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| Product NDC Code | 46708-138 | ||||||||||
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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, FILM COATED | ||||||||||
| RxCUI drug identifier | 312743, 312744, 312745, 317174, 616483, 616487 |
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| Application Number | ANDA203390 | ||||||||||
| Labeler Name | Alembic Pharmaceuticals Limited | ||||||||||
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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 has not been systematically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine fumarate, 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 is 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 is not a controlled substance. 9.2 Abuse Quetiapine fumarate has not been systematically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine fumarate, 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 reactions. 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 and sedation, tachycardia and hypotension. 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. There were also very rare reports of overdose of quetiapine fumarate alone resulting in death or coma. 10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of quetiapine fumarate. Similarly it is reasonable to expect that the alpha-drenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension. There is no specific antidote to quetiapine fumarate. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
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 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 Warning and Precautins (5.1)] · Suicidal thoughts and behaviors in adolescents and young adults [see Warning and Precautins (5.2)] · Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see Warning and Precautins (5.3)] · Neuroleptic Malignant Syndrome (NMS) [ see Warning and Precautins (5.4) ] · Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [ see Warning and Precautins (5.5) ] · Tardive dyskinesia [ see Warning and Precautins (5.6) ] · Hypotension [ see Warning and Precautins (5.7) ] • Falls [see Warnings and Precautions 5.8] · Increases in blood pressure (children and adolescents) [ see Warning and Precautins (5.9) ] · Leukopenia, neutropenia and agranulocytosis [ see Warning and Precautins (5.10) ] · Cataracts [ see Warning and Precautins (5.11) ] · QT Prolongation [ see Warning and Precautins (5.12) ] · Seizures [ see Warning and Precautins (5.13) ] · Hypothyroidism [ see Warning and Precautins (5.14) ] · Hyperprolactinemia[ see Warning and Precautins (5.15) ] · Potential for cognitive and motor impairment [ see Warning and Precautins (5.16) ] · Body temperature regulation[ see Warning and Precautins (5.17) ] · Dysphagia [ see Warning and Precautins (5.18) ] · Discontinuation Syndrome [ see Warning and Precautins (5.19) ] • Most common adverse reactions (incidence ≥5% and twice placebo): Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia (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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Study Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adults: The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 4300 patients. This database includes 698 patients exposed to quetiapine fumarate for the treatment of bipolar depression, 405 patients exposed to quetiapine fumarate for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to quetiapine fumarate for the maintenance treatment of bipolar I disorder as adjunct therapy, and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of quetiapine fumarate for the treatment of schizophrenia. Of these approximately 4300 subjects, approximately 4000 (2300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2400 patient-years. The conditions and duration of treatment with quetiapine fumarate varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia: Overall, there was little difference in the incidence of discontinuation due to adverse reactions (4% for quetiapine fumarate vs. 3% for placebo) in a pool of controlled trials. However, discontinuations due to somnolence (0.8% quetiapine fumarate vs. 0% placebo) and hypotension (0.4% quetiapine fumarate vs. 0% placebo) were considered to be drug related [see Warnings and Precautions (5.7 and 5.19)]. Bipolar Disorder: Mania: Overall, discontinuations due to adverse reactions were 5.7% for quetiapine fumarate vs. 5.1% for placebo in monotherapy and 3.6% for quetiapine fumarate vs. 5.9% for placebo in adjunct therapy. Depression: Overall, discontinuations due to adverse reactions were 12.3% for quetiapine fumarate 300 mg vs. 19% for quetiapine fumarate 600 mg and 5.2% for placebo. Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials, the most commonly observed adverse reactions associated with the use of quetiapine fumarate monotherapy (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (18%), dizziness (11%), dry mouth (9%), constipation (8%), ALT increased (5%), weight gain (5%), and dyspepsia (5%). Adverse Reactions Occurring at an Incidence of 2% or More Among Quetiapine Fumarate Treated Patients in Short-Term, Placebo-Controlled Trials: The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied. Table 9 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 2% or more of patients treated with quetiapine fumarate (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. Table 9: Adverse Reaction Incidence in 3- to 12-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy) Preferred Term Quetiapine Fumarate (n=719) PLACEBO (n=404) Headache 21% 14% Agitation 20% 17% Somnolence 18% 8% Dizziness 11% 5% Dry Mouth 9% 3% Constipation 8% 3% Pain 7% 5% Tachycardia 6% 4% Vomiting 6% 5% Asthenia 5% 3% Dyspepsia 5% 1% Weight Gain 5% 1% ALT Increased 5% 1% Anxiety 4% 3% Pharyngitis 4% 3% Rash 4% 2% Abdominal Pain 4% 1% Postural Hypotension 4% 1% Back Pain 3% 1% AST Increased 3% 1% Rhinitis 3% 1% Fever 2% 1% Gastroenteritis 2% 0% Amblyopia 2% 1% In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies, the most commonly observed adverse reactions associated with the use of quetiapine fumarate (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (34%), dry mouth (19%), asthenia (10%), constipation (10%), abdominal pain (7%), postural hypotension (7%), pharyngitis (6%), and weight gain (6%). Table 10 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 2% or more of patients treated with quetiapine fumarate (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. Table 10: Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy) Preferred Term Quetiapine Fumarate (n=196) PLACEBO (n=203) Somnolence 34% 9% Dry Mouth 19% 3% Headache 17% 13% Asthenia 10% 4% Constipation 10% 5% Dizziness 9% 6% Tremor 8% 7% Abdominal Pain 7% 3% Postural Hypotension 7% 2% Agitation 6% 4% Weight Gain 6% 3% Pharyngitis 6% 3% Back Pain 5% 3% Hypertonia 4% 3% Rhinitis 4% 2% Peripheral Edema 4% 2% Twitching 4% 1% Dyspepsia 4% 3% Depression 3% 2% Amblyopia 3% 2% Speech Disorder 3% 1% Hypotension 3% 1% HormoneLevel Altered 3% 0% Heaviness 2% 1% Infection 2% 1% Fever 2% 1% Hypertension 2% 1% Tachycardia 2% 1% Increased Appetite 2% 1% Hypothyroidism 2% 1% Incoordination 2% 1% Thinking Abnormal 2% 0% Anxiety 2% 0% Ataxia 2% 0% Sinusitis 2% 1% Sweating 2% 1% Urinary Tract Infection 2% 1% In bipolar depression studies (up to 8 weeks), the most commonly observed treatment emergent adverse reactions associated with the use of quetiapine fumarate (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (57%), dry mouth (44%), dizziness (18%), constipation (10%), and lethargy (5%). Table 11 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 2% or more of patients treated with quetiapine fumarate (doses of 300 and 600 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. T able 11: Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression. Preferred Term Quetiapine Fumarate (n=698) PLACEBO (n=347) Somnolence 3 57% 15% Dry Mouth 44% 13% Dizziness 18% 7% Constipation 10% 4% Fatigue 10% 8% Dyspepsia 7% 4% Vomiting 5% 4% Increased Appetite 5% 3% Lethargy 5% 2% Nasal Congestion 5% 3% Orthostatic Hypotension 4% 3% Akathisia 4% 1% Palpitations 4% 1% Vision Blurred 4% 2% Weight increased 4% 1% Arthralgia 3% 2% Paraesthesia 3% 2% Cough 3% 1% Extrapyramidal Disorder 3% 1% Irritability 3% 1% Dysarthria 3% 0% Hypersomnia 3% 0% Sinus Congestion 2% 1% Abnormal Dreams 2% 1% Tremor 2% 1% Gastroesophageal Reflux Disease 2% 1% Pain in Extremity 2% 1% Asthenia 2% 1% Balance Disorder 2% 1% Hypoesthesia 2% 1% Dysphagia 2% 0% Restless Legs Syndrome 2% 0% 3 Somnolence combines adverse reaction terms somnolence and sedation Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors. Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials Dose-related Adverse Reactions: Spontaneously elicited adverse reaction data from a study of schizophrenia comparing five fixed doses of quetiapine fumarate (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse reactions. Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse reactions: dyspepsia, abdominal pain, and weight gain. Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label: The following adverse reactions have also been reported with quetiapine: nightmares, hypersensitivity and elevations in serum creatine phosphokinase (not associated with NMS), galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope) decreased platelets, somnambulism (and other related events), elevations in gamma-GT levels, hypothermia, 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: Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of quetiapine fumarate (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of treatment-emergent extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with quetiapine fumarate treatment. Three methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (3) use of anticholinergic medications to treat emergent EPS. In Table 12, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder. Table 12: Adverse Reactions Associated with EPS in a Short-Term, Placebo-Controlled Multiple Fixed-Dose Phase III Schizophrenia Trial (6 weeks duration) Preferred Term Quetiapine Fumarate 75 mg/day (N=53) Quetiapine Fumarate 150 mg/day (N=48) Quetiapine Fumarate 300 mg/day (N=52) Quetiapine Fumarate 600 mg/day (N=51) Quetiapine Fumarate 750 mg/day (N=54) Placebo (N=51) n % n % n % n % n % n % Dystonic event 2 3.8 2 4.2 0 0 2 3.9 3 5.6 4 7.8 Parkinsonism 2 3.8 0 0 1 1.9 1 2 1 1.9 4 7.8 Akathisia 1 1.9 1 2.1 0 0 0 0 1 1.9 4 7.8 Dyskinetic event 2 3.8 0 0 0 0 1 2 0 0 0 0 Other extrapyramidal event 2 3.8 0 0 3 5.8 3 5.9 1 1.9 4 7.8 Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75, 150, 300, 600, 750 mg/day) were: -0.6; -1, -1.2; -1.6; -1.8 and -1.8. The rate of anticholinergic medication use to treat emergent EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12% and 11%. In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of quetiapine fumarate, there were no differences between the quetiapine fumarate and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS. In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of quetiapine fumarate, the incidence of adverse reactions potentially related to EPS was 12% in both dose groups and 6% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group. The 3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment. The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups. Children and Adolescents The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 1000 pediatric patients. This database includes 677 patients exposed to quetiapine fumarate for the treatment of schizophrenia and 393 children and adolescents (10 to 17 years old) exposed to quetiapine fumarate for the treatment of acute bipolar mania. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on quetiapine fumarate 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 and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0). Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia ( 7%). In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%). In an acute (8-week) quetiapine fumarate extended-release tablets trial in children and adolescents (10 to17 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%. Adverse Reactions Occurring at an Incidence of ≥2% among Quetiapine Fumarate Treated Patients in Short-Term, Placebo-Controlled Trials Schizophrenia (Adolescents, 13 to 17 years old) The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day. Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with quetiapine fumarate (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine fumarate was at least twice the incidence in placebo-treated patients. Adverse events that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%). Table 13: Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients Preferred Term Quetiapine Fumarate 400 mg (n=73) Quetiapine Fumarate 800 mg (n=74) Placebo (n=75) Somnolence 1 33% 35% 11% Dizziness 8% 15% 5% Dry Mouth 4% 10% 1% Tachycardia 2 6% 11% 0% Irritability 3% 5% 0% Arthralgia 1% 3% 0% Asthenia 1% 3% 1% Back Pain 1% 3% 0% Dyspnea 0% 3% 0% Abdominal Pain 3% 1% 0% Anorexia 3% 1% 0% Tooth Abscess 3% 1% 0% Dyskinesia 3% 0% 0% Epistaxis 3% 0% 1% Muscle Rigidity 3% 0% 0% 1 Somnolence combines adverse reaction terms somnolence and sedation. 2 Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia. 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. Commonly Observed Adverse Reactions In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%). Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with quetiapine fumarate (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. Adverse events that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50% vs. 57%), nausea (6% vs. 10%) and tachycardia (6% vs. 9%). Table 14: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients Preferred Term Quetiapine Fumarate 400 mg (n=95) Quetiapine Fumarate 600 mg (n=98) Placebo (n=90) Somnolence 1 50% 57% 14% Dizziness 19% 17% 2% Nausea 6% 10% 4% Fatigue 14% 9% 4% Increased Appetite 10% 9% 1% Tachycardia 2 6% 9% 1% Dry Mouth 7% 7% 0% Vomiting 8% 7% 3% Nasal Congestion 3% 6% 2% Weight Increased 6% 6% 0% Irritability 3% 5% 1% Pyrexia 1% 4% 1% Aggression 1% 3% 0% Musculoskeletal Stiffness 1% 3% 1% Accidental Overdose 0% 2% 0% Acne 3% 2% 0% Arthralgia 4% 2% 1% Lethargy 2% 2% 0% Pallor 1% 2% 0% Stomach Discomfort 4% 2% 1% Syncope 2% 2% 0% Vision Blurred 3% 2% 0% Constipation 4% 2% 0% Ear Pain 2% 0% 0% Paraesthesia 2% 0% 0% Sinus Congestion 3% 0% 0% Thirst 2% 0% 0% 1 Somolence combines adverse reactions terms somnolence and sedation. 2 Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia. Extrapyramidal Symptoms: In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for quetiapine fumarate and 5.3% (4/75) for placebo, though the incidence of the individual adverse events (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) or quetiapine fumarate and 1.1% (1/90) for placebo. Table 15 presents a listing of patients with adverse reactions potentially associated with extrapyramidal symptoms in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration). In Tables 15 – 16 dystonic event included nuchal rigidity, hypertonia, and muscle rigidity; parkinsonism included cogwheel rigidity and tremor; akathisia included akathisia only; dyskinetic event included tardive dyskinesia, dyskinesia, and choreoathetosis; and other extrapyramidal event included restlessness and extrapyramidal disorder. Table 15: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-controlled Trial in Adolescent Patients with Schizophrenia (6-week duration) Preferred Term Quetiapine Fumarate 400 mg/day (N=73) Quetiapine Fumarate 800 mg/day (N=74) All Quetiapine Fumarate (N=147) Placebo (N=75) n % n % n % n % Dystonic event 2 2.7 0 0 2 1.4 0 0 Parkinsonism 4 5.5 4 5.4 8 5.4 2 2.7 Akathisia 3 4.1 4 5.4 7 4.8 3 4 Dyskinetic event 2 2.7 0 0 2 1.4 0 0 Other Extrapyramidal event 2 2.7 2 2.7 4 2.7 0 0 Table 16 presents a listing of patients with adverse reactions associated with extrapyramidal symptoms in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration). Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trialin Children and Adolescent Patients with Bipolar I Mania (3-week duration) Preferred Term 1 Quetiapine Fumarate 400 mg/day (N=95) Quetiapine Fumarate 600 mg/day (N=98) All Quetiapine Fumarate (N=193) Placebo (N=90) n % n % n % n % Parkinsonism 2 2.1 1 1 3 1.6 1 1.1 Akathisia 1 1 1 1 2 1 0 0 Other Extrapyramidal event 1 1.1 1 1 2 1 0 0 1 There were no adverse experiences with the preferred term of dystonic or dyskinetic events. Other Adverse Reactions Observed During the Pre-Marketing Evaluation of Quetiapine Fumarate Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with quetiapine fumarate at multiple doses ≥ 75 mg/day during any phase of a trial within the premarketing database of approximately 2200 patients treated for schizophrenia. All reported reactions are included except those already listed in the tables or elsewhere in labeling, those reactions for which a drug cause was remote, and those reaction terms which were so general as to be uninformative. It is important to emphasize that, although the reactions reported occurred during treatment with quetiapine fumarate, they were not necessarily caused by it. Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Nervous System: Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased 2 , urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia; Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased 2 , neuralgia, stuttering, subdural hematoma. Body as a Whole: Frequent: flu syndrome; Infrequent: neck pain, pelvic pain 2 suicide attempt, malaise, photosensitivity reaction, chills, face edema, moniliasis; Rare: abdomen enlarged. Digestive System: Frequent: anorexia; Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema; Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis. Cardiovascular System: Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accident, deep thrombophlebitis, T wave inversion; Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration. Respiratory System: Frequent: cough increased, dyspnea; Infrequent: pneumonia, epistaxis, asthma; Rare: hiccup, hyperventilation. Metabolic and Nutritional System: Infrequent: weight loss, alkaline phosphatase increased, hyperlipidemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia; Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication. Skin and Appendages System: Infrequent: pruritus, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer; Rare: exfoliative dermatitis, psoriasis, skin discoloration. Urogenital System: Infrequent: dysmenorrhea 2 , vaginitis 2 , urinary incontinence, metrorrhagia 2 , impotence 2 , dysuria, vaginal moniliasis 2 , abnormal ejaculation 2 , cystitis, urinary frequency, amenorrhea 2 , female lactation 2 , leukorrhea 2 , vaginal hemorrhage 2 , vulvovaginitis 2 , orchitis 2 ; Rare: gynecomastia 2 , nocturia, polyuria, acute kidney failure. _____________________________________ 2 Adjusted for gender Special Senses: Infrequent: conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain; Rare: abnormality of accommodation, deafness, glaucoma. Musculoskeletal System: Infrequent: pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain. Hemic and Lymphatic System: Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis; Rare: hemolysis, thrombocytopenia. Endocrine System: Infrequent: hypothyroidism, diabetes mellitus; Rare: hyperthyroidism. Laboratory, ECG and vital sign changes observed in clinical studies Laboratory Changes: Neutrophil Counts Adults : In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1x10 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 fumarate, 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. 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 compared to 1% (3/194) for placebo. In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 12-week placebo-controlled trials were approximately 1% for both quetiapine fumarate (3/560) and placebo (3/294). These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine fumarate. In bipolar depression trials, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in two 8-week placebo-controlled trials was 1% (5/698) for quetiapine fumarate and 2% (6/347) for placebo. Decreased Hemoglobin Adults : In short-term placebo-controlled trials, decreases in hemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients. Interference with Urine Drug Screens There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g., chromatographic methods) should be considered. ECG Changes Adults: Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant quetiapine fumarate/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for quetiapine fumarate compared to 0.6% (1/156) incidence for placebo. In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for quetiapine fumarate compared to 0% (0/178) incidence for placebo. In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for quetiapine fumarate compared to 0% (0/171) incidence for placebo. In bipolar depression trials, no patients had heart rate increases to >120 beats per minute. quetiapine fumarate use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia in adults may be related to quetiapine fumarate's potential for inducing orthostatic changes [see Warnings and Precautions (5.7)] . Children and Adolescents: In the acute (6 week) schizophrenia trial in adolescents, increases in heart rate (>110 bpm) occurred in 5.2% (3/73) of patients receiving quetiapine fumarate 400 mg and 8.5% (5/74) of patients receiving quetiapine fumarate 800 mg compared to 0% (0/75) of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for quetiapine fumarate 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) bipolar mania trial in children and adolescents, increases in heart rate (>110 bpm) occurred in 1.1% (1/89) of patients receiving quetiapine fumarate 400 mg and 4.7% (4/85) of patients receiving quetiapine fumarate 600 mg compared to 0% (0/98) of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for quetiapine fumarate 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)] . In an acute (8-week) quetiapine fumarate extended-release tablets trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10 to 12 years and 13 to 17 years) occurred in 0% of patients receiving quetiapine 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)] . 6.2 Postmarketing Experience The following adverse reactions were identified during post approval of quetiapine fumarate. 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), and toxic epidermal necrolysis (TEN).
| Headache | 21% | 14% |
| Agitation | 20% | 17% |
| Somnolence | 18% | 8% |
| Dizziness | 11% | 5% |
| Dry Mouth | 9% | 3% |
| Constipation | 8% | 3% |
| Pain | 7% | 5% |
| Tachycardia | 6% | 4% |
| Vomiting | 6% | 5% |
| Asthenia | 5% | 3% |
| Dyspepsia | 5% | 1% |
| Weight Gain | 5% | 1% |
| ALT Increased | 5% | 1% |
| Anxiety | 4% | 3% |
| Pharyngitis | 4% | 3% |
| Rash | 4% | 2% |
| Abdominal Pain | 4% | 1% |
| Postural Hypotension | 4% | 1% |
| Back Pain | 3% | 1% |
| AST Increased | 3% | 1% |
| Rhinitis | 3% | 1% |
| Fever | 2% | 1% |
| Gastroenteritis | 2% | 0% |
| Amblyopia | 2% | 1% |
| Somnolence | 34% | 9% |
| Dry Mouth | 19% | 3% |
| Headache | 17% | 13% |
| Asthenia | 10% | 4% |
| Constipation | 10% | 5% |
| Dizziness | 9% | 6% |
| Tremor | 8% | 7% |
| Abdominal Pain | 7% | 3% |
| Postural Hypotension | 7% | 2% |
| Agitation | 6% | 4% |
| Weight Gain | 6% | 3% |
| Pharyngitis | 6% | 3% |
| Back Pain | 5% | 3% |
| Hypertonia | 4% | 3% |
| Rhinitis | 4% | 2% |
| Peripheral Edema | 4% | 2% |
| Twitching | 4% | 1% |
| Dyspepsia | 4% | 3% |
| Depression | 3% | 2% |
| Amblyopia | 3% | 2% |
| Speech Disorder | 3% | 1% |
| Hypotension | 3% | 1% |
| HormoneLevel Altered | 3% | 0% |
| Heaviness | 2% | 1% |
| Infection | 2% | 1% |
| Fever | 2% | 1% |
| Hypertension | 2% | 1% |
| Tachycardia | 2% | 1% |
| Increased Appetite | 2% | 1% |
| Hypothyroidism | 2% | 1% |
| Incoordination | 2% | 1% |
| Thinking Abnormal | 2% | 0% |
| Anxiety | 2% | 0% |
| Ataxia | 2% | 0% |
| Sinusitis | 2% | 1% |
| Sweating | 2% | 1% |
| Urinary Tract Infection | 2% | 1% |
| Somnolence3 | 57% | 15% |
| Dry Mouth | 44% | 13% |
| Dizziness | 18% | 7% |
| Constipation | 10% | 4% |
| Fatigue | 10% | 8% |
| Dyspepsia | 7% | 4% |
| Vomiting | 5% | 4% |
| Increased Appetite | 5% | 3% |
| Lethargy | 5% | 2% |
| Nasal Congestion | 5% | 3% |
| Orthostatic Hypotension | 4% | 3% |
| Akathisia | 4% | 1% |
| Palpitations | 4% | 1% |
| Vision Blurred | 4% | 2% |
| Weight increased | 4% | 1% |
| Arthralgia | 3% | 2% |
| Paraesthesia | 3% | 2% |
| Cough | 3% | 1% |
| Extrapyramidal Disorder | 3% | 1% |
| Irritability | 3% | 1% |
| Dysarthria | 3% | 0% |
| Hypersomnia | 3% | 0% |
| Sinus Congestion | 2% | 1% |
| Abnormal Dreams | 2% | 1% |
| Tremor | 2% | 1% |
| Gastroesophageal Reflux Disease | 2% | 1% |
| Pain in Extremity | 2% | 1% |
| Asthenia | 2% | 1% |
| Balance Disorder | 2% | 1% |
| Hypoesthesia | 2% | 1% |
| Dysphagia | 2% | 0% |
| Restless Legs Syndrome | 2% | 0% |
| Dystonic event | 2 | 3.8 | 2 | 4.2 | 0 | 0 | 2 | 3.9 | 3 | 5.6 | 4 | 7.8 |
| Parkinsonism | 2 | 3.8 | 0 | 0 | 1 | 1.9 | 1 | 2 | 1 | 1.9 | 4 | 7.8 |
| Akathisia | 1 | 1.9 | 1 | 2.1 | 0 | 0 | 0 | 0 | 1 | 1.9 | 4 | 7.8 |
| Dyskinetic event | 2 | 3.8 | 0 | 0 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 |
| Other extrapyramidal event | 2 | 3.8 | 0 | 0 | 3 | 5.8 | 3 | 5.9 | 1 | 1.9 | 4 | 7.8 |
| Somnolence1 | 33% | 35% | 11% |
| Dizziness | 8% | 15% | 5% |
| Dry Mouth | 4% | 10% | 1% |
| Tachycardia2 | 6% | 11% | 0% |
| Irritability | 3% | 5% | 0% |
| Arthralgia | 1% | 3% | 0% |
| Asthenia | 1% | 3% | 1% |
| Back Pain | 1% | 3% | 0% |
| Dyspnea | 0% | 3% | 0% |
| Abdominal Pain | 3% | 1% | 0% |
| Anorexia | 3% | 1% | 0% |
| Tooth Abscess | 3% | 1% | 0% |
| Dyskinesia | 3% | 0% | 0% |
| Epistaxis | 3% | 0% | 1% |
| Muscle Rigidity | 3% | 0% | 0% |
| Somnolence1 | 50% | 57% | 14% |
| Dizziness | 19% | 17% | 2% |
| Nausea | 6% | 10% | 4% |
| Fatigue | 14% | 9% | 4% |
| Increased Appetite | 10% | 9% | 1% |
| Tachycardia2 | 6% | 9% | 1% |
| Dry Mouth | 7% | 7% | 0% |
| Vomiting | 8% | 7% | 3% |
| Nasal Congestion | 3% | 6% | 2% |
| Weight Increased | 6% | 6% | 0% |
| Irritability | 3% | 5% | 1% |
| Pyrexia | 1% | 4% | 1% |
| Aggression | 1% | 3% | 0% |
| Musculoskeletal Stiffness | 1% | 3% | 1% |
| Accidental Overdose | 0% | 2% | 0% |
| Acne | 3% | 2% | 0% |
| Arthralgia | 4% | 2% | 1% |
| Lethargy | 2% | 2% | 0% |
| Pallor | 1% | 2% | 0% |
| Stomach Discomfort | 4% | 2% | 1% |
| Syncope | 2% | 2% | 0% |
| Vision Blurred | 3% | 2% | 0% |
| Constipation | 4% | 2% | 0% |
| Ear Pain | 2% | 0% | 0% |
| Paraesthesia | 2% | 0% | 0% |
| Sinus Congestion | 3% | 0% | 0% |
| Thirst | 2% | 0% | 0% |
| Dystonic event | 2 | 2.7 | 0 | 0 | 2 | 1.4 | 0 | 0 |
| Parkinsonism | 4 | 5.5 | 4 | 5.4 | 8 | 5.4 | 2 | 2.7 |
| Akathisia | 3 | 4.1 | 4 | 5.4 | 7 | 4.8 | 3 | 4 |
| Dyskinetic event | 2 | 2.7 | 0 | 0 | 2 | 1.4 | 0 | 0 |
| Other Extrapyramidal event | 2 | 2.7 | 2 | 2.7 | 4 | 2.7 | 0 | 0 |
| Parkinsonism | 2 | 2.1 | 1 | 1 | 3 | 1.6 | 1 | 1.1 |
| Akathisia | 1 | 1 | 1 | 1 | 2 | 1 | 0 | 0 |
| Other Extrapyramidal event | ||||||||
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 to 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 to 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 in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine fumarate, caution should be used when it is taken in combination with other centrally acting drugs. Qetiapine fumarate potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine. Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.) and decreased by the prototype CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors. CYP3A4 inhibitors: Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure. The dose of quetiapine fumarate should be reduced to one sixth of the original dose if co-administered 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 5fold. Increased doses of quetiapine fumarate 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 should be reduced to the original level within 7 to 14 days [see Dosage and Administration (2.6)] . The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied [see Clinical Pharmacology (12.3)] . 7.2 Effect of Quetiapine on Other Drugs Because of its potential for inducing hypotension, quetiapine fumarate may enhance the effects of certain antihypertensive agents. Qetiapine fumarate may antagonize the effects of levodopa and dopamine agonists. There are no clinically relevant pharmacokinetic interactions of Quetiapine fumarate 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 fumarate is unknown. However, it has been proposed that the efficacy of quetiapine fumarate in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other effects of quetiapine fumarate. Quetiapine fumarate’s antagonism of histamine H 1 receptors may explain the somnolence observed with this drug. Quetiapine fumarate’s antagonism of adrenergic α 1 receptors may explain the orthostatic hypotension observed with this drug. 12.2 Pharmacodynamics Quetiapine fumarate is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HT 1A and 5HT 2 (IC 50s =717 & 148nM, respectively), dopamine D 1 and D 2 (IC 50s =1268 & 329nM, respectively), histamine H 1 (IC 50 =30nM), and adrenergic α 1 and α 2 receptors (IC 50s =94 & 271nM, respectively). quetiapine fumarate has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC 50s >5000 nM). 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 Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely 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 to 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 is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C max and AUC values increased by 25% and 15%, respectively. 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. 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 N-desalkyl quetiapine. Age Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary [see Dosage and Administration (2.3)]. Gender There is no gender effect on the pharmacokinetics of quetiapine. Race There is no race effect on the pharmacokinetics of quetiapine. Smoking Smoking has no effect on the oral clearance of quetiapine. Renal Insufficiency Patients with severe renal impairment (Cl cr =10 to 30 mL/min/1.73 m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (Cl cr > 80 mL/min/1.73 m 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 two 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 [s ee 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 17 [see Dosage and Administration (2.5 and 2.6) and Drug Interactions (7.1)] . Table 17: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine Coadministered drug Dose schedules Effect on quetiapinepharmacokinetics Coadministered drug Quetiapine Phenytoin 100 mg threetimesdaily 250 mg three timesdaily 5 fold increase in oralclearance Divalproex 500 mg twice daily 150 mg twice daily 17% increasemeanmaxplasmaconcentration at steady state. Noeffect on absorptionormean oral clearance Thioridazine 200 mg twice daily 300 mg twice daily 65% increaseinoralclearance Cimetidine 400 mg three timesdaily for 4 days 150 mg three timesdaily 20% decrease in mean oral clearance Ketoconazole(potentCYP 3A4inhibitor) 200 mg once daily for 4 days 25 mgsingledose 84% decrease in oralclearanceresulting in a 6.2 foldincrease in AUC of quetiapine Fluoxetine 60 mg once daily 300 mg twice daily Nochange in steady state PK Imipramine 75 mg twice daily 300 mg twice daily Nochange in steady state PK Haloperidol 7.5 mg twice daily 300 mg twice daily Nochange in steady state PK Risperidone 3 mg twice daily 300 mg twice daily Nochange in steady state PK 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 (Table 18) [see Drug Interactions (7.2)] . Table 18: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs Coadministered drug Dose schedules Effect on otherdrugspharmacokinetics Coadministered drug Quetiapine Lorazepam 2 mg,single dose 250 mg three times daily Oral clearance of lorazepam reducedby20% Divalproex 500 mg twice daily 150 mg twice daily Cmax andAUC of freevalproicacid at steady-statewas decreased by 10 to 12% Lithium Up to 2400 mg/daygivenintwice daily doses 250 mg three times daily No effect on steady-statepharmacokinetics of lithium Antipyrine 1 g, single dose 250 mg three times daily No effect on clearance of antipyrine or urinaryrecoveryofitsmetabolites
| Phenytoin | 100 mg threetimesdaily | 250 mg three timesdaily | 5 fold increase in oralclearance |
| Divalproex | 500 mg twice daily | 150 mg twice daily | 17% increasemeanmaxplasmaconcentration at steady state. Noeffect on absorptionormean oral clearance |
| Thioridazine | 200 mg twice daily | 300 mg twice daily | 65% increaseinoralclearance |
| Cimetidine | 400 mg three timesdaily for 4 days | 150 mg three timesdaily | 20% decrease in mean oral clearance |
| Ketoconazole(potentCYP 3A4inhibitor) | 200 mg once daily for 4 days | 25 mgsingledose | 84% decrease in oralclearanceresulting in a 6.2 foldincrease in AUC of quetiapine |
| Fluoxetine | 60 mg once daily | 300 mg twice daily | Nochange in steady state PK |
| Imipramine | 75 mg twice daily | 300 mg twice daily | Nochange in steady state PK |
| Haloperidol | 7.5 mg twice daily | 300 mg twice daily | Nochange in steady state PK |
| Risperidone | 3 mg twice daily | 300 mg twice daily | Nochange in steady state PK |
| Lorazepam | 2 mg,single dose | 250 mg three times daily | Oral clearance of lorazepam reducedby20% |
| Divalproex | 500 mg twice daily | 150 mg twice daily | Cmax andAUC of freevalproicacid at steady-statewas decreased by 10 to 12% |
| Lithium | Up to 2400 mg/daygivenintwice daily doses | 250 mg three times daily | No effect on steady-statepharmacokinetics of lithium |
| Antipyrine | 1 g, single dose | 250 mg three times daily | No effect on clearance of antipyrine or urinaryrecoveryofitsmetabolites |
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 fumarate is unknown. However, it has been proposed that the efficacy of quetiapine fumarate in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other effects of quetiapine fumarate. Quetiapine fumarate’s antagonism of histamine H 1 receptors may explain the somnolence observed with this drug. Quetiapine fumarate’s antagonism of adrenergic α 1 receptors may explain the orthostatic hypotension observed with this drug.
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 fumarate is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HT 1A and 5HT 2 (IC 50s =717 & 148nM, respectively), dopamine D 1 and D 2 (IC 50s =1268 & 329nM, respectively), histamine H 1 (IC 50 =30nM), and adrenergic α 1 and α 2 receptors (IC 50s =94 & 271nM, respectively). quetiapine fumarate has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC 50s >5000 nM). 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 Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely 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 to 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 is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C max and AUC values increased by 25% and 15%, respectively. 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. 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 N-desalkyl quetiapine. Age Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary [see Dosage and Administration (2.3)]. Gender There is no gender effect on the pharmacokinetics of quetiapine. Race There is no race effect on the pharmacokinetics of quetiapine. Smoking Smoking has no effect on the oral clearance of quetiapine. Renal Insufficiency Patients with severe renal impairment (Cl cr =10 to 30 mL/min/1.73 m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (Cl cr > 80 mL/min/1.73 m 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 two 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 [s ee 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 17 [see Dosage and Administration (2.5 and 2.6) and Drug Interactions (7.1)] . Table 17: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine Coadministered drug Dose schedules Effect on quetiapinepharmacokinetics Coadministered drug Quetiapine Phenytoin 100 mg threetimesdaily 250 mg three timesdaily 5 fold increase in oralclearance Divalproex 500 mg twice daily 150 mg twice daily 17% increasemeanmaxplasmaconcentration at steady state. Noeffect on absorptionormean oral clearance Thioridazine 200 mg twice daily 300 mg twice daily 65% increaseinoralclearance Cimetidine 400 mg three timesdaily for 4 days 150 mg three timesdaily 20% decrease in mean oral clearance Ketoconazole(potentCYP 3A4inhibitor) 200 mg once daily for 4 days 25 mgsingledose 84% decrease in oralclearanceresulting in a 6.2 foldincrease in AUC of quetiapine Fluoxetine 60 mg once daily 300 mg twice daily Nochange in steady state PK Imipramine 75 mg twice daily 300 mg twice daily Nochange in steady state PK Haloperidol 7.5 mg twice daily 300 mg twice daily Nochange in steady state PK Risperidone 3 mg twice daily 300 mg twice daily Nochange in steady state PK 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 (Table 18) [see Drug Interactions (7.2)] . Table 18: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs Coadministered drug Dose schedules Effect on otherdrugspharmacokinetics Coadministered drug Quetiapine Lorazepam 2 mg,single dose 250 mg three times daily Oral clearance of lorazepam reducedby20% Divalproex 500 mg twice daily 150 mg twice daily Cmax andAUC of freevalproicacid at steady-statewas decreased by 10 to 12% Lithium Up to 2400 mg/daygivenintwice daily doses 250 mg three times daily No effect on steady-statepharmacokinetics of lithium Antipyrine 1 g, single dose 250 mg three times daily No effect on clearance of antipyrine or urinaryrecoveryofitsmetabolites
| Phenytoin | 100 mg threetimesdaily | 250 mg three timesdaily | 5 fold increase in oralclearance |
| Divalproex | 500 mg twice daily | 150 mg twice daily | 17% increasemeanmaxplasmaconcentration at steady state. Noeffect on absorptionormean oral clearance |
| Thioridazine | 200 mg twice daily | 300 mg twice daily | 65% increaseinoralclearance |
| Cimetidine | 400 mg three timesdaily for 4 days | 150 mg three timesdaily | 20% decrease in mean oral clearance |
| Ketoconazole(potentCYP 3A4inhibitor) | 200 mg once daily for 4 days | 25 mgsingledose | 84% decrease in oralclearanceresulting in a 6.2 foldincrease in AUC of quetiapine |
| Fluoxetine | 60 mg once daily | 300 mg twice daily | Nochange in steady state PK |
| Imipramine | 75 mg twice daily | 300 mg twice daily | Nochange in steady state PK |
| Haloperidol | 7.5 mg twice daily | 300 mg twice daily | Nochange in steady state PK |
| Risperidone | 3 mg twice daily | 300 mg twice daily | Nochange in steady state PK |
| Lorazepam | 2 mg,single dose | 250 mg three times daily | Oral clearance of lorazepam reducedby20% |
| Divalproex | 500 mg twice daily | 150 mg twice daily | Cmax andAUC of freevalproicacid at steady-statewas decreased by 10 to 12% |
| Lithium | Up to 2400 mg/daygivenintwice daily doses | 250 mg three times daily | No effect on steady-statepharmacokinetics of lithium |
| Antipyrine | 1 g, single dose | 250 mg three times daily | No effect on clearance of antipyrine or urinaryrecoveryofitsmetabolites |
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 Hypersensitivity to quetiapine or to any excipients in the quetiapine fumarate formulation. Anaphylactic reactions have been reported in patients treated with quetiapine fumarate. Known hypersensitivity to quetiapine fumarate or any components in the formulation. (4)
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 a psychotropic agent 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 cream colored powder which is practically insoluble in water. Quetiapine fumarate tablets are supplied for oral administration as 25 mg (round, white to off-white), 50 mg (round, white to off-white), 100 mg (round, white to off-white), 200 mg (round, white to off-white), 300 mg (capsule-shaped, white to off-white), and 400 mg (capsule-shaped, white to off-white) tablets. Inactive ingredients are povidone, dibasic calcium phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, magnesium stearate, hypromellose, hydroxypropyl cellulose and titanium dioxide. Structure
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 • Quetiapine fumarate can be taken with or without food (2.1). Indication Initial Dose Recommended Dose Maximum Dose Schizophrenia-Adults (2.2) 25 mg twice daily 150 to 750 mg/day 750 mg/day Schizophrenia-Adolescents (13 to 17 years) (2.2) 25 mg twice daily 400 to 800 mg/day 800 mg/day Bipolar Mania-Adults Monotherapy or as an adjunct to lithium or divalproex (2.2) 50 mg twice daily 400 to 800 mg/day 800 mg/day Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy (2.2) 25 mg twice daily 400 to 600 mg/day 600 mg/day Bipolar Depression-Adults (2.2) 50 mg once daily at bedtime 300 mg/day 300 mg/day · 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 (25 mg/day) and slower titration may be needed (2.4, 8.7, 12.3) 2.1 Important Administration Instructions Quetiapine fumarate can be taken with or without food. 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine fumarate dose for each approved indication is displayed in Table 1. 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 and 14.2) ]. Table 1: Recommended Dosing for Quetiapine Fumarate Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia-Adults Day 1: 25 mg twice daily. Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4. Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days. 150 to 750 mg/day 750 mg/day Schizophrenia-Adolescents (13 to 17 years) Day 1: 25 mg twice daily. Day 2: Twice daily dosing totaling 100 mg. Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 800 mg/day. Based on response and tolerability, may be administered three times daily. 400 to 800 mg/day 800 mg/day Schizophrenia-Maintenance N/A 1 400 to 800 mg/day 800 mg/day Bipolar Mania-Adults Monotherapy or as an adjunct to lithium or divalproex Day 1: Twice daily dosing totaling 100 mg. Day 2: Twice daily dosing totaling 200 mg. Day 3: Twice daily dosing totaling300 mg. Day 4: Twice daily dosing totaling 400 mg. Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day. 400 to 800 mg/day 800 mg/day Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy Day 1: 25 mg twice daily. Day 2: Twice daily dosing totaling 100 mg. Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 600 mg/day. Based on response and tolerability, may be administered three times daily. 400 to 600 mg/day 600 mg/day Bipolar Depression-Adults Administer once daily at bedtime. Day 1: 50 mg Day 2: 100 mg Day 3: 200 mg Day 4: 300 mg 300 mg/day 300 mg/day Bipolar I Disorder Maintenance Therapy-Adults Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized. 400 to 800 mg/day 800 mg/day 1 N/A Not applicable 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 (14.2)] . 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 Clinical Pharmacology (12.3)] . When indicated, dose escalation should be performed with caution in these patients. Elderly patients should be started on quetiapine fumarate 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 25 mg/day. The dose should be increased daily in increments of 25 mg/day to 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 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 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 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 to 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 tolerability of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate should be reduced to the original level within 7 to 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 for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine fumarate for less than one week, gradual dose escalation may not be required and the maintenance dose may be re-initiated. 2.8 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine fumarate, or concerning concomitant administration with antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
| Indication | Initial Dose | Recommended Dose | Maximum Dose |
| Schizophrenia-Adults (2.2) | 25 mg twice daily | 150 to 750 mg/day | 750 mg/day |
| Schizophrenia-Adolescents (13 to 17 years) (2.2) | 25 mg twice daily | 400 to 800 mg/day | 800 mg/day |
| Bipolar Mania-Adults Monotherapy or as an adjunct to lithium or divalproex (2.2) | 50 mg twice daily | 400 to 800 mg/day | 800 mg/day |
| Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy (2.2) | 25 mg twice daily | 400 to 600 mg/day | 600 mg/day |
| Bipolar Depression-Adults (2.2) | 50 mg once daily at bedtime | 300 mg/day | 300 mg/day |
| Schizophrenia-Adults | Day 1: 25 mg twice daily. Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4. Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days. | 150 to 750 mg/day | 750 mg/day |
| Schizophrenia-Adolescents (13 to 17 years) | Day 1: 25 mg twice daily. Day 2: Twice daily dosing totaling 100 mg. Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 800 mg/day. Based on response and tolerability, may be administered three times daily. | 400 to 800 mg/day | 800 mg/day |
| Schizophrenia-Maintenance | N/A | 400 to 800 mg/day | 800 mg/day |
| Bipolar Mania-Adults Monotherapy or as an adjunct to lithium or divalproex | Day 1: Twice daily dosing totaling 100 mg. Day 2: Twice daily dosing totaling 200 mg. Day 3: Twice daily dosing totaling300 mg. Day 4: Twice daily dosing totaling 400 mg. Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day. | 400 to 800 mg/day | 800 mg/day |
| Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy | Day 1: 25 mg twice daily. Day 2: Twice daily dosing totaling 100 mg. Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 600 mg/day. Based on response and tolerability, may be administered three times daily. | 400 to 600 mg/day | 600 mg/day |
| Bipolar Depression-Adults | Administer once daily at bedtime. Day 1: 50 mg Day 2: 100 mg Day 3: 200 mg Day 4: 300 mg | 300 mg/day | 300 mg/day |
| Bipolar I Disorder Maintenance Therapy-Adults | Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized. | 400 to 800 mg/day | 800 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 25 mg tablets are white to off white, round, biconvex, film coated tablets debossed with ‘224’ on one side and ‘L’ on the other side. 50 mg tablets are white to off white, round, biconvex, film coated tablets debossed with ‘225’ on one side and ‘L’ on the other side. 100 mg tablets are white to off white, round, biconvex, film coated tablets debossed with ‘226’ on one side and ‘L’ on the other side. 200 mg tablets are white to off white, round, biconvex, film coated tablets, debossed with ‘L227’ on one side and plain on the other side. 300 mg tablets are white to off white, capsule shaped, biconvex, film coated tablets, debossed with ‘L228’ on one side and plain on the other side. 400 mg tablets are white to off white, capsule shaped, biconvex, film coated tablets, debossed with ‘L229’ on one side and plain on the other side. 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg (3)
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 is an atypical antipsychotic indicated for the treatment of: · Schizophrenia (1.1) · Bipolar I disorder manic episodes (1.2) · Bipolar disorder, depressive episodes (1.2) 1.1 Schizophrenia Quetiapine fumarate is indicated for the treatment of schizophrenia. The efficacy of quetiapine fumarate in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents (13 to 17 years). The effectiveness of quetiapine fumarate for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [ see Clinical Studies (14.1) ]. 1.2 Bipolar Disorder Quetiapine fumarate is indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. Efficacy was established in two 12-week monotherapy trials in adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10 to 17 years) [ see Clinical Studies (14.2)]. Quetiapine fumarate is indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder. Efficacy was established in two 8-week monotherapy trials in adult patients with bipolar I and bipolar II disorder [ see Clinical Studies (14.2)]. Quetiapine fumarate is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was established in two maintenance trials in adults. The effectiveness of quetiapine fumarate as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [ see Clinical Studies (14.2)]. 1.3 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 QUETIAPINE FUMARATE QUETIAPINE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A POTATO ANHYDROUS DIBASIC CALCIUM PHOSPHATE POVIDONE K30 MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED HYDROXYPROPYL CELLULOSE (1600000 WAMW) TITANIUM DIOXIDE White to off white Round, biconvex 224;L Quetiapine Fumarate quetiapine fumarate QUETIAPINE FUMARATE QUETIAPINE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A POTATO ANHYDROUS DIBASIC CALCIUM PHOSPHATE POVIDONE K30 MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED HYDROXYPROPYL CELLULOSE (1600000 WAMW) TITANIUM DIOXIDE White to off white Round, biconvex 225;L Quetiapine Fumarate quetiapine fumarate QUETIAPINE FUMARATE QUETIAPINE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A POTATO ANHYDROUS DIBASIC CALCIUM PHOSPHATE POVIDONE K30 MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED HYDROXYPROPYL CELLULOSE (1600000 WAMW) TITANIUM DIOXIDE White to off white Round, biconvex 226;L Quetiapine Fumarate quetiapine fumarate QUETIAPINE FUMARATE QUETIAPINE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A POTATO ANHYDROUS DIBASIC CALCIUM PHOSPHATE POVIDONE K30 MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED HYDROXYPROPYL CELLULOSE (1600000 WAMW) TITANIUM DIOXIDE White to off white Round, biconvex L227 Quetiapine Fumarate quetiapine fumarate QUETIAPINE FUMARATE QUETIAPINE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A POTATO ANHYDROUS DIBASIC CALCIUM PHOSPHATE POVIDONE K30 MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED HYDROXYPROPYL CELLULOSE (1600000 WAMW) TITANIUM DIOXIDE White to off white Capsule shaped, biconvex L228 Quetiapine Fumarate quetiapine fumarate QUETIAPINE FUMARATE QUETIAPINE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A POTATO ANHYDROUS DIBASIC CALCIUM PHOSPHATE POVIDONE K30 MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED HYDROXYPROPYL CELLULOSE (1600000 WAMW) TITANIUM DIOXIDE White to off white Capsule shaped, biconvex L229
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 to 250 mg/kg in rats and 75 to 750 mg/kg in mice; these doses are 0.1 to 3, and 0.1 to 4.5 times the maximum recommended human dose (MRHD) of 800 mg/day on mg/m 2 body surface area, respectively. 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 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 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 maximum human dose (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 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 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 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 on mg/m 2 body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests. Impairment of Fertility Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day 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 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 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 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 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 maximum human dose (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 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 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 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 on mg/m 2 body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests. Impairment of Fertility Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day 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 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 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 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 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 to 250 mg/kg in rats and 75 to 750 mg/kg in mice; these doses are 0.1 to 3, and 0.1 to 4.5 times the maximum recommended human dose (MRHD) of 800 mg/day on mg/m 2 body surface area, respectively. 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 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 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 - 25 mg Quetiapine Fumarate Tablets 25 mg (30 Tablets in 1 Bottle) Each coated tablet contains quetiapine fumarate equivalent to 25 mg of quetiapine 46708-134-30 25 mg 30's bottle pack
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 50 mg Quetiapine Fumarate Tablets 50 mg (30 Tablets in 1 Bottle) Each coated tablet contains quetiapine fumarate equivalent to 50 mg of quetiapine 46708-135-30 50 mg 30's bottle pack
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 100 mg Quetiapine Fumarate Tablets 100 mg (30 Tablets in 1 Bottle) Each coated tablet contains quetiapine fumarate equivalent to 100 mg of quetiapine 46708-136-30 100 mg 30's bottle pack
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 200 mg Quetiapine Fumarate Tablets 200 mg (30 Tablets in 1 Bottle) Each coated tablet contains quetiapine fumarate equivalent to 200 mg of quetiapine 46708-137-30 200 mg 30's bottle pack
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 300 mg Quetiapine Fumarate Tablets 300 mg (30 Tablets in 1 Bottle) Each coated tablet contains quetiapine fumarate equivalent to 300 mg of quetiapine 46708-138-30 300 mg 30's bottle pack
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 400 mg Quetiapine Fumarate Tablets 400 mg (30 Tablets in 1 Bottle) Each coated tablet contains quetiapine fumarate equivalent to 400 mg of quetiapine 46708-139-30 400 mg 30's bottle pack
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.Warnings and Precautions, Falls (5.8) 02/2017
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 See FDA-approved patient labeling (Medication Guide) Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with quetiapine fumarate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for quetiapine fumarate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking quetiapine fumarate. Increased Mortality in Elderly Patients with Dementia-Related Psychosis Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. Quetiapine is 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 [ 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 and Nursing Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with quetiapine fumarate [ see Use in Specific Populations (8.1) and (8.3) ]. Need for Comprehensive Treatment Program Quetiapine fumarate is 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 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 (1.3) ].
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 Quetiapine Fumarate (kwe-TYE-a-peen FUE-ma-rate) Tablets Read this Medication Guide before you start taking quetiapine fumarate and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about quetiapine fumarate? quetiapine fumarate may cause serious side effects, including: 1. risk of death in the elderly with dementia. Medicines like quetiapine fumarate can increase the risk of death in elderly people who have memory loss (dementia). Quetiapine fumarate is 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 your or 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 medications 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 member 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 is quetiapine fumarate? Quetiapine fumarate is 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 It is not known if quetiapine fumarate is safe and effective in children under 10 years of age. What should I tell my healthcare provider before taking quetiapine fumarate? Before you take quetiapine fumarate, 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 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 will harm your unborn baby. · Breast-feeding or plans to breast-feed. quetiapine fumarate can pass into your breast milk. You and your healthcare provider should decide if you will take quetiapine fumarate or breast-feed. You should not do both. 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 and other medicines may affect each other causing serious side effects. quetiapine fumarate may affect the way other medicines work, and other medicines may affect how quetiapine fumarate works. Tell your healthcare provider if you are having a urine drug screen because quetiapine fumarate may affect your test results. Tell those giving the test that you are taking quetiapine fumarate. How should I take quetiapine fumarate? · Take quetiapine fumarate exactly as your healthcare provider tells you to take it. Do not change the dose yourself. · Take quetiapine fumarate by mouth, with or without food. · If you feel you need to stop quetiapine fumarate, talk with your healthcare provider first . If you suddenly stop taking quetiapine fumarate, 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, 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? · Do not drive, operate machinery, or do other dangerous activities until you know how quetiapine fumarate affects you. quetiapine fumarate 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. It may make some side effects of quetiapine fumarate worse. What are possible side effects of quetiapine fumarate? Quetiapine fumarate can cause serious side effects, including: · See “What is the most important information I should know about quetiapine fumarate?” · stroke that can lead to death can happen in elderly people with dementia who take medicines like quetiapine fumarate · neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including quetiapine fumarate. 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. 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. 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 and during therapy. Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking quetiapine fumarate: 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. You may not have any symptoms, so your healthcare provider may decide to check your cholesterol and triglycerides during your treatment with quetiapine fumarate. · increase in weight (weight gain). Weight gain is common in people who take quetiapine fumarate 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. Tardive dyskinesia may also start after you stop taking quetiapine fumarate. · 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 and during therapy. · low white blood cell count · 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. These symptoms usually get better 1 week after you start having them. The most common side effects of quetiapine fumarate include: In Adults: · dry mouth · constipation · dizziness · sore throat · weakness · difficulty moving · abdominal pain In Children and Adolescents: · nausea · increased appetite · dry mouth · vomiting · weight gain · rapid heart beat These are not all the possible side effects of quetiapine fumarate. 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 ? · Store quetiapine fumarate at room temperature, between 68°F to 77°F (20°C to 25°C). · Keep quetiapine fumarate and all medicines out of the reach of children. General information about the safe and effective use of quetiapine fumarate. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use quetiapine fumarate for a condition for which it was not prescribed. Do not give quetiapine fumarate 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. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about quetiapine fumarate that is written for health professionals. What are the ingredients in quetiapine fumarate? Active ingredient: quetiapine fumarate Inactive ingredients: povidone, dibasic calcium phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, magnesium stearate, hypromellose, hydroxypropyl cellulose and titanium dioxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P. O. Tajpura, Near Baska, Taluka-Halol, Panchmahal, Gujarat, India. Revised: 03/2017
| · dry mouth | · constipation |
| · dizziness | · sore throat |
| · weakness | · difficulty moving |
| · abdominal pain |
| · nausea | · increased appetite |
| · dry mouth | · vomiting |
| · weight gain | · rapid heart beat |
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 in the treatment of schizophrenia was established in 3 short-term (6-week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia. Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of quetiapine fumarate and haloperidol. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. The results of the trials follow: 1. In a 6-week, placebo-controlled trial (n=361) (study 1) involving 5 fixed doses of quetiapine fumarate (75 mg/day, 150 mg/day, 300 mg/day, 600 mg/day and 750 mg/day given in divided doses three times per day), the 4 highest doses of quetiapine fumarate were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster and the CGI severity score, with the maximal effect seen at 300 mg/day, and the effects of doses of 150 mg/day to 750 mg/day were generally indistinguishable. 2. In a 6-week, placebo-controlled trial (n=286) (study 2) involving titration of quetiapine fumarate in high (up to 750 mg/day given in divided doses three times per day) and low (up to 250 mg/day given in divided doses three times per day) doses, only the high dose quetiapine fumarate group (mean dose, 500 mg/day) was superior to placebo on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score. 3. In a 6-week dose and dose regimen comparison trial (n=618) (study 3) involving two fixed doses of quetiapine fumarate (450 mg/day given in divided doses both twice daily and three times daily and 50 mg/day given in divided doses twice daily), only the 450 mg/day (225 mg given twice daily) dose group was superior to the 50 mg/day (25 mg given twice daily) quetiapine fumarate dose group on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score. The primary efficacy results of these three studies in the treatment of schizophrenia in adults are presented in Table 19. Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 years compared to those older than 40. The clinical significance of this finding is unknown. Adolescents (ages 13 to 17) The efficacy of quetiapine fumarate in the treatment of schizophrenia in adolescents (13 to 17 years of age) was demonstrated in a 6-week, double-blind, placebo-controlled trial (study 4). Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: quetiapine fumarate 400 mg/day (n = 73), quetiapine fumarate 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 at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score. The primary efficacy results of this study in the treatment of schizophrenia in adolescents are presented in Table 19. Table 19: Schizophrenia Short-Term Trials Study Treatment Group Primary Efficacy Endpoint: BPRS Total Number Mean Baseline Score (SD) LS Mean Change from Baseline(SE) Placebo-subtracted Difference 3 (95% CI) Quetiapine fumarate (75 mg/day) 45.7 (10.9) -2.2 (2) -4 (-11.2, 3.3) Quetiapine fumarate (150 mg/day) 1 47.2 (10.1) -8.7 (2.1) -10.4 (-17.8, -3) Study 1 Quetiapine fumarate (300 mg/day) 1 45.3 (10.9) -8.6 (2.1) -10.3 (-17.6, -3) Quetiapine fumarate (600 mg/day) 1 43.5 (11.3) -7.7 (2.1) -9.4 (-16.7, -2.1) quetiapine fumarate (750 mg/day) 1 45.7 (11) -6.3 (2) -8 (-15.2, -0.8) Placebo 45.3 (9.2) 1.7 (2.1) - Study 2 quetiapine fumarate (250 mg/day) 38.9 (9.8) -4.2 (1.6) -3.2 (-7.6, 1.2) quetiapine fumarate (750 mg/day) 1 41 (9.6) -8.7 (1.6) -7.8 (-12.2, -3.4) Placebo 38.4 (9.7) -1 (1.6) - Study 3 quetiapine fumarate (450 mg/dayBID) 42.1 (10.7) -10 (1.3) -4.6 (-7.8, -1.4) quetiapine fumarate (450 mg/dayTID) 2 42.7 (10.4) -8.6 (1.3) -3.2 (-6.4, 0) quetiapine fumarate (50 mg BID) 41.7 (10) -5.4 (1.3) - Primary Efficacy Endpoint: PANSS Total Mean Baseline Score (SD) LS Mean Change from Baseline(SE) Placebo-subtracted Difference 3 (95% CI) Study 4 quetiapine fumarate (400 mg/day) 1 96.2 (17.7) -27.3 (2.6) -8.2 (-16.1, -0.3) quetiapine fumarate (800 mg/day) 1 96.9 (15.3) -28.4 (1.8) -9.3 (-16.2, -2.4) Placebo 96.2 (17.7) -19.2 (3) - SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. 1 Doses that are statistically significantsuperior to placebo. 2 Doses that are statistically significantsuperior to quetiapine fumarate 50 mg BID. 3 Difference (drug minus placebo) in least-squaresmean change from baseline. 14.2 Bipolar Disorder Bipolar I disorder, manic or mixed episodes Adults The efficacy of quetiapine fumarate in the acute treatment of manic episodes was 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 Young Mania Rating Scale (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 with lithium or divalproex. The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The results of the trials follow: Monotherapy The efficacy of quetiapine fumarate in the acute treatment of bipolar mania was established in 2 placebo-controlled trials. In two 12-week trials (n=300, n=299) comparing quetiapine fumarate to placebo, quetiapine fumarate was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking quetiapine fumarate were dosed in a range between 400 mg/day and 800 mg per day (studies 1 and 2 in Table 20). Adjunct Therapy In this 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥20) were randomized to receive quetiapine fumarate 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 was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score (study 3 in Table 20). The majority of patients in this trial taking quetiapine fumarate were dosed in a range between 400 mg/day and 800 mg per day. In a similarly designed trial (n=200), quetiapine fumarate was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect. The primary efficacy results of these studies in the treatment of mania in adults are presented in Table 20. Children and Adolescents (ages 10 to 17) The efficacy of quetiapine fumarate in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial (study 4 in Table 20). Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: quetiapine fumarate 400 mg/day (n = 95), quetiapine fumarate 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 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (Table 20). Table 20: Mania Trials Study Number Treatment Group Primary Efficacy Measure: YMRS Total Mean Baseline Score (SD) 4 LS Mean Change from Baseline(SE) Placebo-subtracted Difference 2 (95% CI) Study 1 Quetiapine fumarate (200 to 800 mg/day) 1,3 34 (6.1) -12.3 (1.3) -4 (-7, -1) Haloperidol 1,3 32.3 (6) -15.7 (1.3) -7.4 (-10.4, -4.4) Placebo 33.1 (6.6) -8.3 (1.3) - Study 2 Quetiapine fumarate (200 to 800 mg/day) 1 32.7 (6.5) -14.6 (1.5) -7.9 (-10.9, -5) Lithium 1,3 33.3 (7.1) -15.2 (1.6) -8.5 (-11.5, -5.5) Placebo 34 (6.9) -6.7 (1.6) - Study 3 Quetiapine fumarate (200 to 800 mg/day) 1 + mood stabilizer 31.5 (5.8) -13.8 (1.6) -3.8 (-7.1, -0.6) Placebo + mood stabilizer 31.1 (5.5) -10 (1.5) - Study 4 Quetiapine fumarate (400 mg/day) 1 29.4 (5.9) -14.3 (0.96) -5.2 (-8.1, -2.3) Quetiapine fumarate (600 mg/day) 1 29.6 (6.4) -15.6 (0.97) -6.6 (-9.5, -3.7) Placebo 30.7 (5.9) -9 (1.1) - Mood stabilizer: lithium or divalproex; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. 1 Doses that are statistically significantly superior to placebo. 2 Difference (drug minus placebo) in least-squaresmean change from baseline. 3 Included in the trialasan active comparator. 4 Adult data mean baseline score is based on patientsincluded in the primary analysis; pediatric mean baseline score is based on all patients in the ITT population. Bipolar Disorder, Depressive Episodes Adults The efficacy of quetiapine fumarate for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week, randomized, double-blind, placebo-controlled studies (N=1045) (studies 5 and 6 in Table 21). 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 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 Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 to 60. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, quetiapine fumarate was superior to placebo in reduction of MADRS score. Improvement in symptoms, as measured by change in MADRS score relative to placebo, was seen in both studies at Day 8 (week 1) and onwards. In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF). The primary efficacy results of these studies in the acute treatment of depressive episodes associated with bipolar disorder in adults is presented in Table 21. Table 21: Depressive Episodes Associated with Bipolar Disorder Study Treatment Group Primary Efficacy Measure: MADRS Total Number Mean Baseline Score (SD) LS Mean Change from Baseline(SE) Placebo-subtracted Difference 2 (95% CI) quetiapine fumarate (300 mg/day) 1 30.3 (5) -16.4 (0.9) -6.1 (-8.3, -3.9) Study 5 quetiapine fumarate (600 mg/day) 1 30.3 (5.3) -16.7 (0.9) -6.5 (-8.7, -4.3) Placebo 30.6 (5.3) -10.3 (0.9) - quetiapine fumarate (300 mg/day) 1 31.1 (5.7) -16.9 (1) -5 (-7.3, -2.7) Study 6 quetiapine fumarate (600 mg/day) 1 29.9 (5.6) -16 (1) -4.1 (-6.4, -1.8) Placebo 29.6 (5.4) -11.9 (1) - SD: standarddeviation; SE: standard error; LS Mean: least-squaresmean; CI: unadjusted confidence interval. 1 Doses that are statistically significantly superior to placebo. 2 Difference (drug minus placebo) in least-squaresmean change from baseline. Maintenance Treatment as an Adjunct to Lithium or Divalproex The efficacy of quetiapine fumarate 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 7 and 8 in Figures 1 and 2). 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 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 (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo. Approximately 50% of the patients had discontinued from the quetiapine fumarate 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. (Figure 1 and Figure 2) In both studies, quetiapine fumarate was superior to placebo in increasing the time to recurrence of any mood event. The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of quetiapine fumarate was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course). Figure 2 Kaplan-Meier Curves of Time to Recurrence of A Mood Event (Study 8) Figure 1 Figure 2
| Quetiapine fumarate (75 mg/day) | 45.7 (10.9) | -2.2 (2) | -4 (-11.2, 3.3) | ||
| Quetiapine fumarate (150 mg/day)1 | 47.2 (10.1) | -8.7 (2.1) | -10.4 (-17.8, -3) | ||
| Quetiapine fumarate (300 mg/day)1 | 45.3 (10.9) | -8.6 (2.1) | -10.3 (-17.6, -3) | ||
| Quetiapine fumarate (600 mg/day)1 | 43.5 (11.3) | -7.7 (2.1) | -9.4 (-16.7, -2.1) | ||
| quetiapine fumarate (750 mg/day)1 | 45.7 (11) | -6.3 (2) | -8 (-15.2, -0.8) | ||
| Placebo | 45.3 (9.2) | 1.7 (2.1) | - | ||
| quetiapine fumarate (250 mg/day) | 38.9 (9.8) | -4.2 (1.6) | -3.2 (-7.6, 1.2) | ||
| quetiapine fumarate (750 mg/day)1 | 41 (9.6) | -8.7 (1.6) | -7.8 (-12.2, -3.4) | ||
| Placebo | 38.4 (9.7) | -1 (1.6) | - | ||
| quetiapine fumarate (450 mg/dayBID) | 42.1 (10.7) | -10 (1.3) | -4.6 (-7.8, -1.4) | ||
| quetiapine fumarate (450 mg/dayTID)2 | 42.7 (10.4) | -8.6 (1.3) | -3.2 (-6.4, 0) | ||
| quetiapine fumarate (50 mg BID) | 41.7 (10) | -5.4 (1.3) | - | ||
| quetiapine fumarate (400 mg/day)1 | 96.2 (17.7) | -27.3 (2.6) | -8.2 (-16.1, -0.3) | ||
| quetiapine fumarate (800 mg/day)1 | 96.9 (15.3) | -28.4 (1.8) | -9.3 (-16.2, -2.4) | ||
| Placebo | 96.2 (17.7) | -19.2 (3) | - | ||
| Quetiapine fumarate (200 to 800 mg/day)1,3 | 34 (6.1) | -12.3 (1.3) | -4 (-7, -1) | |
| Haloperidol1,3 | 32.3 (6) | -15.7 (1.3) | -7.4 (-10.4, -4.4) | |
| Placebo | 33.1 (6.6) | -8.3 (1.3) | - | |
| Quetiapine fumarate (200 to 800 mg/day)1 | 32.7 (6.5) | -14.6 (1.5) | -7.9 (-10.9, -5) | |
| Lithium1,3 | 33.3 (7.1) | -15.2 (1.6) | -8.5 (-11.5, -5.5) | |
| Placebo | 34 (6.9) | -6.7 (1.6) | - | |
| Quetiapine fumarate (200 to 800 mg/day)1 | 31.5 (5.8) | -13.8 (1.6) | -3.8 (-7.1, -0.6) | |
| Placebo + mood stabilizer | 31.1 (5.5) | -10 (1.5) | - | |
| Quetiapine fumarate (400 mg/day)1 | 29.4 (5.9) | -14.3 (0.96) | -5.2 (-8.1, -2.3) | |
| Quetiapine fumarate (600 mg/day)1 | 29.6 (6.4) | -15.6 (0.97) | -6.6 (-9.5, -3.7) | |
| Placebo | 30.7 (5.9) | -9 (1.1) | - | |
| quetiapine fumarate (300 mg/day)1 | 30.3 (5) | -16.4 (0.9) | -6.1 (-8.3, -3.9) | |
| Study 5 | quetiapine fumarate (600 mg/day)1 | 30.3 (5.3) | -16.7 (0.9) | -6.5 (-8.7, -4.3) |
| Placebo | 30.6 (5.3) | -10.3 (0.9) | - | |
| quetiapine fumarate (300 mg/day)1 | 31.1 (5.7) | -16.9 (1) | -5 (-7.3, -2.7) | |
| Study 6 | quetiapine fumarate (600 mg/day)1 | 29.9 (5.6) | -16 (1) | -4.1 (-6.4, -1.8) |
| Placebo | 29.6 (5.4) | -11.9 (1) | - | |
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 Of the approximately 3700 patients in clinical studies with quetiapine fumarate, 7% (232) were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine fumarate, 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 fumarate was reduced by 30% to 50% in elderly patients when compared to younger patients [ see Clinical Pharmacology (12.3) and Dosage and Administration (2.3) ].
Labor and delivery
Information about the drug’s use during labor or delivery, whether or not the use is stated in the indications section of the labeling, including the effect of the drug on the mother and fetus, on the duration of labor or delivery, on the possibility of delivery-related interventions, and the effect of the drug on the later growth, development, and functional maturation of the child.8.2 Labor & Delivery The effect of quetiapine fumarate on labor and delivery in humans is unknown.
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.3 Nursing Mothers Quetiapine fumarate was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from quetiapine fumarate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother’s health. In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).
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 In general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%) [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)]. Schizophrenia The efficacy and safety of quetiapine fumarate in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [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 in pediatric patients less than 13 years of age with schizophrenia have not been established. Maintenance The safety and effectiveness of quetiapine fumarate in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age. The safety and effectiveness of quetiapine fumarate in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients. Bipolar Mania The efficacy and safety of quetiapine fumarate in the treatment of mania in children and adolescents ages 10 to 17 years with Bipolar I disorder was demonstrated in a 3-week, double-blind, placebo controlled, multicenter trial [see Indications and Usage (1.2), Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Studies (14.2)] . Safety and effectiveness of quetiapine fumarate in pediatric patients less than 10 years of age with bipolar mania have not been established. Bipolar Depression Safety and effectiveness of quetiapine fumarate in pediatric patients less than 18 years of age with bipolar depression have not been established. A clinical trial with quetiapine fumarate extended-release tablets was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not established. Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and Cmax of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight [see Clinical Pharmacology (12.3)] .
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 Category C: Risk Summary There are no adequate and well-controlled studies of quetiapine fumarate use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including quetiapine fumarate), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Animal Data When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect at doses up to 2.4 times the maximum recommended human dose (MRHD) for schizophrenia of 800 mg/day based on mg/m 2 body surface area. However, there was evidence of embryo-fetal toxicity, which included delays in skeletal ossification occurring 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 approximately 1 to 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, 0.12, and 0.24 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: Limited human data. Based on animal data, may cause fetal harm. Quetiapine should be used only if the potential benefit justifies the potential risk (8.1) · Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother’s health (8.3) 8.1 Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of quetiapine fumarate use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including quetiapine fumarate), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Animal Data When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect at doses up to 2.4 times the maximum recommended human dose (MRHD) for schizophrenia of 800 mg/day based on mg/m 2 body surface area. However, there was evidence of embryo-fetal toxicity, which included delays in skeletal ossification occurring 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 approximately 1 to 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, 0.12, and 0.24 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 Labor & Delivery The effect of quetiapine fumarate on labor and delivery in humans is unknown. 8.3 Nursing Mothers Quetiapine fumarate was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from quetiapine fumarate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother’s health. In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg). 8.4 Pediatric Use In general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%) [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)]. Schizophrenia The efficacy and safety of quetiapine fumarate in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [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 in pediatric patients less than 13 years of age with schizophrenia have not been established. Maintenance The safety and effectiveness of quetiapine fumarate in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age. The safety and effectiveness of quetiapine fumarate in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients. Bipolar Mania The efficacy and safety of quetiapine fumarate in the treatment of mania in children and adolescents ages 10 to 17 years with Bipolar I disorder was demonstrated in a 3-week, double-blind, placebo controlled, multicenter trial [see Indications and Usage (1.2), Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Studies (14.2)] . Safety and effectiveness of quetiapine fumarate in pediatric patients less than 10 years of age with bipolar mania have not been established. Bipolar Depression Safety and effectiveness of quetiapine fumarate in pediatric patients less than 18 years of age with bipolar depression have not been established. A clinical trial with quetiapine fumarate extended-release tablets was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not established. Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and Cmax of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight [see Clinical Pharmacology (12.3)] . 8.5 Geriatric Use Of the approximately 3700 patients in clinical studies with quetiapine fumarate, 7% (232) were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine fumarate, 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 fumarate was reduced by 30% to 50% in elderly patients when compared to younger patients [ see Clinical Pharmacology (12.3) and Dosage and Administration (2.3) ]. 8.6 Renal Impairment Clinical experience with quetiapine fumarate 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 25 mg/day is recommended and the dose may be increased in increments of 25 mg/day to 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 Quetiapine Fumarate Tablets are supplied as below: 25 mg: White to off white, round, biconvex, film coated tablets debossed with ‘224’ on one side and ‘L’ on the other side. NDC 46708-134-30 bottle of 30 tablets NDC 46708-134-31 bottle of 100 tablets NDC 46708-134-91 bottle of 1000 tablets NDC 46708-134-10 100 (10 x 10) Tablets Unit dose package 50 mg: White to off white, round, biconvex, film coated tablets debossed with ‘225’ on one side and ‘L’ on the other side. NDC 46708-135-30 bottle of 30 tablets NDC 46708-135-31 bottle of 100 tablets NDC 46708-135-91 bottle of 1000 tablets NDC 46708-135-10 100 (10 x 10) Tablets Unit dose package 100 mg: White to off white, round, biconvex, film coated tablets debossed with ‘226’ on one side and ‘L’ on the other side. NDC 46708-136-30 bottle of 30 tablets NDC 46708-136-31 bottle of 100 tablets NDC 46708-136-91 bottle of 1000 tablets NDC 46708-136-10 100 (10 x 10) Tablets Unit dose package 200 mg: White to off white, round, biconvex, film coated tablets, debossed with ‘L227’ on one side and plain on the other side. NDC 46708-137-30 bottle of 30 tablets NDC 46708-137-31 bottle of 100 tablets NDC 46708-137-91 bottle of 1000 tablets NDC 46708-137-10 100 (10 x 10) Tablets Unit dose package 300 mg: White to off white, capsule shaped, biconvex, film coated tablets, debossed with ‘L228’ on one side and plain on the other side. NDC 46708-138-30 bottle of 30 tablets NDC 46708-138-60 bottle of 60 tablets NDC 46708-138-91 bottle of 1000 tablets NDC 46708-138-10 100 (10 x 10) Tablets Unit dose package 400 mg: White to off white, capsule shaped, biconvex, film coated tablets, debossed with ‘L229’ on one side and plain on the other side. NDC 46708-139-30 bottle of 30 tablets NDC 46708-139-31 bottle of 100 tablets NDC 46708-139-71 bottle of 500 tablets NDC 46708-139-10 100 (10 x 10) Tablets Unit dose package Store at 25ºC (77ºF); excursions permitted to 15° to 30ºC (59° to 86ºF) [see USP].
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 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 is not approved for the treatment of patients with dementia-related psychosis [ see Warnings and Precautions (5.1) ]. Suicidal Thoughts and Behaviors 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 is not approved for use in pediatric patients under ten years of age [ see Use in Specific Populations (8.4) ]. 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 is 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)
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