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| Product NDC Code | 51407-076 | ||||
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| Drug Name | Quetiapine fumarate |
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| Type | Generic | ||||
| Pharm Class | Atypical Antipsychotic [EPC] | ||||
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| Route | ORAL | ||||
| Dosage Form | TABLET, EXTENDED RELEASE | ||||
| RxCUI drug identifier | 721791, 721794, 721796, 853201, 895670 |
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| Application Number | ANDA208947 | ||||
| Labeler Name | Golden State Medical Supply, Inc. | ||||
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| Check if available Online | Get Medication Prices online with Discount |
Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse Quetiapine fumarate extended-release tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine fumarate extended-release tablets (e.g., development of tolerance, increases in dose, drug-seeking behavior).
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance Quetiapine fumarate extended-release tablets are not a controlled substance.
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Quetiapine fumarate extended-release tablets are not a controlled substance. 9.2 Abuse Quetiapine fumarate extended-release tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine fumarate extended-release tablets (e.g., development of tolerance, increases in dose, drug-seeking behavior).
Overdosage of quetiapine fumarate
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE 10.1 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 [see Warnings and Precautions ( 5.12 )] . 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. 10.2 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 quetiapine fumarate extended-release tablet overdosage, contact a certified Regional Poison Control Center (1-800-222-1222).
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS Most common adverse reactions (incidence 5% and twice placebo): Adults: somnolence, dry mouth, constipation, dizziness, increased appetite, dyspepsia, weight gain, fatigue, dysarthria, and nasal congestion ( 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 Ingenus Pharmaceuticals, LLC Toll-Free at 1-877-748-1970 or FDA at FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 )] 6.1 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 quetiapine fumarate extended-release tablets consisting of approximately 3400 patients exposed to quetiapine fumarate 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: There were no adverse reactions leading to discontinuation that occurred at an incidence of 2% for quetiapine fumarate extended-release tablets 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 quetiapine fumarate extended-release tablets in the bipolar mania trial. Bipolar Disorder, Depressive Episode: In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on quetiapine fumarate extended-release tablets discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of 2% in quetiapine fumarate extended-release tablets in the bipolar depression trial. MDD, Adjunctive Therapy: In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on quetiapine fumarate extended-release tablets discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of 2% in quetiapine fumarate extended-release tablets 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 quetiapine fumarate extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine fumarate 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 fumarate 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 fumarate extended-release tablets (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate 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 Preferred Term Quetiapine fumarate 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% 1. Somnolence combines adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: cogwheel rigidity, drooling, dyskinesia dystonia, extrapyramidal disorder, hypertonia, movement disorder, muscle rigidity, parkinsonism, parkinsonian gait, and tardive dyskinesia. In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine fumarate 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 fumarate extended-release tablets (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate extended-release tablets 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 Preferred Term Quetiapine fumarate 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. Somnolence combines adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: muscle spasms, akathisia, cogwheel rigidity, dystonia, extrapyramidal disorder, restlessness and tremor. In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine fumarate 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 fumarate extended-release tablets 300 mg/day where the incidence in patients treated with quetiapine fumarate extended-release tablets 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 Depression Preferred Term Quetiapine fumarate 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. Somnolence combines adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: dystonia, extrapyramidal disorder, hypertonia, and tremor. 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 fumarate extended-release tablets (incidence of 5% or greater and observed at a rate on quetiapine fumarate 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 fumarate extended-release tablets (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with quetiapine fumarate 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 fumarate extended-release tablets 150mg (N=315) Quetiapine fumarate extended-release tablets 300mg (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. Somnolence combines the adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, hypokinesia, psychomotor hyperactivity, restlessness, and tremor. 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: (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 emergent EPS. Adults: In placebo-controlled clinical trials with quetiapine, utilizing doses up to 800 mg per day, the incidence of any adverse reactions related to EPS ranged from 8% to 11% for quetiapine and 4% to 11% for placebo. In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of quetiapine fumarate extended-release tablets, the incidence of any adverse reactions related to EPS was 8% for quetiapine fumarate extended-release tablets and 8% for quetiapine fumarate tablets (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 quetiapine fumarate tablets 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 Schizophrenia Preferred Term Quetiapine Fumarate * ER tablets 300 mg/day (N=91) Quetiapine Fumarate * ER tablets 400 mg/day (N=227) Quetiapine Fumarate * ER tablets 600 mg/day (N=310) Quetiapine Fumarate * ER tablets 800mg/day (N=323) All Doses (N=951) Placebo (N=319) n % n % n % n % n % n % Dystonic event 3 3.3 0 0.0 4 1.3 1 0.3 8 0.8 0 0.0 Parkinsonism 1 1.1 3 1.3 11 3.6 7 2.2 22 2.3 4 1.3 Akathisia 0 0.0 3 1.3 7 2.3 7 2.2 17 1.8 4 1.3 Dyskinetic event 2 2.2 1 0.4 1 0.3 1 0.3 5 0.5 2 0.6 Other extrapyramidal event 3 3.3 4 1.8 7 2.3 12 3.7 26 2.7 7 2.2 * ER = Extended-Release In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400-800 mg/day of quetiapine fumarate extended-release tablets, the incidence of any adverse reactions related to EPS was 6.6% for quetiapine fumarate 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. In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of quetiapine fumarate extended-release tablets, the incidence of any adverse reactions related to EPS was 4.4% for quetiapine fumarate 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. In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of quetiapine fumarate extended-release tablets, the incidence of any adverse reactions related to EPS was 5.1% for quetiapine fumarate 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: Children and Adolescents The information below is derived from a clinical trial database for quetiapine fumarate tablets consisting of over 1000 pediatric patients. This database includes 677 adolescents (13-17 years old) exposed to quetiapine fumarate tablets for the treatment of schizophrenia and 393 children and adolescents (10-17 years old) exposed to quetiapine fumarate tablets 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. The adverse reactions leading to discontinuation in 2% or more of patients on quetiapine fumarate tablets and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0%). Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: In an acute (8-week) quetiapine fumarate extended-release tablets 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 quetiapine fumarate 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 quetiapine fumarate tablet Treated Patients in Short-Term, Placebo-Controlled Trials Schizophrenia (Adolescents, 13 – 17 years old) The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day. Table 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 quetiapine fumarate tablets (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine fumarate tablets 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. 11%). 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 quetiapine fumarate tablets (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate tablets was greater than the incidence in placebo-treated patients. Adverse reactions that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50% vs. 57%), nausea (6% vs. 10%) and tachycardia (6% vs. 9%). Extrapyramidal Symptoms: Safety and effectiveness of quetiapine fumarate extended-release tablets are supported by studies of quetiapine fumarate tablets in children and adolescent patients 10-17 years of age [see Clinical Studies( 14.1 and 14.2 )] In a short-term placebo-controlled quetiapine fumarate extended-release tablets 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 quetiapine fumarate extended-release tablets and 0% (0/100) for placebo. In a short-term placebo-controlled quetiapine fumarate tablets 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 quetiapine fumarate tablets 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 a short-term placebo-controlled quetiapine fumarate tablets monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) for quetiapine fumarate tablets 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 quetiapine fumarate tablets monotherapy trial in adolescent patients with schizophrenia (6-week duration). 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). Laboratory, ECG and vital sign changes observed in clinical studies Laboratory Changes: Neutrophil Counts Adults: In three-arm quetiapine fumarate extended-release tablets 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 quetiapine fumarate extended-release tablets and 1.5% for quetiapine fumarate tablets, compared to 0.8% in placebo-treated patients. In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 10 9 /L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine, compared to 0.1% (2/1349) in patients treated with placebo [see Warnings and Precautions ( 5.10 )] 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 quetiapine fumarate extended-release tablets compared to 2% for placebo. In schizophrenia trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483) for quetiapine fumarate tablets compared to 1% (3/194) 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. Decreased Hemoglobin Adults: In short-term placebo-controlled trials, decreases in hemoglobin to 13 g/dL males, 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decrease in hemoglobin to 13 g/dL males, 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients. Interference with Urine Drug Screens There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g., chromatographic methods) should be considered. ECG Changes: Adults: 2.5% of quetiapine fumarate extended-release tablets patients, and 2.3% of placebo patients, had tachycardia (>120 bpm) at any time during the trials. Quetiapine fumarate extended-release tablets 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 quetiapine fumarate tablets. The incidence of adverse reactions of tachycardia was 1.9% for quetiapine fumarate extended-release tablets compared to 0.5% for placebo. Quetiapine fumarate tablets 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 [see Warnings and Precautions ( 5.7 )]. Children and Adolescents: Safety and effectiveness of quetiapine fumarate extended-release tablets is supported by studies of quetiapine fumarate tablets in children and adolescent patients 10-17 years of age [(see Clinical Studies (14.1 and 14.2)] . In an acute (8-week) quetiapine fumarate extended-release tablets trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10-12 years and 13-17 years) occurred in 0% of patients receiving quetiapine fumarate extended-release tablets and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine fumarate extended-release tablets, compared to 0.3 bpm in the placebo group [see Warnings and Precautions ( 5.7 )]. In the acute (6-week) quetiapine fumarate tablets schizophrenia trial in adolescents (13-17 years of age), increases in heart rate (>110 bpm) occurred in 5.2% of patients receiving quetiapine fumarate tablets 400 mg and 8.5% of patients receiving quetiapine fumarate tablets 800 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for quetiapine fumarate tablets 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group [see Warnings and Precautions ( 5.7 )]. In the acute (3-week) quetiapine fumarate tablets bipolar mania trial in children and adolescents (10-17 years of age), increases in heart rate (>110 bpm) occurred in 1.1% of patients receiving quetiapine fumarate tablets 400 mg and 4.7% of patients receiving quetiapine fumarate tablets 600 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for quetiapine fumarate tablets 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 )] . Image Image Image Image Image Image Image 6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of quetiapine fumarate tablets. 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, and acute generalized exanthematous pustulosis (AGEP).
| 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% |
| 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% |
| 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% |
| 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% |
| n | % | n | % | n | % | n | % | n | % | n | % | |
| Dystonic event | 3 | 3.3 | 0 | 0.0 | 4 | 1.3 | 1 | 0.3 | 8 | 0.8 | 0 | 0.0 |
| Parkinsonism | 1 | 1.1 | 3 | 1.3 | 11 | 3.6 | 7 | 2.2 | 22 | 2.3 | 4 | 1.3 |
| Akathisia | 0 | 0.0 | 3 | 1.3 | 7 | 2.3 | 7 | 2.2 | 17 | 1.8 | 4 | 1.3 |
| Dyskinetic event | 2 | 2.2 | 1 | 0.4 | 1 | 0.3 | 1 | 0.3 | 5 | 0.5 | 2 | 0.6 |
| Other extrapyramidal event | 3 | 3.3 | 4 | 1.8 | 7 | 2.3 | 12 | 3.7 | 26 | 2.7 | 7 | 2.2 |
quetiapine fumarate Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Concomitant use of strong CYP3A4 inhibitors: Reduce quetiapine dose to one sixth when coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) ( 2.5 , 7.1 , 12.3 ) Concomitant use of strong CYP3A4 inducers: Increase quetiapine dose up to 5 fold when used in combination with a chronic treatment (more than 7-14 days) of potent CYP3A4 inducers (e.g., phenytoin, rifampin, St. John's wort) ( 2.6 , 7.1 , 12.3 ) Discontinuation of strong CYP3A4 inducers: Reduce quetiapine dose by 5 fold within 7-14 days of discontinuation of CYP3A4 inducers ( 2.6 , 7.1 , 12.3 ) 7.1 Effect of Other Drugs on Quetiapine The risks of using quetiapine fumarate extended-release tablets in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine fumarate 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.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 [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . CYP3A4 inducers: Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine fumarate 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 ( 2.6 ) and Clinical Pharmacology ( 12.3 )] . When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate extended-release tablets should be reduced to the original level within 7-14 days [see Dosage and Administration ( 2.6 )]. The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied. 7.2 Effect of Quetiapine on Other Drugs Because of its potential for inducing hypotension, quetiapine fumarate extended-release tablets may enhance the effects of certain antihypertensive agents. Quetiapine fumarate extended-release tablets may antagonize the effects of levodopa and dopamine agonists. There are no clinically relevant pharmacokinetic interactions of quetiapine fumarate tablets on other drugs based on the CYP pathway. Quetiapine fumarate and its metabolites are non-inhibitors of major metabolizing CYP's (1A2, 2C9, 2C19, 2D6 and 3A4).
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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 ) and serotonin type 2A (5HT 2A ) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D 2 , but greater activity at 5HT 2A receptors, than the parent drug (quetiapine). 12.2 Pharmacodynamics Quetiapine and its metabolite norquetiapine have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general. The Ki values for quetiapine and norquetiapine at the dopamine D 1 are 428/99.8 nM, at D 2 626/489nM, at serotonin 5HT 1A 1040/191 nM at 5HT 2A 38/2.9 nM, at histamine H 1 4.4/1.1 nM, at muscarinic M 1 1086/38.3 nM, and at adrenergic 1 b 14.6/46.4 nM and, at 2 receptors 617/1290 nM, respectively. Quetiapine and norquetiapine lack appreciable affinity to the benzodiazepine receptors. 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)] , in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval. 12.3 Pharmacokinetics 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 and AUC of norquetiapine are about 21-27% and 46-56%, respectively, of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine fumarate extended-release tablets areunlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes. Children and Adolescents At steady state, the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C max of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and C max were 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults [see Use in Specific Populations ( 8.4 )] . Absorption Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. Quetiapine fumarate extended-release tablets dosed once daily at steady state has comparable bioavailability to an equivalent total daily dose of quetiapine fumarate tablets 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 fumarate extended-release tablets C max and AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the C max or AUC of quetiapine. It is recommended that quetiapine fumarate extended-release tablets be taken without food or with a light meal [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 , quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine. Metabolism and Elimination Following a single oral dose of 14 C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine. 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 studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite norquetiapine. Age Oral clearance of quetiapine was reduced by 40% in elderly patients ( 65 years, n=9) compare 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 = 10 - 30 mL/min/1.73m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (CL cr >80 mL/min/1.73m 2 , n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients [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 were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.7 )] . Drug-Drug Interaction Studies The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 24 [see Dosage and Administration ( 2.5 and 2.6 ) and Drug Interactions ( 7.1 )] . In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes CYP 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table25) [see Drug Interactions ( 7.2 )] . Table25: The Effect of Quetiapine on the Pharmacokineticsof 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 Cmax and AUC of free valproic acid at steady-state was decreased by 10-12% 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 Image
| 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 | Cmax and AUC of free valproic acid at steady-state was decreased by 10-12% |
| 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 |
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action 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 ) and serotonin type 2A (5HT 2A ) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D 2 , but greater activity at 5HT 2A receptors, than the parent drug (quetiapine).
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Quetiapine and its metabolite norquetiapine have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general. The Ki values for quetiapine and norquetiapine at the dopamine D 1 are 428/99.8 nM, at D 2 626/489nM, at serotonin 5HT 1A 1040/191 nM at 5HT 2A 38/2.9 nM, at histamine H 1 4.4/1.1 nM, at muscarinic M 1 1086/38.3 nM, and at adrenergic 1 b 14.6/46.4 nM and, at 2 receptors 617/1290 nM, respectively. Quetiapine and norquetiapine lack appreciable affinity to the benzodiazepine receptors. 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)] , in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics 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 and AUC of norquetiapine are about 21-27% and 46-56%, respectively, of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine fumarate extended-release tablets areunlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes. Children and Adolescents At steady state, the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C max of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and C max were 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults [see Use in Specific Populations ( 8.4 )] . Absorption Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. Quetiapine fumarate extended-release tablets dosed once daily at steady state has comparable bioavailability to an equivalent total daily dose of quetiapine fumarate tablets 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 fumarate extended-release tablets C max and AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the C max or AUC of quetiapine. It is recommended that quetiapine fumarate extended-release tablets be taken without food or with a light meal [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 , quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine. Metabolism and Elimination Following a single oral dose of 14 C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine. 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 studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite norquetiapine. Age Oral clearance of quetiapine was reduced by 40% in elderly patients ( 65 years, n=9) compare 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 = 10 - 30 mL/min/1.73m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (CL cr >80 mL/min/1.73m 2 , n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients [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 were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.7 )] . Drug-Drug Interaction Studies The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 24 [see Dosage and Administration ( 2.5 and 2.6 ) and Drug Interactions ( 7.1 )] . In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes CYP 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table25) [see Drug Interactions ( 7.2 )] . Table25: The Effect of Quetiapine on the Pharmacokineticsof 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 Cmax and AUC of free valproic acid at steady-state was decreased by 10-12% 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 Image
| 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 | Cmax and AUC of free valproic acid at steady-state was decreased by 10-12% |
| 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 |
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Known hypersensitivity to quetiapine fumarate extended-release tablets or any components in the formulation. ( 4 ) Hypersensitivity to quetiapine or to any excipients in the quetiapine fumarate extended-release tablets formulation. Anaphylactic reactions have been reported in patients treated with quetiapine fumarate extended-release tablets.
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Quetiapine fumarate is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [ b , f ] [1,4] thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C 42 H 50 N 6 O 4 S 2 •C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is: Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water. Quetiapine fumarate extended-release tablets are supplied for oral administration as 50 mg (pink), 150 mg (white), 200 mg (yellow), 300 mg (light yellow) and 400 mg (white). All tablets are capsule shaped and film coated. Inactive ingredients: The following are common in all 5 tablet strengths: microcrystalline cellulose, hypromellose, magnesium stearate, povidone, polyethylene glycol, and titanium dioxide. Additional inactive ingredients include: 50 mg - polyvinyl alcohol, talc, iron oxide yellow, iron oxide red, iron oxide black, lecithin (soya);150 mg - polydextrose and triacetin; 200 mg - polyvinyl alcohol, talc, lecithin (soya), D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake and FD&C blue #2 aluminum lake; 300 mg - polyvinyl alcohol, talc, lecithin (soya), iron oxide yellow and iron oxide black; 400 mg - polydextrose, and triacetin. Each 50 mg tablet contains 58 mg of quetiapine fumarate equivalent to 50 mg quetiapine. Each 150 mg tablet contains 173 mg of quetiapine fumarate equivalent to 150 mg quetiapine. Each 200 mg tablet contains 230 mg of quetiapine fumarate equivalent to 200 mg quetiapine. Each 300 mg tablet contains 345 mg of quetiapine fumarate equivalent to 300 mg quetiapine. Each 400 mg tablet contains 461 mg of quetiapine fumarate equivalent to 400 mg quetiapine. Meets USP dissolution test 6. Image
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION 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: Consider a lower starting dose (50 mg/day), slower titration, and careful monitoring during the initial dosing period in the elderly. ( 2.3 , 8.5 ) Hepatic Impairment: Lower starting dose (50 mg/day) and slower titration may be needed ( 2.4 , 8.7 , 12.3 ) 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 2.1 Important Administration Instructions Quetiapine fumarate extended-release tablets should be swallowed whole and not split, chewed or crushed. It is recommended that quetiapine fumarate extended-release tablets be taken without food or with a light meal (approximately 300 calories) [see Clinical Pharmacology ( 12.3 )]. Quetiapine fumarate extended-release tablets should be administered once daily, preferably in the evening. 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine fumarate 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 ( 14.1 , 14.2 and 14.3 )]. Table 1 Recommended Dosing for Quetiapine fumarate 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 - 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 - 800 mg/day 800 mg/day Schizophrenia Maintenance Monotherapy-Adults Not applicable 400 - 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 - 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 - 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 - 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 - 300 mg/day 300 mg/day 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 [see Clinical Studies ( 14.1 , 14.2 )] 2.3 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 [see Use in Specific Populations ( 8.5 , 8.7 ) and Clinical Pharmacology ( 12.3 )] . When indicated, dose escalation should be performed with caution in these patients. Elderly patients should be started on quetiapine fumarate 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. 2.4 Dose Modifications in Hepatically Impaired Patients Patients with hepatic impairment should be started on quetiapine fumarate 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. 2.5 Dose Modifications when used with CYP3A4 Inhibitors Quetiapine fumarate extended-release tablets 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 quetiapine fumarate extended-release tablets should be increased by 6-fold [see Clinical Pharmacology ( 12.3 ) and Drug Interactions ( 7.1 )]. 2.6 Dose Modifications when used with CYP3A4 Inducers Quetiapine fumarate extended-release tablets 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 quetiapine fumarate extended-release tablets should be reduced to the original level within 7-14 days [see Clinical Pharmacology ( 12.3 ) and Drug Interactions ( 7.1 )]. 2.7 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 quetiapine fumarate extended-release tablets for more than one-week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine fumarate extended-release tablets for less than one-week, gradual dose escalation may not be required and the maintenance dose may be re-initiated. 2.8 Switching Patients from Quetiapine Fumarate Tablets to Quetiapine Fumarate Extended-Release Tablets Patients who are currently being treated with quetiapine fumarate tablets (immediate release formulation) may be switched to quetiapine fumarate extended-release tablets at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary. 2.9 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients from other antipsychotics to quetiapine fumarate 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 fumarate extended-release tablets therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.
| Indication | Initial Dose | Recommended Dose | Maximum Dose |
| Schizophrenia-Adults ( | 300 mg/day | 400 to 800 mg/day | 800 mg/day |
| Schizophrenia-Adolescents (13 to 17 years) ( | 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 ( | 300 mg/day | 400 to 800 mg/day | 800 mg/day |
| Bipolar I Disorder, manic Acute monotherapy Children and Adolescents (10 to 17 years) ( | 50 mg/day | 400 to 600 mg/day | 600 mg/day |
| Bipolar Disorder, Depressive Episodes-Adults ( | 50 mg/day | 300 mg/day | 300 mg/day |
| Major Depressive Disorder, Adjunctive Therapy with Antidepressants- Adults | 50 mg/day | 150 to 300 mg/day | 300 mg/day |
| 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 - 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 - 800 mg/day | 800 mg/day |
| Schizophrenia Maintenance Monotherapy-Adults | Not applicable | 400 - 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 - 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 - 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 - 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 - 300 mg/day | 300 mg/day |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Extended-Release Tablets: 50 mg, 150 mg, 200 mg, 300 mg, and 400 mg ( 3 ) 50 mg quetiapine fumarate extended-release tablets are pink, film-coated, capsule- -shaped, biconvex, debossed tablet with "NT 50" on one side and plain on the other side 150 mg quetiapine fumarate extended-release tablets are white, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 150" on one side and plain on the other side 200 mg quetiapine fumarate extended-release tablets are yellow, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 200" on one side and plain on the other side 300 mg quetiapine fumarate extended-release tablets are light yellow, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 300" on one side and plain on the other side 400 mg quetiapine fumarate extended-release tablets are white, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 400" on one side and plain on the other side
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Quetiapine fumarate extended-release tablet are 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 ) 1.1 Schizophrenia Quetiapine fumarate extended-release tablets are indicated for the treatment of schizophrenia. The efficacy of quetiapine fumarate 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 (13-17 years) treated with quetiapine fumarate tablets [see Clinical Studies ( 14.1 )]. 1.2 Bipolar Disorder Quetiapine fumarate 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 fumarate 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 – 17 years) with manic episodes associated with bipolar I disorder treated with quetiapine fumarate tablets [see Clinical Studies ( 14.2 )]. Quetiapine fumarate extended-release tablets are indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of quetiapine fumarate extended-release tablets was 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 quetiapine fumarate tablets [see Clinical Studies ( 14.2 )]. Quetiapine fumarate 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 quetiapine fumarate tablets. 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 )]. 1.3 Adjunctive Treatment of Major Depressive Disorder (MDD) Quetiapine fumarate extended-release tablets are indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of quetiapine fumarate 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 )]. 1.4 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder 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.
Spl product data elements
Usually a list of ingredients in a drug product.Quetiapine Fumarate quetiapine fumarate CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES POVIDONE POLYETHYLENE GLYCOL 3350 TITANIUM DIOXIDE POLYVINYL ALCOHOL, UNSPECIFIED TALC FERRIC OXIDE RED FERRIC OXIDE YELLOW MAGNESIUM STEARATE FERROSOFERRIC OXIDE LECITHIN, SOYBEAN QUETIAPINE FUMARATE QUETIAPINE biconvex NT50 Quetiapine Fumarate quetiapine fumarate CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES POVIDONE POLYETHYLENE GLYCOL 8000 TITANIUM DIOXIDE POLYDEXTROSE TRIACETIN MAGNESIUM STEARATE QUETIAPINE FUMARATE QUETIAPINE biconvex NT150 Quetiapine Fumarate quetiapine fumarate CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES MAGNESIUM STEARATE POVIDONE POLYETHYLENE GLYCOL 3350 TITANIUM DIOXIDE POLYVINYL ALCOHOL, UNSPECIFIED TALC LECITHIN, SOYBEAN D&C YELLOW NO. 10 FD&C YELLOW NO. 6 FD&C BLUE NO. 2 QUETIAPINE FUMARATE QUETIAPINE biconvex NT200 Quetiapine Fumarate quetiapine fumarate CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES MAGNESIUM STEARATE POVIDONE POLYETHYLENE GLYCOL 3350 TITANIUM DIOXIDE POLYVINYL ALCOHOL, UNSPECIFIED TALC LECITHIN, SOYBEAN FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE QUETIAPINE FUMARATE QUETIAPINE light yellow biconvex NT300 Quetiapine Fumarate quetiapine fumarate CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES MAGNESIUM STEARATE POVIDONE POLYETHYLENE GLYCOL 8000 TITANIUM DIOXIDE POLYDEXTROSE TRIACETIN QUETIAPINE FUMARATE QUETIAPINE biconvex NT400
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and/or Pharmacology 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 0.1, 0.3, 0.6, 1, 2 and 3-times the MRHD of 800 mg/day based on mg/m 2 body surface area, respectively. Doses in the mouse carcinogenicity study were 20, 75, 250 and 750 mg/kg which are approximately 0.1, 0.5, 1.5, and 4.5 times the MRHD of 800 mg/day based on mg/m 2 body surface area. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown. In dogs receiving quetiapine for 6 or 12 months, but not for 1-month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day based on mg/m 2 body surface area. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta-8-cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the MRHD of 800 mg/day based on mg/m 2 body surface area.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis&Impairment of Fertility 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 0.1, 0.5, 1.5, and 4.5 times the MRHD of 800 mg/day based on mg/m 2 body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m 2 body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD based on mg/m 2 body surface area and in male rats at a dose of 3 times the MRHD on mg/m 2 body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD based on mg/m 2 body surface area). 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 Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose based on mg/m 2 body surface area. 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 theMRHD of 800 mg/day based on mg/m 2 body surface area. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the MRHD dose based on mg/m 2 body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day based on mg/m 2 body surface area. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or approximately 0.1 and 1 times the MRHD of 800 mg/day based on mg/m 2 body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day based on mg/m 2 body surface area.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis&Impairment of Fertility 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 0.1, 0.5, 1.5, and 4.5 times the MRHD of 800 mg/day based on mg/m 2 body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m 2 body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD based on mg/m 2 body surface area and in male rats at a dose of 3 times the MRHD on mg/m 2 body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD based on mg/m 2 body surface area). 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 Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose based on mg/m 2 body surface area. 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 theMRHD of 800 mg/day based on mg/m 2 body surface area. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the MRHD dose based on mg/m 2 body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day based on mg/m 2 body surface area. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or approximately 0.1 and 1 times the MRHD of 800 mg/day based on mg/m 2 body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day based on mg/m 2 body surface area. 13.2 Animal Toxicology and/or Pharmacology 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 0.1, 0.3, 0.6, 1, 2 and 3-times the MRHD of 800 mg/day based on mg/m 2 body surface area, respectively. Doses in the mouse carcinogenicity study were 20, 75, 250 and 750 mg/kg which are approximately 0.1, 0.5, 1.5, and 4.5 times the MRHD of 800 mg/day based on mg/m 2 body surface area. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown. In dogs receiving quetiapine for 6 or 12 months, but not for 1-month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day based on mg/m 2 body surface area. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta-8-cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the MRHD of 800 mg/day based on mg/m 2 body surface area.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Package/Label Display Panel – 50 mg NDC 51407-073-60 60 tablets Quetiapine Fumarate Extended-Release Tablets 50 mg Once Daily Swallow Whole - Do not split, crush or chew Rx only 51407-073-60LB.jpg
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Package/Label Display Panel – 150 mg NDC 51407-074-60 60 tablets Quetiapine Fumarate Extended-Release Tablets 150 mg Once Daily Swallow Whole - Do not split, crush or chew Rx only 51407-074-60OL.jpg
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Package/Label Display Panel – 200 mg NDC 51407-075-60 60 tablets Quetiapine Fumarate Extended-Release Tablets 200 mg Once Daily Swallow Whole - Do not split, crush or chew Rx only 51407-075-60OL.jpg
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Package/Label Display Panel – 300 mg NDC 51407-076-60 60 tablets Quetiapine Fumarate Extended-Release Tablets 300 mg Once Daily Swallow Whole - Do not split, crush or chew Rx only 51407-076-60OL.jpg
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Package/Label Display Panel – 400 mg NDC 51407-077-60 60 tablets Quetiapine Fumarate Extended-Release Tablets 400 mg Once Daily Swallow Whole - Do not split, crush or chew Rx only 51407-077-60OL.jpg
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.RECENT MAJOR CHANGES Warnings and Precautions, Tardive Dyskinesia ( 5.6 ) 08/2019
quetiapine fumarate: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking quetiapine fumarate extended-release tablets. Increased Mortality in Elderly Patients with Dementia-Related Psychosis Patients and caregivers should be advised that elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. Quetiapine fumarate extended-release tablets are not approved for elderly patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] Suicidal Thoughts and Behaviors Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Warnings and Precautions ( 5.2 )] . Neuroleptic Malignant Syndrome (NMS) Patients should be advised to report to their physician any signs or symptoms that may be related to NMS. These may include muscle stiffness and high fever [see Warnings and Precautions ( 5.4 )] Hyperglycemia and Diabetes Mellitus Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [see Warnings and Precautions ( 5.5 )] . Hyperlipidemia Patients should be advised that elevations in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol may occur. Patients should have their lipid profile monitored at the beginning of and periodically during treatment [see Warnings and Precautions ( 5.5 )] . Weight Gain Patients should be advised that they may experience weight gain. Patients should have their weight monitored regularly [see Warnings and Precautions ( 5.5 )] . Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls) especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions ( 5.7 )] . Increased Blood Pressure in Children and Adolescents Children and adolescent patients should have their blood pressure measured at the beginning of, and periodically during, treatment [see Warnings and Precautions ( 5.9 )] . Leukopenia/Neutropenia Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking quetiapine fumarate extended-release tablets. Patients should be advised to talk to their doctor as soon as possible if they have a fever, flu-like symptoms, sore throat, or any other infection as this could be a result of a very low WBC, which may require quetiapine fumarate extended-release tablets to be stopped and/or treatment to be given [see Warnings and Precautions ( 5.10 )] . Interference with Cognitive and Motor Performance Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration. Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely. [see Warnings and Precautions ( 5.16 )] . Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions ( 5.17 )] . Concomitant Medication As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs [see Drug Interactions ( 7.1 )] . Pregnancy Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with quetiapine fumarate extended-release tablets. Advise patients that quetiapine fumarate extended-release tablets may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to quetiapine fumarate extended-release tablets during pregnancy [see Use in Specific Populations ( 8.1 )] . Infertility Advise females of reproductive potential that quetiapine fumarate extended-release tablets may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations ( 8.3 )] . Need for Comprehensive Treatment Program Quetiapine fumarate extended-release tablets are indicated as an integral part of a total treatment program for adolescents with schizophrenia and pediatric bipolar disorder that may include other measures (psychological, educational, and social). Effectiveness and safety of quetiapine fumarate extended-release tablets have not been established in pediatric patients less than 13 years of age for schizophrenia or less than 10 years of age for bipolar mania. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms. [see Indications and Usage ( 1.4 )] . Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 Product of Italy. I0081 Rev. E Iss. Feb 2020 Marketed/Packaged by: GSMS, Inc. Camarillo, CA USA 93012 ingenus
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.Medication Guide for Quetiapine Fumarate Extended-Release Tablets (kweh-TYE-uh-peen) Read this Medication Guide before you start taking quetiapine fumarate extended-release tablets and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about quetiapine fumarate extended-release tablets? Quetiapine fumarate extended-release tablets may cause serious side effects, including: 1. risk of death in the elderly with dementia: Medicines like quetiapine fumarate extended-release tablets can increase the risk of death in elderly people who have memory loss (dementia). Quetiapine fumarate extended-release tablets are not for treating psychosis in the elderly with dementia. 2. risk of suicidal thoughts or actions (antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions). • Talk to youror your family member's, healthcare provider about: o all risks and benefits of treatment with antidepressant medicines o all treatment choices for depression or other serious mental illness • Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness), or suicidal thoughts or actions. • How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? o Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed o Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings o Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to your healthcare provider . Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses . It is important to discuss all the risks of treating depression, and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects . Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines . Know all of the medicines that you or your family members take. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children . Talk to your child's healthcare provider for more information. What are quetiapine fumarate extended-release tablets? Quetiapine fumarate extended-release tablets are a prescription medicine used to treat: • schizophrenia in people 13 years of age or older • bipolar disorder in adults, including: o depressive episodes associated with bipolar disorder o manic episodes associated with bipolar I disorder alone or with lithium or divalproex o long-term treatment of bipolar I disorder with lithium or divalproex • manic episodes associated with bipolar I disorder in children ages 10 to 17 years old • major depressive disorder as add-on treatment with antidepressant medicines when your healthcare provider determines that 1 antidepressant alone is not enough to treat your depression. It is not known if quetiapine fumarate extended-release tablets are safe and effective in children under 10 years of age. Who should not take quetiapine fumarate extended-release tablets? Do not take quetiapine fumarate extended-release tablets if you are allergic to quetiapine fumarate or any of the ingredients in quetiapine fumarate extended-release tablets . See the end of this Medication Guide for a complete list of ingredients in quetiapine fumarate extended-release tablets. What should I tell my healthcare provider before taking quetiapine fumarate extended-release tablets? Before you take quetiapine fumarate extended-release tablets, tell your healthcare provider if you have or have had: • diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start quetiapine fumarate extended-release tablets and also during therapy • high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol • low or high blood pressure • low white blood cell count • cataracts • seizures • abnormal thyroid tests • high prolactin levels • heart problems • liver problems • any other medical condition • pregnancy or plans to become pregnant. It is not known if quetiapine fumarate extended-release tablets will harm your unborn baby. • If you become pregnant while receiving quetiapine fumarate extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ • breast-feeding or plans to breast-feed. Quetiapine fumarate extended-release tablets can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive quetiapine fumarate extended-release tablets. • if you have or have had a condition where you cannot completely empty your bladder (urinary retention), have an enlarged prostate, or constipation, or increased pressure inside your eyes. Tell the healthcare provider about all the medicines that you take or recently have taken including prescription medicines, over-the-counter medicines, herbal supplements and vitamins. Quetiapine fumarate extended-release tablets and other medicines may affect each other causing serious side effects. Quetiapine fumarate extended-release tablets may affect the way other medicines work, and other medicines may affect how quetiapine fumarate extended-release tablets work. Tell your healthcare provider if you are having a urine drug screen because quetiapine fumarate extended-release tablets may affect your test results. Tell those giving the test that you are taking quetiapine fumarate extended-release tablets. How should I take quetiapine fumarate extended-release tablets? • Take quetiapine fumarate extended-release tablets exactly as your healthcare provider tells you to take it. Do not change the dose yourself • Take quetiapine fumarate extended-release tablets by mouth, with a light meal or without food. • Quetiapine fumarate extended-release tablets should be swallowed whole and not split, chewed or crushed. • If you feel you need to stop quetiapine fumarate extended-release tablets, talk with your healthcare provider first . If you suddenly stop taking quetiapine fumarate extended-release tablets, you may have side effects such as trouble sleeping or trouble staying asleep (insomnia), nausea, and vomiting. • If you miss a dose of quetiapine fumarate extended-release tablets, take it as soon as you remember. If you are close to your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider. What should I avoid while taking quetiapine fumarate extended-release tablets? • Do not drive, operate machinery, or do other dangerous activities until you know how quetiapine fumarate extended-release tablets affects you. Quetiapine fumarate extended-release tablets may make you drowsy • Avoid getting overheated or dehydrated o Do not over-exercise o In hot weather, stay inside in a cool place if possible o Stay out of the sun. Do not wear too much or heavy clothing o Drink plenty of water • Do not drink alcohol while taking quetiapine fumarate extended-release tablets. It may make some side effects of quetiapine fumarate extended-release tablets worse. What are possible side effects of quetiapine fumarate extended-release tablets? Quetiapine fumarate extended-release tablets can cause serious side effects, including: See "What is the most important information I should know about quetiapine fumarate extended-release tablets?" • stroke that can lead to death can happen in elderly people with dementia who take medicines like quetiapine fumarate extended-release tablets • neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including quetiapine fumarate extended-release tablets. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have some or all of these symptoms: o high fever o excessive sweating o rigid muscles o confusion o changes in your breathing, heartbeat, and blood pressure • falls can happen in some people who take quetiapine fumarate extended-release tablets. These falls may cause serious injuries. • high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to: o build up of acid in your blood due to ketones (ketoacidosis) o coma o death Increases in blood sugar can happen in some people who take quetiapine fumarate extended-release tablets. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start quetiapine fumarate extended-release tablets and during therapy. Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking quetiapine fumarate extended-release tablets: o feel very thirsty o need to urinate more than usual o feel very hungry o feel weak or tired o feel sick to your stomach o feel confused, or your breath smells fruity • high fat levels in your blood (increased cholesterol and triglycerides). High fat levels may happen in people treated with quetiapine fumarate extended-release tablets. You may not have any symptoms, so your healthcare provider may decide to check your cholesterol and triglycerides during your treatment with quetiapine fumarate extended-release tablets. • increase in weight (weight gain). Weight gain is common in people who take quetiapine fumarate extended-release tablets so you and your healthcare provider should check your weight regularly. Talk to your healthcare provider about ways to control weight gain, such as eating a healthy, balanced diet, and exercising. • movements you cannot control in your face, tongue, or other body parts (tardive dyskinesia). These may be signs of a serious condition. Tardive dyskinesia may not go away, even if you stop taking quetiapine fumarate extended-release tablets. Tardive dyskinesia may also start after you stop taking quetiapine fumarate extended-release tablets. • decreased blood pressure (orthostatic hypotension), including lightheadedness or fainting caused by a sudden change in heart rate and blood pressure when rising too quickly from a sitting or lying position • increases in blood pressure in children and teenagers. Your healthcare provider should check blood pressure in children and adolescents before starting quetiapine fumarate extended-release tablets and during therapy. Quetiapine fumarate extended-release tablets are not approved for patients under 10 years of age • low white blood cell count. Tell your health care provider as soon as possible if you have a fever, flu-like symptoms, or any other infection, as this could be a result of a very low white blood cell count. Your healthcare provider may check your white blood cell level to determine if further treatment or other action is needed • cataracts • seizures • abnormal thyroid tests: Your healthcare provider may do blood tests to check your thyroid hormone level • increases in prolactin levels: Your healthcare provider may do blood tests to check your prolactin levels • sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities • increased body temperature • difficulty swallowing • trouble sleeping or trouble staying asleep (insomnia), nausea, or vomiting if you suddenly stop taking quetiapine fumarate extended-release tablets. These symptoms usually get better 1 week after you start having them. The most common side effects of quetiapine fumarate extended-release tablets include: • dry mouth • constipation • dizziness • increased appetite • upset stomach • fatigue • stuffy nose • difficulty moving • disturbance in speech or language Children and Adolescents: • drowsiness • dizziness • fatigue • stuffy nose • increased appetite • upset stomach • vomiting • dry mouth • tachycardia • weight increased These are not all the possible side effects of quetiapine fumarate extended-release tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store quetiapine fumarate extended-release tablets? • Store quetiapine fumarate extended-release tablets at room temperature, between 68°F to 77°F (20°C to 25°C) • Keep quetiapine fumarate extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of quetiapine fumarate extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use quetiapine fumarate extended-release tablets for a condition for which it was not prescribed. Do not give quetiapine fumarate extended-release tablets to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about quetiapine fumarate extended-release tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about quetiapine fumarate extended-release tablets that is written for health professionals. For more information, please call Ingenus Pharmaceuticals , LLC at 1-877-748-1970. What are the ingredients in quetiapine fumarate extended-release tablets? Active ingredient: quetiapine fumarate Inactive ingredients: The following are common in all 5 tablet strengths: microcrystalline cellulose, hypromellose, magnesium stearate, povidone, polyethylene glycol, and titanium dioxide. Additional inactive ingredients include: 50mg - polyvinyl alcohol, talc, iron oxide yellow, iron oxide red, iron oxide black, lecithin (soya) ; 150 mg - polydextrose and triacetin; 200 mg - polyvinyl alcohol, talc, lecithin (soya), D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake and FD&C blue #2 aluminum lake; 300 mg - polyvinyl alcohol, talc, lecithin (soya), iron oxide yellow and iron oxide black; 400 mg - polydextroseand triacetin. This medication guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, Florida 32839-6408 Product of Italy. Rev. E Iss. Feb 2020 Marketed/Packaged by: GSMS, Inc. Camarillo, CA USA 93012
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Schizophrenia Short-term Trials – Adults The efficacy of quetiapine fumarate 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 fumarate 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 fumarate 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 –Adolescents (ages 13-17) The efficacy of quetiapine fumarate extended-release tablets in the treatment of schizophrenia in adolescents (13–17 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: Quetiapine fumarate tablets 400 mg/day (n=73), quetiapine fumarate tablets 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). Quetiapine fumarate tablets at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score (study 2 in Table26). 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 fumarate extended-release tablets (400 mg/day-800 mg/day) were randomized to placebo or to continue on their current quetiapine fumarate extended-release tablets (400 mg/day-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 fumarate 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 fumarate extended-release tablets experienced a statistically significant longer time to relapse than did patients on placebo (Figure 1). Image Image 14.2 Bipolar Disorder Bipolar I Disorder, manic or mixed episodes Adults The efficacy of quetiapine fumarate extended-release tablets in the acute treatment of manic episodes was established in one 3-week, placebo- controlled trial (Study 1 in Table27) 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 fumarate 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 fumarate extended-release tablets were superior to placebo in the reduction of the YMRS total score at week 3. The efficacy of quetiapine fumarate tablets 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 quetiapine fumarate tablets with lithium or divalproex. The results of the trials follow: Monotherapy In two 12-week trials (n=300, n=299) comparing quetiapine fumarate tablets to placebo, quetiapine fumarate tablets were superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking quetiapine fumarate tablets 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 quetiapine fumarate tablets 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. Quetiapine fumarate tablets were 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 quetiapine fumarate tablets were dosed in a range between 400 mg/day and 800 mg/day (study 4 in Table 27). Children and Adolescents (ages 10-17) The efficacy of quetiapine fumarate 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: quetiapine fumarate tablets 400 mg/day (n=95), quetiapine fumarate tablets 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. Quetiapine fumarate tablets 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (study 5 in Table 27). Bipolar Disorder, Depressive Episodes Adults The efficacy of quetiapine fumarate 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 fumarate 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 fumarate extended-release tablets was superior to placebo in reduction of MADRS score at week 8 (study 6 in Table 28). The efficacy of quetiapine fumarate tablets 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 quetiapine fumarate tablets 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, quetiapine fumarate tablets was superior to placebo in reduction of MADRS score at week 8 (Studies 7 and 8 in Table28). 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-LESQ (SF). Maintenance Treatment as an Adjunct to Lithium or Divalproex The efficacy of quetiapine fumarate tablets 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 quetiapine fumarate tablets 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 quetiapine fumarate tablets (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo. Approximately 50% of the patients had discontinued from the quetiapine fumarate tablets 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, quetiapine fumarate tablets 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 quetiapine fumarate tablets was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course). Image Image Image Image 14.3 Major Depressive Disorder, Adjunctive Therapy to Antidepressants The efficacy of quetiapine fumarate 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 fumarate 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 fumarate 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 fumarate 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 fumarate 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). Image
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Sixty-eight patients in clinical studies with quetiapine fumarate extended-release tablets were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate 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 fumarate 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 ) and Clinical Pharmacology ( 12.3 )] .
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness of quetiapine fumarate extended-release tablets is supported by studies of quetiapine fumarate tablets for schizophrenia in adolescent patients 13 - 17 years of age and in bipolar mania in children and adolescent patients 10 - 17 years of age [see Clinical Studies( 14.1 and 14.2 )] . In general, the adverse reactions observed in children and adolescents during the clinical trials with quetiapine fumarate tablets 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%) [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.1 )]. Bipolar Depression The effectiveness of quetiapine fumarate 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 fumarate 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 fumarate 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 fumarate extended-release tablets. The primary results of this study did not show a difference between quetiapine fumarate extended-release tablets and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder. In this study, patients treated with quetiapine fumarate extended-release tablets exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate [see Warnings and Precautions ( 5.5 , 5.9 ) and Adverse Reactions ( 6.1 )] . 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 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 [see Clinical Pharmacology ( 12.3 )] Schizophrenia The efficacy and safety of quetiapine fumarate extended-release tablets in the treatment of schizophrenia in adolescents aged 13 - 17 years is supported by one 6-week, double-blind, placebo-controlled trial with quetiapine fumarate tablets [see Indications and Usage ( 1.1 ), Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.1 )] . Safety and effectiveness of quetiapine fumarate extended-release tablets in pediatric patients less than 13 years of age with schizophrenia have not been established. The safety and effectiveness of quetiapine fumarate 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 fumarate 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 quetiapine fumarate tablets [see Indications and Usage ( 1.2 ), Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.2 )] . Safety and effectiveness of quetiapine fumarate 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 fumarate extended-release tablets in the maintenance treatment of bipolar disorder has not been established in patients less than 18 years of age.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine fumarate 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 fumarate extended-release tablets, 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, quetiapine fumarate extended-release tablets 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 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 fumarate 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 0.3, 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 body surface area. 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. 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 at approximately 1-2 times the MRHD (all doses tested) in rabbits. In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day based on mg/m 2 body surface area. 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine fumarate 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 fumarate extended-release tablets, 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, quetiapine fumarate extended-release tablets 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 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 fumarate 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 0.3, 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 body surface area. 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. 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 at approximately 1-2 times the MRHD (all doses tested) in rabbits. In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day based on mg/m 2 body surface area. 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. 8.2 Lactation Risk Summary Limited data from published literature report the presence of quetiapine in human breast milk at relative infant dose of <1% of the maternal weight-adjusted dosage. There are no consistent adverse events that have been reported in infants exposed to quetiapine through breast milk. There is no information on the effects of quetiapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for quetiapine fumarate extended-release tablets and any potential adverse effects on the breastfed child from quetiapine fumarate extended-release tablets or from the mother's underlying condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of quetiapine (D2 antagonism), treatment with quetiapine fumarate extended-release tablets may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.15 )] . 8.4 Pediatric Use Safety and effectiveness of quetiapine fumarate extended-release tablets is supported by studies of quetiapine fumarate tablets for schizophrenia in adolescent patients 13 - 17 years of age and in bipolar mania in children and adolescent patients 10 - 17 years of age [see Clinical Studies( 14.1 and 14.2 )] . In general, the adverse reactions observed in children and adolescents during the clinical trials with quetiapine fumarate tablets 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%) [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.1 )]. Bipolar Depression The effectiveness of quetiapine fumarate 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 fumarate 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 fumarate 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 fumarate extended-release tablets. The primary results of this study did not show a difference between quetiapine fumarate extended-release tablets and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder. In this study, patients treated with quetiapine fumarate extended-release tablets exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate [see Warnings and Precautions ( 5.5 , 5.9 ) and Adverse Reactions ( 6.1 )] . 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 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 [see Clinical Pharmacology ( 12.3 )] Schizophrenia The efficacy and safety of quetiapine fumarate extended-release tablets in the treatment of schizophrenia in adolescents aged 13 - 17 years is supported by one 6-week, double-blind, placebo-controlled trial with quetiapine fumarate tablets [see Indications and Usage ( 1.1 ), Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.1 )] . Safety and effectiveness of quetiapine fumarate extended-release tablets in pediatric patients less than 13 years of age with schizophrenia have not been established. The safety and effectiveness of quetiapine fumarate 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 fumarate 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 quetiapine fumarate tablets [see Indications and Usage ( 1.2 ), Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.2 )] . Safety and effectiveness of quetiapine fumarate 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 fumarate extended-release tablets in the maintenance treatment of bipolar disorder has not been established in patients less than 18 years of age. 8.5 Geriatric Use Sixty-eight patients in clinical studies with quetiapine fumarate extended-release tablets were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate 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 fumarate 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 ) and Clinical Pharmacology ( 12.3 )] . 8.6 Renal Impairment Clinical experience with quetiapine fumarate extended-release tablets in patients with renal impairment is limited [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment 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 ( 2.4 ) and Clinical Pharmacology ( 12.3 )] .
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 50 mg Tablets (NDC 51407-073) pink, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 50"on one side and plain on the other are supplied in bottles of 60 (NDC 51407-073-60) tablets. 150 mg Tablets (NDC 51407-074) white, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 150" on one side and plain on the other are supplied in bottles of 60 (NDC 51407-074-60) tablets. 200 mg Tablets (NDC 51407-075) yellow, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 200" on one side and plain on the other are supplied in bottles of 60 (NDC 51407-075-60) tablets. 300 mg Tablets (NDC 51407-076) light yellow, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 300" on one side and plain on the other are supplied in bottles of 60 (NDC 51407-076-60) tablets. 400 mg Tablets (NDC 51407-077) white, film-coated, capsule-shaped, biconvex, debossed tablet with "NT 400" on one side and plain on the other are supplied in bottles of 60 (NDC 51407-077-60) tablets. Store quetiapine fumarate extended-release tablets at 25 ºC (77 ºF); excursions permitted to 15-30 ºC (59-86 ºF) [See USP Controlled Room Temperature].
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Quetiapine fumarate extended-release tablets are not approved for elderly patients with dementia-related psychosis. ( 5.1 ) Suicidal Thoughts and Behaviors Increased risk of suicidal thoughts and behavior in children, adolescents and young adults taking antidepressants. ( 5.2 ) Monitor for worsening and emergence of suicidal thoughts and behaviors. ( 5.2 ) Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [see Warnings and Precautions ( 5.1 )] . Quetiapine fumarate extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . Suicidal Thoughts and Behavior Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions ( 5.2 )] . In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions ( 5.2 )]. Quetiapine fumarate extended-release tablets are not approved for use in pediatric patients under ten years of age [see Use in Specific Populations ( 8.4 )].
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API