QUETIAPINE FUMARATE- quetiapine fumarate_tablet, extended release

The mechanism of action of quetiapine in the listed indications is unclear. However, the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D 2 2A 2 2A Quetiapine and its metabolite norquetiapine have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general. The K i 1 2 1A 2A 1 1 1 Effect on QT Interval In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (10. 1) Adults Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean C max Children and Adolescents At steady-state, the pharmacokinetics of the parent compound, in children and adolescents (10 to 17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C max max [see Use in Specific Populations (8. 4) Absorption Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. Quetiapine Extended-release tablets dosed once daily at steady state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the quetiapine extended-release tablets C max max [see Dosage and Administration (2. 1) Distribution Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10+/-4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro Metabolism and Elimination Following a single oral dose of 14 Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro Age Oral clearance of quetiapine was reduced by 40% in elderly patients (>=65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary [see Dosage and Administration (2. 3) Gender There is no gender effect on the pharmacokinetics of quetiapine. Race There is no race effect on the pharmacokinetics of quetiapine. Smoking Smoking has no effect on the oral clearance of quetiapine. Renal Insufficiency Patients with severe renal impairment (CL cr 2 cr 2 [see Use in Specific Populations (8. 6) Hepatic Insufficiency Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In 2 of the 8 hepatically impaired patients, AUC and C max [see Dosage and Administration (2. 7) Drug-Drug Interaction Studies The in vivo [see Dosage and Administration ( 2. 1) Table 24: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine Coadministered Drug Dose Schedules Effect on Quetiapine Pharmacokinetics Coadministered Drug Quetiapine Phenytoin 100 mg three times daily 250 mg three times daily 5-fold increase in oral clearance Divalproex 500 mg twice daily 150 mg twice daily 17% increase mean max plasma concentration at steady state. No effect on absorption or mean oral clearance Thioridazine 200 mg twice daily 300 mg twice daily 65% increase in oral clearance Cimetidine 400 mg three times daily for 4 days 150 mg three times daily 20% decrease in mean oral clearance Ketoconazole (potent CYP 3A4 inhibitor) 200 mg once daily for 4 days 25 mg single dose 84% decrease in oral clearance resulting in a 6. 2-fold increase in AUC of quetiapine Fluoxetine 60 mg once daily 300 mg twice daily No change in steady state PK Imipramine 75 mg twice daily 300 mg twice daily No change in steady state PK Haloperidol 7. 5 mg twice daily 300 mg twice daily No change in steady state PK Risperidone 3 mg twice daily 300 mg twice daily No change in steady state PK In vitro in vivo [see Drug Interactions (7. 2) Table 25: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs Coadministered Drug Dose Schedules Effect on Other Drugs Pharmacokinetics Coadministered Drug Quetiapine Lorazepam 2 mg, single dose 250 mg three times daily Oral clearance of lorazepam reduced by 20% Divalproex 500 mg twice daily 150 mg twice daily C max Lithium Up to 2400 mg/day given in twice daily doses 250 mg three times daily No effect on steady-state pharmacokinetics of lithium Antipyrine 1 g, single dose 250 mg three times daily No effect on clearance of antipyrine or urinary recovery of its metabolites.

Quetiapine Extended-release tablet is an atypical antipsychotic indicated for the treatment of: Schizophrenia (1. 1) Bipolar I disorder, manic, or mixed episodes (1. 2) Bipolar disorder, depressive episodes (1. 2) Major depressive disorder, adjunctive therapy with antidepressants (1. 3) Quetiapine Extended-release tablets are indicated for the treatment of schizophrenia. The efficacy of quetiapine extended-release tablets in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13 to 17 years) treated with SEROQUEL [see Clinical Studies (14. 1) Quetiapine Extended-release tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of quetiapine extended-release tablets in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 to 17 years) with manic episodes associated with bipolar I disorder treated with SEROQUEL [see Clinical Studies (14. 2) Quetiapine Extended-release tablets are indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of quetiapine extended-release tablets were established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with SEROQUEL [see Clinical Studies (14. 2) Quetiapine Extended-release tablets are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with SEROQUEL. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials [see Clinical Studies (14. 2) Quetiapine Extended-release tablets are indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of quetiapine extended-release tablets as adjunctive therapy to antidepressants in MDD was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant treatment [see Clinical Studies (14. 3) Pediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.

Swallow tablets whole and do not split, chew or crush (2. 1) Take without food or with a light meal (approx. 300 calories) (2. 1) Administer once daily, preferably in the evening (2. 1) Geriatric Use: 2. 5 Hepatic Impairment: 2. 3 Indication Initial Dose Recommended Dose Maximum Dose Schizophrenia- Adults (2. 2) 300 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia-Adolescents (13 to 17 years )(2. 2) 50 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder manic or mixed-Acute monotherapy or adjunct to lithium or divalproex-Adults (2. 2) 300 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder, manic Acute monotherapy -Children and Adolescents (10 to 17 years) (2. 2) 50 mg/day 400 to 600 mg/day 600 mg/day Bipolar Disorder, Depressive Episodes-Adults (2. 2) 50 mg/day 300 mg/day 300 mg/day Major Depressive Disorder, Adjunctive Therapy with Antidepressants-Adults (2. 2) 50 mg/day 150 to 300 mg/day 300 mg/day Quetiapine Extended-release tablets should be swallowed whole and not split, chewed, or crushed. It is recommended that quetiapine extended-release tablets be taken without food or with a light meal (approximately 300 calories) [see Clinical Pharmacology (12. 3) Quetiapine Extended-release tablets should be administered once daily, preferably in the evening. The recommended initial dose, titration, dose range and maximum quetiapine extended-release tablets 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 [see Clinical Studies ( 14. 3 Table 1: Recommended Dosing for Quetiapine Extended-release tablets Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia- Adults Day 1: 300 mg/day Dose increases can be made at intervals as short as 1 day and in increments of up to 300 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia-Adolescents (13 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia Maintenance-Monotherapy-Adults Not applicable 400 to 800 mg/day 800 mg/day Bipolar I Disorder manic or mixed-Acute monotherapy or adjunct to lithium or divalproex-Adults Day 1: 300 mg/day Day 2: 600 mg/day Day 3: between 400 and 800 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder, manic -Acute monotherapy -Children and Adolescents (10 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 600 mg/day 600 mg/day Bipolar Disorder, Depressive Episodes-Adults Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day 300 mg/day 300 mg/day Bipolar I Disorder Maintenance- Adjunct to lithium or divalproex-Adults Not applicable 400 to 800 mg/day 800 mg/day Major Depressive Disorder- Adjunctive Therapy with Antidepressants-Adults Day 1: 50 mg/day Day 2: 50 mg/day Day 3: 150 mg/day 150 to 300 mg/day 300 mg/day Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatmentem dashPatients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14. 2 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 [see Use in Specific Populations ( 8. 7 Clinical Pharmacology (12. 3) Elderly patients should be started on quetiapine extended-release tablets 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. Patients with hepatic impairment should be started on quetiapine extended-release tablets 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. Quetiapine Extended-release tablets dose should be reduced to one-sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e. , ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc. When the CYP3A4 inhibitor is discontinued, the dose of quetiapine extended-release tablets should be increased by 6-fold [see Clinical Pharmacology (12. 1 Quetiapine Extended-release tablets dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (e. , greater than 7 to 14 days) of a potent CYP3A4 inducer (e. , 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 quetiapine extended-release tablets should be reduced to the original level within 7 to 14 days [see Clinical Pharmacology (12. 1) 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 quetiapine extended-release tablets for more than one-week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine extended-release tablets for less than one-week, gradual dose escalation may not be required and the maintenance dose may be re-initiated. Patients who are currently being treated with SEROQUEL (immediate release formulation) may be switched to quetiapine extended-release tablets at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary. There are no systematically collected data to specifically address switching patients from other antipsychotics to quetiapine extended-release tablets, 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 quetiapine extended-release tablets therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Warnings and Precautions (5. 1) Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions (5. 2) Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see Warnings and Precautions (5. 3) Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5. 4) Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [see Warnings and Precautions (5. 5) Tardive dyskinesia [see Warnings and Precautions (5. 6) Hypotension [see Warnings and Precautions (5. 7) Falls [see Warnings and Precautions (5. 8) Increases in blood pressure (children and adolescents) [see Warnings and Precautions (5. 9) Leukopenia, neutropenia and agranulocytosis [see Warnings and Precautions (5. 10) Cataracts [see Warnings and Precautions (5. 11) QT Prolongation [see Warnings and Precautions (5. 12) Seizures [see Warnings and Precautions (5. 13) Hypothyroidism [see Warnings and Precautions (5. 14) Hyperprolactinemia [see Warnings and Precautions (5. 15) Potential for cognitive and motor impairment [see Warnings and Precautions (5. 16) Body temperature regulation [see Warnings and Precautions (5. 17) Dysphagia [see Warnings and Precautions (5. 18) Discontinuation Syndrome [see Warnings and Precautions (5. 19) Anticholinergic (antimuscarinic) Effects [see Warnings and Precautions (5. 20) Most common adverse reactions (incidence >=5% and twice placebo): (6. 1) Children and Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, weight increased (6. 1) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or 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 quetiapine extended-release tablets consisting of approximately 3400 patients exposed to quetiapine extended-release tablets 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: Bipolar I Disorder, Manic or Mixed Episodes: There were no adverse reactions leading to discontinuation that occurred at an incidence of >=2% for quetiapine extended-release tablets in the bipolar mania trial. Bipolar Disorder, Depressive Episode: 1 MDD, Adjunctive Therapy: 2 2 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 quetiapine extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine extended-release tablets 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 Quetiapine Extended-Release Tablets 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 quetiapine extended-release tablets (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with quetiapine extended-release tablets were greater than the incidence in placebo-treated patients. Table 12: Adverse Reactions in 6-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia 1 2 Preferred Term Quetiapine Extended-release tablets (N=951) Placebo (N=319) Somnolence 1 25% 10% Dry Mouth 12% 1% Dizziness 10% 4% Extrapyramidal Symptoms 2 8% 5% Orthostatic Hypotension 7% 5% Constipation 6% 5% Dyspepsia 5% 2% Heart Rate Increased 4% 1% Tachycardia 3% 1% Fatigue 3% 2% Hypotension 3% 1% Vision Blurred 2% 1% Toothache 2% 0% Increased Appetite 2% 0% Muscle Spasms 2% 1% Tremor 2% 1% Akathisia 2% 1% Anxiety 2% 1% Schizophrenia 2% 1% Restlessness 2% 1% In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of quetiapine extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine extended-release tablets at least twice that of placebo were somnolence (50%), dry mouth (34%), dizziness (10%), constipation (10%), weight gain (7%), dysarthria (5%), and nasal congestion (5%). Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 2% or more of patients treated with quetiapine extended-release tablets (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with quetiapine extended-release tablets were 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 Preferred Term Quetiapine Extended-release tablets (N=151) Placebo (N=160) Somnolence 1 50% 12% Dry Mouth 34% 7% Dizziness 10% 4% Constipation 10% 3% Dyspepsia 7% 4% Fatigue 7% 4% Weight Gain 7% 1% Extrapyramidal Symptoms 2 7% 4% Nasal Congestion 5% 1% Dysarthria 5% 0% Increased Appetite 4% 2% Back Pain 3% 2% Toothache 3% 1% Heart Rate Increased 3% 0% Abnormal Dreams 3% 0% Orthostatic Hypotension 3% 0% Tachycardia 2% 1% Vision Blurred 2% 1% Sluggishness 2% 1% Lethargy 2% 1% 1 2 In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of quetiapine extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine extended-release tablets 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 quetiapine extended-release tablets 300 mg/day where the incidence in patients treated with quetiapine extended-release tablets were 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 Depression Preferred Term Quetiapine Extended-release tablets (N=137) Placebo (N=140) Somnolence 1 52% 13% Dry Mouth 37% 7% Dizziness 13% 11% Increased Appetite 12% 6% Constipation 8% 6% Dyspepsia 7% 1% Weight Gain 7% 1% Fatigue 6% 2% Irritability 4% 3% Viral Gastroenteritis 4% 1% Arthralgia 4% 1% Extrapyramidal Symptoms 2 4% 1% Paraesthesia 3% 2% Back Pain 3% 1% Muscle Spasms 3% 1% Toothache 3% 0% Abnormal Dreams 3% 0% Ear Pain 2% 1% Seasonal Allergy 2% 1% Sinusitis 2% 1% Decreased Appetite 2% 1% Myalgia 2% 1% Disturbance in Attention 2% 1% Migraine 2% 1% Restless Legs Syndrome 2% 1% Anxiety 2% 1% Sinus Headache 2% 1% Libido Decreased 2% 1% Pollakiuria 2% 1% Sinus Congestion 2% 1% Hyperhidrosis 2% 1% Orthostatic Hypotension 2% 1% Urinary Tract Infection 2% 0% Heart Rate Increased 2% 0% Neck Pain 2% 0% Dysarthria 2% 0% Akathisia 2% 0% Hypersomnia 2% 0% Mental Impairment 2% 0% Confusional State 2% 0% Disorientation 2% 0% 1 2 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 quetiapine extended-release tablets (incidence of 5% or greater and observed at a rate on quetiapine extended-release tablets and at least twice that of placebo) were somnolence (150 mg: 37%; 300 mg: 43%), dry mouth (150 mg: 27%; 300 mg: 40%), fatigue (150 mg: 14%; 300 mg: 11%), constipation 300 mg only: 11%), and weight increased (300 mg only: 5%). 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 quetiapine extended-release tablets (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with quetiapine extended-release tablets were 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 Preferred Term Quetiapine Extended-release tablets 150 mg (N=315) Quetiapine Extended-release tablets 300 mg (N=312) Placebo (N=309) Somnolence 1 37% 43% 9% Dry Mouth 27% 40% 8% Fatigue 14% 11% 4% Dizziness 11% 12% 7% Nausea 7% 8% 7% Constipation 6% 11% 4% Irritability 4% 2% 3% Extrapyramidal Symptoms 2 4% 6% 4% Vomiting 3% 1% 1% Upper Respiratory Tract Infection 3% 2% 2% Weight Increased 3% 5% 0% Increased Appetite 3% 5% 3% Back Pain 3% 3% 1% Vertigo 2% 2% 1% Vision Blurred 2% 1% 1% Dyspepsia 2% 3% 2% Influenza 2% 1% 0% Fall 2% 0% 1% Muscle Spasms 2% 1% 1% Lethargy 2% 1% 1% Akathisia 2% 2% 1% Abnormal Dreams 2% 2% 1% Anxiety 2% 2% 1% Depression 2% 1% 1% 1 2 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 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 In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of quetiapine extended-release tablets, the incidence of any adverse reactions related to EPS was 8% for quetiapine extended-release tablets 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 to 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 Schizophrenia Preferred term Quetiapine Extended-release tablets 300 mg/day (N=91) Quetiapine Extended-release tablets 400 mg/day (N=227) Quetiapine Extended-release tablets 600 mg/day (N=310) Quetiapine Extended-release tablets 800 mg/day (N=323) All Doses (N=951) Placebo (N=319) n % n % n % n % n % n % Dystonic event 3 3. 0 Parkinsonism 1 1. 3 Akathisia 0 0. 3 Dyskinetic event 2 2. 6 Other extrapyramidal event 3 3. 2 In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400 to 800 mg/day of quetiapine extended-release tablets, the incidence of any adverse reactions related to EPS was 6. 6% for quetiapine extended-release tablets 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 Preferred Term 1 Quetiapine Extended-release tablets (N=151) Placebo (N=160) n % n % Dystonic event 1 0. 0 Parkinsonism 4 2. 9 Akathisia 2 1. 6 Other extrapyramidal event 3 2. 3 1 In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of quetiapine extended-release tablets, the incidence of any adverse reactions related to EPS was 4. 4% for quetiapine extended-release tablets 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 Depression Preferred Term 1 Quetiapine Extended-release tablets (N=137) Placebo (N=140) n % n % Dystonic event 2 1. 0 Parkinsonism 1 0. 7 Akathisia 2 1. 0 Other extrapyramidal event 1 0. 0 1 In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of quetiapine extended-release tablets, the incidence of any adverse reactions related to EPS was 5. 1% for quetiapine extended-release tablets 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) Preferred term Quetiapine Extended-release tablets (N=315) Quetiapine Extended-release tablets (N=312) All Doses (N=627) Placebo (N=309) n % n % n % n % Dystonic event 1 0. 0 Parkinsonism 3 1. 6 Akathisia 5 1. 0 Dyskinetic event 0 0. 0 Other extrapyramidal event 5 1. 6 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 to 17 years old) exposed to SEROQUEL for the treatment of schizophrenia and 393 children and adolescents (10 to 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: Bipolar I Mania: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: In an acute (8-week) quetiapine extended-release tablets trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of quetiapine extended-release tablets (incidence of 5% or greater and at least twice that for placebo) were: dizziness 7%, diarrhea 5%, fatigue 5% and nausea 5%. 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%). Adverse Reactions Occurring at an Incidence of >=2% among SEROQUEL Treated Patients in Short-Term, Placebo-Controlled Trials Schizophrenia (Adolescents, 13 to 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 20 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 greater than 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. Table 20: Adverse Reactions in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients Preferred Term SEROQUEL (N=73) SEROQUEL (N=74) Placebo (N=75) Somnolence 1 33% 35% 11% Dizziness 8% 15% 5% Dry Mouth 4% 10% 1% Tachycardia 2 6% 11% 0% Irritability 3% 5% 0% Arthralgia 1% 3% 0% Asthenia 1% 3% 1% Back Pain 1% 3% 0% Dyspnea 0% 3% 0% Abdominal Pain 3% 1% 0% Anorexia 3% 1% 0% Tooth Abscess 3% 1% 0% Dyskinesia 3% 0% 0% Epistaxis 3% 0% 1% Muscle Rigidity 3% 0% 0% 1 2 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. 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. Table 21: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients Preferred Term SEROQUEL (N=95) SEROQUEL (N=98) Placebo (N=90) Somnolence 1 50% 57% 14% Dizziness 19% 17% 2% Nausea 6% 10% 4% Fatigue 14% 9% 4% Increased Appetite 10% 9% 1% Tachycardia 2 6% 9% 0% Dry Mouth 7% 7% 0% Vomiting 8% 7% 3% Nasal Congestion 3% 6% 2% Weight Increased 6% 6% 0% Irritability 3% 5% 1% Pyrexia 1% 4% 1% Aggression 1% 3% 0% Musculoskeletal Stiffness 1% 3% 1% Accidental Overdose 0% 2% 0% Acne 3% 2% 0% Arthralgia 4% 2% 1% Lethargy 2% 2% 0% Pallor 1% 2% 0% Stomach Discomfort 4% 2% 1% Syncope 2% 2% 0% Vision Blurred 3% 2% 0% Constipation 4% 2% 0% Ear Pain 2% 0% 0% Paresthesia 2% 0% 0% Sinus Congestion 3% 0% 0% Thirst 2% 0% 0% 1 2 Extrapyramidal Symptoms: Safety and effectiveness of quetiapine extended-release tablets are supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age [see Clinical Studies ( 14. 2 In a short-term placebo-controlled quetiapine extended-release tablets monotherapy trial in children and adolescent patients (10 to 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 quetiapine extended-release tablets and 0% (0/100) for placebo. In a short-term placebo-controlled SEROQUEL monotherapy trial in adolescent patients (13 to 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. , 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 SEROQUEL monotherapy trial in children and adolescent patients (10 to 17 years of age) with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3. 6% (7/193) for SEROQUEL and 1. 1% (1/90) for placebo. 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 Schizophrenia (6-week duration) Preferred term SEROQUEL 400 mg/day (N=73) SEROQUEL 800 mg/day (N=74) All SEROQUEL (N=147) Placebo (N=75) n % n % n % n % Dystonic event 2 2. 0 Parkinsonism 4 5. 7 Akathisia 3 4. 0 Dyskinetic Event 2 2. 0 Other Extrapyramidal Event 2 2. 0 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) Preferred Term 1 SEROQUEL 400 mg/day (N=95) SEROQUEL 600 mg/day (N=98) All SEROQUEL (N=193) Placebo (N=90) n % n % n % n % Parkinsonism 2 2. 1 Akathisia 1 1. 0 Other Extrapyramidal Event 1 1. 0 1 Laboratory, ECG and vital sign changes observed in clinical studies Laboratory Changes: Neutrophil Counts Adults: 9 9 In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1. 0 x 10 9 [see Warnings and Precautions (5. 10) Transaminase Elevations Adults: Decreased Hemoglobin Adults: 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. , chromatographic methods) should be considered. ECG Changes: Adults: [see Warnings and Precautions (5. 7) Children and Adolescents: [see Clinical Studies ( 14. 2 In an acute (8-week) quetiapine extended-release tablets trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10 to 12 years and 13 to 17 years) occurred in 0% of patients receiving quetiapine extended-release tablets and 1. 2% of patients receiving placebo. Mean increases in heart rate were 3. 4 bpm for quetiapine extended-release tablets, compared to 0. 3 bpm in the placebo group [see Warnings and Precautions (5. 7) In the acute (6-week) SEROQUEL schizophrenia trial in adolescents (13 to 17 years of age), increases in heart rate (>110 bpm) occurred in 5. 2% of patients receiving SEROQUEL 400 mg and 8. 5% of patients receiving SEROQUEL 800 mg compared to 0% of patients receiving placebo. 8 bpm and 11. 2 bpm for SEROQUEL 400 mg and 800 mg groups, respectively, compared to a decrease of 3. 7) In the acute (3-week) SEROQUEL bipolar mania trial in children and adolescents (10 to 17 years of age), increases in heart rate (>110 bpm) occurred in 1. 1% of patients receiving SEROQUEL 400 mg and 4. 7% of patients receiving SEROQUEL 600 mg compared to 0% 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 [see Warnings and Precautions (5. 7) The following adverse reactions were identified during post approval use 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, sleep apnea, urinary retention, acute generalized exanthematous pustulosis (AGEP), confusional state and cutaneous vasculitis. Bezoar observed in overdosage [see Overdosage (10).

Hypersensitivity to quetiapine or to any excipients in the quetiapine extended-release tablets formulation. Anaphylactic reactions have been reported in patients treated with quetiapine extended-release tablets. Known hypersensitivity to quetiapine extended-release tablets or any components in the formulation.

Pregnancy: (8. 1) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine extended-release tablets, 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 quetiapine extended-release tablets, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) (see Data) (see Clinical Considerations) 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, 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 quetiapine extended-release tablets, 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. Doses were 25, 50 and 200 mg/kg in rats and 25, 50 and 100 mg/kg in rabbits which are approximately 0. 6 and 2-times (rats) and 0. 6, 1 and 2-times (rabbits) the MRHD, for schizophrenia of 800 mg/day based on mg/m 2 In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0. 2 times the MRHD of 800 mg/day based on mg/m 2 Risk Summary Infertility Females [see Warnings and Precautions (5. 15) Safety and effectiveness of quetiapine extended-release tablets are supported by studies of SEROQUEL for schizophrenia in adolescent patients 13 to 17 years of age and in bipolar mania in children and adolescent patients 10 to 17 years of age [see Clinical Studies ( 14. 2 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 to 7%) compared to children and adolescents (<1%) [see Warnings and Precautions (5. 1) Bipolar Depression The effectiveness of quetiapine extended-release tablets 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 quetiapine extended-release tablets in the treatment of bipolar depression in pediatric patients 10 to 17 years of age. The primary objective of the study was to evaluate whether quetiapine extended-release tablets 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 to 17 years of age with bipolar depression. A total of 193 patients with bipolar depression were randomized to placebo or quetiapine extended-release tablets. The primary results of this study did not show a difference between quetiapine extended-release tablets and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder. In this study, patients treated with quetiapine extended-release tablets exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate [see Warnings and Precautions ( 5. 1) Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and Cmax 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 [see Clinical Pharmacology (12. 3) Schizophrenia The efficacy and safety of quetiapine extended-release tablets in the treatment of schizophrenia in adolescents aged 13 to 17 years is supported by one 6-week, double-blind, placebo-controlled trial with SEROQUEL [see Indications and Usage (1. 1) Safety and effectiveness of quetiapine extended-release tablets in pediatric patients less than 13 years of age with schizophrenia have not been established. The safety and effectiveness of quetiapine extended-release tablets 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 quetiapine extended-release tablets in the treatment of bipolar mania in children and adolescents ages 10 to 17 years is supported by one 3-week, double-blind, placebo controlled trial with SEROQUEL [see Indications and Usage (1. 2) Safety and effectiveness of quetiapine extended-release tablets in pediatric patients less than 10 years of age with bipolar mania have not been established. The safety and effectiveness of quetiapine extended-release tablets in the maintenance treatment of bipolar disorder has not been established in patients less than 18 years of age. Sixty-eight patients in clinical studies with quetiapine extended-release tablets were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine extended-release tablets in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine extended-release tablets, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [see Dosage and Administration (2. 3) Clinical experience with quetiapine extended-release tablets in patients with renal impairment is limited [see Clinical Pharmacology (12. 3) Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. In this population, a low starting dose of 50 mg/day is recommended and the dose may be increased in increments of 50 mg/day [see Dosage and Administration (2.

Concomitant use of strong CYP3A4 inhibitors: 2. 3 Concomitant use of strong CYP3A4 inducers: 2. 3 Discontinuation of strong CYP3A4 inducers: 2. 3 The risks of using quetiapine extended-release tablets in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine extended-release tablets, 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. , 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 [see Dosage and Administration (2. 3) CYP3A4 inducers: Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine extended-release tablets 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 [see Dosage and Administration (2. 3) [see Dosage and Administration (2. 6) Anticholinergic Drugs: [see Warnings and Precautions (5. 20) The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied. [see Clinical Pharmacology (12. 3) Because of its potential for inducing hypotension, quetiapine extended-release tablets may enhance the effects of certain antihypertensive agents. Quetiapine Extended-release tablets 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).

OVERDOSAGE
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. , 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 [see Warnings and Precautions (5. 12) 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 quetiapine extended-release-tablets overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Quetiapine extended-release tablets 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0. 5 times the MRHD of 800 mg/day based on mg/m 2 2 2 2 2 Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown. Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32-and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see Warnings and Precautions (5. 15) Mutagenesis Quetiapine was not mutagenic or clastogenic in standard genotoxicity tests. The mutagenic potential of quetiapine was tested in the in vitro in vitro in vitro in vivo 2 Impairment of Fertility Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the MRHD of 800 mg/day based on mg/m 2 2 2 2 2 Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10, 25, 50, 75, 150 and 250 mg/kg in rat studies which are approximately 0. 6, 1, 2 and 3-times the MRHD of 800 mg/day based on mg/m 2 2 In dogs receiving quetiapine for 6 or 12 months, but not for 1-month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day based on mg/m 2 2.
CLINICAL STUDIES
Short-term Trials en dash Adults The efficacy of quetiapine extended-release tablets in the treatment of schizophrenia was demonstrated in 1 short-term, 6-week, fixed-dose, placebo-controlled trial of inpatients and outpatients with schizophrenia (n=573) who met DSM-IV criteria for schizophrenia. Quetiapine Extended-release tablets (once daily) was administered as 300 mg on Day 1, and the dose was increased to either 400 mg or 600 mg by Day 2, or 800 mg by Day 3. The primary endpoint was the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment (Day 42). Quetiapine Extended-release tablets doses of 400 mg, 600 mg and 800 mg once daily were superior to placebo in the PANSS total score at Day 42 (Study 1 in Table 26). Short-term Trials en dashAdolescents (ages 13 to 17) The efficacy of quetiapine extended-release tablets in the treatment of schizophrenia in adolescents (13 to 17 years of age) was supported by a 6-week, double-blind, placebo-controlled trial. Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: SEROQUEL 400 mg/day (n=73), SEROQUEL 800 mg/day (n=74), or placebo (n=75). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and given two or three times per day). Subsequently, the dose was titrated to the target dose of 400 mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times daily. The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS). SEROQUEL at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score (Study 2 in Table 26). Table 26: Schizophrenia Short-Term Trials Study Number Treatment Group Primary Efficacy Endpoint: PANSS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference 2 (95% CI) Study 1 Quetiapine Extended-release tablets 1 95. 6) Quetiapine Extended-release tablets 1 96. 7) Quetiapine Extended-release tablets 1 97. 1) SEROQUEL 1,3 96. 4) Placebo 96. 5) -- Study 2 (adolescents) SEROQUEL 1 96. 3) SEROQUEL 1 96. 0) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. 1 2 3 Maintenance Trials In a longer-term trial (Study 3), clinically stable adult outpatients (n=171) meeting DSM-IV criteria for schizophrenia who remained stable following 16 weeks of open-label treatment with flexible doses of quetiapine extended-release tablets (400 mg/day to 800 mg/day) were randomized to placebo or to continue on their current quetiapine extended-release tablets (400 mg/day to 800 mg/day) for observation for possible relapse during the double-blind continuation (maintenance) phase. Stabilization during the open-label phase was defined as receiving a stable dose of quetiapine extended-release tablets and having a CGI-S<=4 and a PANSS score <=60 from beginning to end of this open-label phase (with no increase of >=10 points in PANSS total score). Relapse during the double-blind phase was defined in terms of a >=30% increase in the PANSS Total score, or CGI-Improvement score of >=6, or hospitalization due to worsening of schizophrenia, or need for any other antipsychotic medication. Patients on quetiapine extended-release tablets experienced a statistically significant longer time to relapse than did patients on placebo (Figure 1). Figure 1 PLA Placebo. QTP Quetiapine. XR Extended-release. Note: Results are from the interim analysis. figure 1 kaplan-meier curves of time to schizophrenic relapse study 3. jpg Bipolar I Disorder, manic or mixed episodes Adults The efficacy of quetiapine extended-release tablets in the acute treatment of manic episodes was established in one 3-week, placebo-controlled trial (Study 1 in Table 27) in patients who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features (N=316). Patients were hospitalized for a minimum of 4 days at randomization. Patients randomized to quetiapine extended-release tablets received 300 mg on Day 1 and 600 mg on Day 2. Afterwards, the dose could be adjusted between 400 mg and 800 mg per day. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptoms in a range from 0 (no manic features) to 60 (maximum score). Quetiapine Extended-release tablets were superior to placebo in the reduction of the YMRS total score at week 3. The efficacy of SEROQUEL in the treatment of acute manic episodes was also established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the YMRS score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of SEROQUEL with lithium or divalproex. The results of the trials follow: Monotherapy In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/ day (Studies 2 and 3 in Table 27). Adjunct Therapy In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS >=20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/day (Study 4 in Table 27). Children and Adolescents (ages 10 to 17) The efficacy of quetiapine extended-release tablets in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was extrapolated from a 3-week, double-blind, placebo-controlled, multicenter trial. Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: SEROQUEL 400 mg/day (n=95), SEROQUEL 600 mg/day (n=98), or placebo (n=91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily). Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy variable was the mean change from baseline in total YMRS score. SEROQUEL 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (Study 5 in Table 27). Table 27: Mania Trials Study Number Treatment Group Primary Efficacy Measure: YMRS Total Mean Baseline Score (SD) 4 LS Mean Change from Baseline (SE) Placebo-subtracted Difference 2 (95% CI) Study 1 Quetiapine Extended-release tablets 1 28. 0) Placebo 28. 9) -- Study 2 SEROQUEL 1 34. 0) Haloperidol 1,3 32. 4) Placebo 33. 3) -- Study 3 SEROQUEL 1 32. 0) Lithium 1,3 33. 5) Placebo + mood stabilizer 34. 6) -- Study 4 SEROQUEL (200 to 800 mg/day) 1 31. 6) Placebo + mood stabilizer 31. 5) -- Study 5 (children and adolescents) SEROQUEL 1 29. 3) SEROQUEL 1 29. 7) Placebo 30. 1) -- Mood stabilizer: lithium or divalproex; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. 1 2 3 4 Bipolar Disorder, Depressive Episodes Adults The efficacy of quetiapine extended-release tablets for the acute treatment of depressive episodes associated with bipolar disorder in patients who met DSM-IV criteria for bipolar disorder was established in one 8-week, randomized, double-blind, placebo-controlled study (N=280 outpatients). This study included patients with bipolar I and II disorder, and those with and without a rapid cycling course. Patients randomized to quetiapine extended-release tablets were administered 50 mg on Day 1, 100 mg on Day 2, 200 mg on Day 3, and 300 mg on Day 4 and after. The primary rating instrument used to assess depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at week 8. Quetiapine Extended-release tablets were superior to placebo in reduction of MADRS score at week 8 (Study 6 in Table 28). The efficacy of SEROQUEL for the treatment of depressive episodes associated with bipolar disorder was established in 2 identical 8-week, randomized, double-blind, placebo-controlled studies (N=1045). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to SEROQUEL were administered fixed doses of either 300 mg or 600 mg once daily. The primary rating instrument used to assess depressive symptoms in these studies was the MADRS. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, SEROQUEL was superior to placebo in reduction of MADRS score at week 8 (Studies 7 and 8 in Table 28). In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF). Table 28: Depressive Episodes Associated with Bipolar Disorder Study Number Treatment Group Primary Efficacy Measure: MADRS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference 2 (95% CI) Study 6 Quetiapine Extended-release tablets 1 29. 9, Placebo 30. 2) -- Study 7 SEROQUEL 1 30. 3, SEROQUEL 1 30. 7, Placebo 30. 9) -- Study 8 SEROQUEL 1 31. 3, SEROQUEL 1 29. 4, Placebo 29. 0) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. 1 2 Maintenance Treatment as an Adjunct to Lithium or Divalproex The efficacy of SEROQUEL in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 9 and 10). The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stable on SEROQUEL plus lithium or divalproex for at least 12 weeks in order to be randomized. On average, patients were stabilized for 15 weeks. In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either SEROQUEL (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo. Approximately 50% of the patients had discontinued from the SEROQUEL group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment. The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed, or depressed episode). A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score >=20 or MADRS score >=20 at 2 consecutive assessments; or study discontinuation due to a mood event. In both studies, SEROQUEL was superior to placebo in increasing the time to recurrence of any mood event (Figure 2 and Figure 3). The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of SEROQUEL was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course). Figure 2 Figure 2 kaplan-Maier Curves of Time to recurrence of a Mood Event. jpg Figure 3 Kaplan-Meier Curves of Time to Recurrence of a Mood Event (Study 19). jpg The efficacy of quetiapine extended-release tablets as adjunctive therapy to antidepressants in the treatment of MDD was demonstrated in two 6-week placebo-controlled, fixed-dose trials (n=936). Quetiapine Extended-release tablets 150 mg/day or 300 mg/day was given as adjunctive therapy to existing antidepressant therapy in patients who had previously shown an inadequate response to at least one antidepressant. Quetiapine Extended-release tablets were administered as 50 mg/day on Days 1 and 2, and increased to 150 mg/day on Day 3 for both dose groups. On Day 5, the dose was increased to 300 mg/day in the 300 mg/day fixed-dose group. Inadequate response was defined as having continued depressive symptoms for the current episode [Hamilton Depression Rating Scale (HAM-D) total score of >= 20] despite using an antidepressant for 6 weeks at or above the minimally effective labelled dose. The mean HAM-D total score at entry was 24, and 17% of patients scored 28 or greater. Patients were on various antidepressants prior to study entry including SSRI’s (paroxetine, fluoxetine, sertraline, escitalopram, or citalopram), SNRI’s, (duloxetine and venlafaxine,) TCA (amitriptyline), and other (bupropion). The primary endpoint in these trials was change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS. ), quetiapine extended-release tablets 300 mg once daily as adjunctive treatment to other antidepressant therapy was superior to antidepressant alone in reduction of MADRS total score in both trials. Quetiapine Extended-release tablets 150 mg once daily as adjunctive treatment was superior to antidepressant therapy alone in reduction of MADRS total score in one trial (studies 1 and 2 in Table 29). Table 29: Major Depressive Disorder, Adjunctive Therapy to Antidepressants Study Number Treatment Group Primary Efficacy Measure: MADRS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference 2 (95% CI) Study 1 Quetiapine Extended-release tablets 27. 1) Quetiapine Extended-release tablets 1 27. 0, Placebo + AD 27. 8) -- Study 2 Quetiapine Extended-release tablets 28. 9, Quetiapine Extended-release tablets 28. 6, Placebo 28. 7) -- AD: Antidepressant; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

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