Seroquel Xr Drug Information

Important Administration Instructions SEROQUEL

XR tablets should be swallowed whole and not split, chewed, or crushed. It is recommended that SEROQUEL XR be taken without food or with a light meal (approximately 300 calories). SEROQUEL XR should be administered once daily, preferably in the evening.

Recommended Dosing

The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient. Table 1: Recommended Dosing for SEROQUEL XR Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment —Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Dose Modifications in Elderly Patients Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions. When indicated, dose escalation should be performed with caution in these patients. Elderly patients should be started on SEROQUEL XR 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.

Dose Modifications in Hepatically Impaired Patients Patients with hepatic impairment should be started on SEROQUEL XR 50 mg/day. The dose can be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

Dose Modifications when used with CYP3A4 Inhibitors SEROQUEL

XR dose should be reduced to one‑sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of SEROQUEL XR should be increased by 6-fold.

Dose Modifications when used with CYP3A4 Inducers SEROQUEL

XR dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7-14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerance of the individual patient.

When the CYP3A4 inducer is discontinued, the dose of SEROQUEL XR should be reduced to the original level within 7-14 days.

Re-initiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off SEROQUEL XR for more than one-week, the initial dosing schedule should be followed. When restarting patients who have been off SEROQUEL XR for less than one-week, gradual dose escalation may not be required and the maintenance dose may be re-initiated.

Switching Patients from SEROQUEL Tablets to SEROQUEL XR Tablets Patients who are currently being treated with SEROQUEL (immediate release formulation) may be switched to SEROQUEL XR at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

Switching from Antipsychotics There are no systematically collected data to specifically address switching patients from other antipsychotics to SEROQUEL XR, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

When switching patients from depot antipsychotics, if medically appropriate, initiate SEROQUEL XR therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults The information below is derived from a clinical trial database for SEROQUEL XR consisting of approximately 3400 patients exposed to SEROQUEL XR for the treatment of Schizophrenia, Bipolar Disorder, and Major Depressive Disorder in placebo-controlled trials. This experience corresponds to approximately 1020.1 patient-years.

Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses, and ECG results. 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: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥2% for SEROQUEL XR in schizophrenia trials.

Bipolar I Disorder, Manic or Mixed Episodes: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥2% for SEROQUEL XR in the bipolar mania trial. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% in SEROQUEL XR in the bipolar depression trial. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% in SEROQUEL XR in MDD trials. ______________ 2 Somnolence combines adverse reaction terms somnolence and sedation.

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: In short-term placebo-controlled studies for schizophrenia the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (25%), dry mouth (12%), dizziness (10%), and dyspepsia (5%). Adverse Reactions Occurring at an Incidence of 2% or More Among SEROQUEL XR Treated Patients in Short-Term, Placebo-Controlled Trials. Table 12 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in 2% or more in patients treated with SEROQUEL XR (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 13: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (52%), dry mouth (37%), increased appetite (12%), weight gain (7%), dyspepsia (7%), and fatigue (6%). Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar depression (up to 8 weeks) in 2% or more of adult patients treated with SEROQUEL XR 300 mg/day where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients. Table 14: Adverse Reactions in an 8-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar In the 6-week placebo-controlled fixed dose adjunctive therapy clinical trials, for MDD, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater and observed at a rate on SEROQUEL XR and at least twice that of placebo) were somnolence (150 mg: ).

Table 15 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during short-term adjunctive therapy of MDD (up to 6 weeks) in 2% or more of patients treated with SEROQUEL XR (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients. Table 15: Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trials for the Treatment of MDD by Fixed Dose Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label Pyrexia, nightmares, peripheral edema, dyspnea, palpitations, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS), somnambulism (and other related events), hypothermia, decreased platelets, galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope), 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: Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, Barnes Akathisia Rating Scale (BARS) Global Assessment Score, incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and use of anticholinergic medications to treat EPS. In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 8% for SEROQUEL XR and 8% for SEROQUEL (without evidence of being dose related), and 5% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) was generally low and did not exceed 3% for any treatment group.

At the end of treatment, the mean change from baseline in SAS total score and BARS Global Assessment score was similar across the treatment groups. The use of concomitant anticholinergic medications was infrequent and similar across the treatment groups. The incidence of extrapyramidal symptoms was consistent with that seen with the profile of SEROQUEL in schizophrenia patients.

In Tables 16-19, 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 16: Adverse Reactions Associated with Extrapyramidal Symptoms in Placebo-Controlled Clinical Trials for In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400-800 mg/day of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 6.6% for SEROQUEL XR and 3.8% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, restlessness, and cogwheel rigidity) did not exceed 2.0% for any adverse reaction.

Table 17: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Clinical Trial for Bipolar Mania In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 4.4% for SEROQUEL XR and 0.7% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, hypertonia) did not exceed 1.5% for any individual adverse reaction. Table 18: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Clinical Trial for Bipolar In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 5.1% for SEROQUEL XR and 4.2% for the placebo group.

Table 19 shows the percentage of patients experiencing adverse reactions associated with EPS in adjunct clinical trials for MDD by dose: Table 19: Adverse Reactions Associated with EPS in MDD Trials by Dose, Adjunctive Therapy Clinical Trials (6 weeks duration) 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 adolescents (13-17 years old) 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 reaction leading to discontinuation in 2% or more of patients on quetiapine 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. Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: 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%).

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 (5 ). Table 20: Adverse Reactions in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar I Mania (Children and Adolescents 10 to 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. Table 21 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.

Table 21: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients Extrapyramidal Symptoms: Safety and effectiveness of SEROQUEL XR is supported by studies of SEROQUEL in children and adolescent patients 10-17 years of age. In a short-term placebo-controlled SEROQUEL XR monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar depression (8-week duration), in which efficacy was not established, the aggregated incidence of extrapyramidal symptoms was 1.1% (1/92) for SEROQUEL XR and 0% (0/100) for placebo. In a short-term placebo-controlled SEROQUEL monotherapy trial in adolescent patients (13-17 years of age) 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 (e.g., akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group.

In Tables 22 and 23, dystonic events included nuchal rigidity, hypertonia, dystonia, 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 22 below presents a listing of patients with adverse reactions associated with EPS in the short-term placebo-controlled SEROQUEL monotherapy trial in adolescent patients with schizophrenia (6-week duration). Table 22: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-Controlled Trial in Adolescent Patients with Table 23 below presents a listing of patients with adverse reactions associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).

Table 23: 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 three-arm SEROQUEL XR placebo-controlled monotherapy clinical trials, among patients with a baseline neutrophil count ≥1.5 x 10 9 /L, the incidence of at least one occurrence of neutrophil count <1.5 x 10 9 /L was 1.5% in patients treated with SEROQUEL XR and 1.5% for SEROQUEL, compared to 0.8% in placebo-treated patients. Transaminase Elevations Adults: Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported. The proportions of adult patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of placebo-controlled trials ranged between 1% and 2% for SEROQUEL XR compared to 2% for placebo.

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 quetiapine. 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: 2.5% of SEROQUEL XR patients, and 2.3% of placebo patients, had tachycardia (>120 bpm) at any time during the trials. SEROQUEL XR was associated with a mean increase in heart rate, assessed by ECG, of 6.3 beats per minute compared to a mean increase of 0.4 beats per minute for placebo. This is consistent with the rates for SEROQUEL.

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. The slight tendency for tachycardia may be related to quetiapine’s potential for inducing orthostatic changes. Mean increases in heart rate were 3.4 bpm for SEROQUEL XR, compared to 0.3 bpm in the placebo group.

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, sleep apnea, urinary retention, acute generalized exanthematous pustulosis (AGEP), confusional state, cutaneous vasculitis, and fecal incontinence. Bezoar observed in overdosage.

Effect of Other Drugs on Quetiapine

The risks of using SEROQUEL XR in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of SEROQUEL XR, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine 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 of 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 should be reduced to one‑sixth of the original dose in patients coadministered with a strong CYP3A4 inhibitor. CYP3A4 inducers: Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold.

Increased doses of SEROQUEL XR 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 XR should be reduced to the original level within 7-14 days. Anticholinergic Drugs: Concomitant treatment with quetiapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility.

SEROQUEL should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects. 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 XR may enhance the effects of certain antihypertensive agents. SEROQUEL XR 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).

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including SEROQUEL XR, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ Risk Summary Neonates exposed to antipsychotic drugs, including SEROQUEL XR, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). Overall available data from published epidemiologic studies of pregnant women exposed to quetiapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ).

There are risks to the mother associated with untreated schizophrenia, bipolar I, or major depressive disorder, and with exposure to antipsychotics, including, SEROQUEL XR during pregnancy (see Clinical Considerations ). In animal studies, embryo-fetal toxicity occurred including delays in skeletal ossification at approximately 1 and 2 times the maximum recommended human dose (MRHD) of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species.

Maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the MRHD in rats and approximately 1-2 times the MRHD in rabbits. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated maternal and/or fetal risk There is a risk to the mother from untreated schizophrenia, or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants.

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including SEROQUEL XR, during the third trimester of pregnancy. These symptoms varied in severity.

Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects.

A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk of major birth defects. Animal Data When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses. However, there was evidence of embryo-fetal toxicity, including delays in skeletal ossification at approximately 1 and 2 times the MRHD of 800 mg/day in both rats and rabbits and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD.

However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD.

Pediatric Use Safety and effectiveness of SEROQUEL XR is supported by studies of SEROQUEL for schizophrenia in adolescent patients 13 - 17 years of age and in bipolar mania in children and adolescent patients 10 - 17 years of age. In general, the adverse reactions observed in children and adolescents during the clinical trials with SEROQUEL were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults.

Orthostatic hypotension occurred more frequently in adults (4-7%) compared to children and adolescents (<1%). Bipolar Depression The effectiveness of SEROQUEL XR for the treatment of bipolar depression in patients under the age of 18 years has not been established. One 8-week trial was conducted to evaluate the safety and efficacy of SEROQUEL XR in the treatment of bipolar depression in pediatric patients 10 - 17 years of age.

The primary objective of the study was to evaluate whether SEROQUEL XR at a dose of 150 to 300 mg/day demonstrated superior efficacy (as measured by change in CDRS-R total score from baseline to end of 8 weeks) compared to placebo in children and adolescents 10 - 17 years of age with bipolar depression. A total of 193 patients with bipolar depression were randomized to placebo or SEROQUEL XR. The primary results of this study did not show a difference between SEROQUEL XR and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder.

In this study, patients treated with SEROQUEL XR exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate. Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 - 17 years of age) and adults. When adjusted for weight, the AUC and C max of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults.

The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight. Schizophrenia The efficacy and safety of SEROQUEL XR in the treatment of schizophrenia in adolescents aged 13 - 17 years is supported by one 6-week, double-blind, placebo-controlled trial with SEROQUEL. Safety and effectiveness of SEROQUEL XR in pediatric patients less than 13 years of age with schizophrenia have not been established.

The safety and effectiveness of SEROQUEL XR in the maintenance treatment of schizophrenia has not been established in patients less than 18 years of age. Bipolar Mania The efficacy and safety of SEROQUEL XR in the treatment of bipolar mania in children and adolescents ages 10-17 years is supported by one 3-week, double-blind, placebo‑controlled trial with SEROQUEL.

Hypersensitivity to quetiapine or to any excipients in the SEROQUEL XR formulation. Anaphylactic reactions have been reported in patients treated with SEROQUEL XR. Known hypersensitivity to SEROQUEL XR or any components in the formulation.

Human Experience

In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone.

In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and anticholinergic toxicity including coma and delirium. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block.

In post-marketing experience, there were cases reported of QT prolongation with overdose.

Management of Overdosage Establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Appropriate supportive measures are the mainstay of management.

For the most up-to-date information on the management of Seroquel XR overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). SEROQUEL XR overdose may lead to gastric bezoar formation and appropriate diagnostic imaging is recommended to further guide patient management. Routine gastric lavage may not be effective in the removal of the bezoar due to gum like sticky consistency of the mass.

Endoscopic pharmacobezoar removal has been performed successfully.