4/75) for placebo, though the incidence of the individual adverse reactions (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group.

In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) or Seroquel and 1.1% (1/90) for placebo.

Table 15 presents a listing of patients with adverse reactions potentially associated with extrapyramidal symptoms in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration).

In Tables 15–16, dystonic event included

• nuchal rigidity, hypertonia, and muscle rigidity;
• parkinsonism included cogwheel rigidity and tremor;
• akathisia included akathisia only;
• dyskinetic event included tardive dyskinesia, dyskinesia, and choreoathetosis; and
• other extrapyramidal event included restlessness and extrapyramidal disorder.

Table 15: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-controlled Trial in Adolescent Patients with Schizophrenia (6-week duration)

Table 16 presents a listing of patients with adverse reactions associated with extrapyramidal symptoms in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).

Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration)

Laboratory, ECG, And Vital Sign Changes Observed In Clinical Studies

Laboratory Changes

Neutrophil Counts

Adults

In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 10⁹/L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine fumarate, compared to 0.1% (2/1349) in patients treated with placebo.

Transaminase Elevations

Adults

• Asymptomatic, transient, and reversible elevations in serum transaminases (primarily ALT) have been reported.
• In schizophrenia trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3-to 6-week placebo-controlled trials were approximately 6% (29/483) for Seroquel compared to 1% (3/194) for placebo.
• In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3-to 12-week placebo-controlled trials were approximately 1% for both Seroquel (3/560) and placebo (3/294).
• These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with Seroquel.
• In bipolar depression trials, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in two 8-week placebo-controlled trials was 1% (5/698) for Seroquel and 2% (6/347) for placebo.

Decreased Hemoglobin

Adults

• In short-term placebo-controlled trials, decreases in hemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo.
• In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients.

Interference With Urine Drug Screens

• There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine.
• Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g., chromatographic methods) should be considered.

ECG Changes

Adults

• Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant Seroquel/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals.
• However, the proportions of patients meeting the criteria for tachycardia were compared in four 3-to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for Seroquel compared to 0.6% (1/156) incidence for placebo.
• In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for Seroquel compared to 0% (0/178) incidence for placebo. In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for Seroquel compared to 0% (0/171) incidence for placebo.
• In bipolar depression trials, no patients had heart rate increases to >120 beats per minute. Seroquel use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients.
• This slight tendency to tachycardia in adults may be related to Seroquel's potential for inducing orthostatic changes.

Children and Adolescents

In the acute (6-week) schizophrenia trial in adolescents, increases in heart rate (>110 bpm) occurred in 5.2% (3/73) of patients receiving Seroquel 400 mg and 8.5% (5/74) of patients receiving Seroquel 800 mg compared to 0% (0/75) of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for Seroquel 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group.

In the acute (3-week) bipolar mania trial in children and adolescents, increases in heart rate (>110 bpm) occurred in 1.1% (1/89) of patients receiving Seroquel 400 mg and 4.7% (4/85) of patients receiving Seroquel 600 mg compared to 0% (0/98) of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for Seroquel 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group.

In an acute (8-week) Seroquel XR trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10-12 years and 13-17 years) occurred in 0% of patients receiving Seroquel XR and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for Seroquel XR, compared to 0.3 bpm in the placebo group.

Postmarketing Experience

The following adverse reactions were identified during post approval of Seroquel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include

• anaphylactic reaction,
• cardiomyopathy,
• drug reaction with eosinophilia and systemic symptoms (DRESS),
• hyponatremia,
• myocarditis,
• nocturnal enuresis,
• pancreatitis,
• retrograde amnesia,
• rhabdomyolysis,
• syndrome of inappropriate antidiuretic hormone secretion (SIADH),
• Stevens-Johnson syndrome (SJS),
• toxic epidermal necrolysis (TEN),
• decreased platelet count,
• serious liver reactions (including hepatitis, liver necrosis, and hepatic failure),
• agranulocytosis,
• intestinal obstruction,
• ileus,
• colon ischemia,
• urinary retention, and
• sleep apnea.

Effect Of Other Drugs On Quetiapine

• The risks of using Seroquel in combination with other drugs have not been extensively evaluated in systematic studies.
• Given the primary CNS effects of Seroquel, caution should be used when it is taken in combination with other centrally acting drugs.
• Seroquel potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine.
• Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.) and decreased by the prototype CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors.

CYP3A4 Inhibitors

• Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure.
• The dose of Seroquel should be reduced to one sixth of the original dose if co-administered with a strong CYP3A4 inhibitor.

CYP3A4 Inducers

• Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5fold.
• Increased doses of Seroquel up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent CYP3A4 inducers.
• When the CYP3A4 inducer is discontinued, the dose of Seroquel should be reduced to the original level within 7-14 days.
• The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied.

Effect Of Quetiapine On Other Drugs

• Because of its potential for inducing hypotension, Seroquel may enhance the effects of certain antihypertensive agents.
• Seroquel may antagonize the effects of levodopa and dopamine agonists.
• There are no clinically relevant pharmacokinetic interactions of Seroquel on other drugs based on the CYP pathway. Seroquel and its metabolites are non-inhibitors of major metabolizing CYP’s (1A2, 2C9, 2C19, 2D6, and 3A4).

Drug Abuse And Dependence

Controlled Substance

Seroquel is not a controlled substance.

Abuse

Seroquel has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence.

While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.

Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of Seroquel, e.g., development of tolerance, increases in dose, drug-seeking behavior.