Quetiapine Fumarate ER

1.1 Schizophrenia Quetiapine Extended-release tablets are indicated for the treatment of schizophrenia. The efficacy of quetiapine extended-release tablets in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13 to 17 years) treated with quetiapine tablets [see Clinical Studies (14.1)]. 1.2 Bipolar Disorder Quetiapine Extended-release tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of quetiapine extended-release tablets in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 to 17 years) with manic episodes associated with bipolar I disorder treated with quetiapine tablets [see CLINICAL STUDIES (14.2)]. Quetiapine Extended-release tablets are indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of quetiapine extended-release tablets were established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with quetiapine tablets [see CLINICAL STUDIES (14.2)]. Quetiapine Extended-release tablets are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with quetiapine tablets. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials [see CLINICAL STUDIES (14.2)]. 1.3 Adjunctive Treatment of Major Depressive Disorder (MDD) Quetiapine Extended-release tablets are indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of quetiapine extended-release tablets as adjunctive therapy to antidepressants in MDD was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant treatment [see CLINICAL STUDIES (14.3)]. 1.4 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.

2.1 Important Administration Instructions Quetiapine extended-release tablets should be swallowed whole and not split, chewed, or crushed. It is recommended that quetiapine extended-release tablets be taken without food or with a light meal (approximately 300 calories) [see Clinical Pharmacology (12.3)]. Quetiapine extended-release tablets should be administered once daily, preferably in the evening. 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine extended-release tablets dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies ( 14.1,14.2 and 14.3)]. Table 1: Recommended Dosing for Quetiapine Extended-Release Tablets Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia -Adults Day 1: 300 mg/day Dose increases can be made at intervals as short as 1 day and in increments of up to 300 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia -Adolescents (13 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia Maintenance - Monotherapy - Adults Not applicable 400 to 800 mg/day 800 mg/day Bipolar I Disorder manic or mixed - Acute monotherapy or adjunct to lithium or divalproex - Adults Day 1: 300 mg/day Day 2: 600 mg/day Day 3: between 400 and 800 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder, manic Acute monotherapy Children and Adolescents (10 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 600 mg/day 600 mg/day Bipolar Disorder, Depressive Episodes - Adults Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day 300 mg/day 300 mg/day Bipolar I Disorder Maintenance - Adjunct to lithium or divalproex - Adults Not applicable 400 to 800 mg/day 800 mg/day Major Depressive Disorder - Adjunctive Therapy with Antidepressants-Adults Day 1: 50 mg/day Day 2: 50 mg/day Day 3: 150 mg/day 150 to 300 mg/day 300 mg/day Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment-Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1, 14.2)]. 2.3 Dose Modifications in Elderly Patients Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see Use in Specific Populations (8.5,8.7), and Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients. Elderly patients should be started on quetiapine extended-release tablets 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient. 2.4 Dose Modifications in Hepatically Impaired Patients Patients with hepatic impairment should be started on quetiapine extended-release tablets 50 mg/day. The dose can be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient. 2.5 Dose Modifications when used with CYP3A4 Inhibitors Quetiapine extended-release tablets dose should be reduced to one-sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of quetiapine extended-release tablets should be increased by 6-fold [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)]. 2.6 Dose Modifications when used with CYP3A4 Inducers Quetiapine extended-release tablets dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment ( …

Quetiapine Extended-release tablets, USP 150 mg are white colored, round shaped, biconvex film-coated tablets, debossed with 'I1' on one side and plain on other. Quetiapine Extended-release tablets, USP 200 mg are yellow colored, round shaped, biconvex film-coated tablets, debossed with 'I2' on one side and plain on other. Quetiapine Extended-release tablets, USP 300 mg are light yellow colored, round shaped, biconvex film-coated tablets, debossed with 'I3' on one side and plain on other. Quetiapine Extended-release tablets, USP 400 mg are white colored, round shaped, biconvex, beveled edge, film-coated tablets, debossed with “I4” on one side and plain on the other.

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

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS (5.1)] Suicidal thoughts and behaviors in adolescents and young adults [see WARNINGS AND PRECAUTIONS (5.2)] Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS (5.3)] Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS (5.4)] Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [see WARNINGS AND PRECAUTIONS (5.5)] Tardive dyskinesia [see WARNINGS AND PRECAUTIONS (5.6)] Hypotension [see WARNINGS AND PRECAUTIONS (5.7)] Falls [see WARNINGS AND PRECAUTIONS (5.8)] Increases in blood pressure (children and adolescents) [see WARNINGS AND PRECAUTIONS (5.9)] Leukopenia, neutropenia and agranulocytosis [see WARNINGS AND PRECAUTIONS (5.10)] Cataracts [see WARNINGS AND PRECAUTIONS (5.11)] QT Prolongation [see WARNINGS AND PRECAUTIONS (5.12)] Seizures [see WARNINGS AND PRECAUTIONS (5.13)] Hypothyroidism [see WARNINGS AND PRECAUTIONS (5.14)] Hyperprolactinemia [see WARNINGS AND PRECAUTIONS (5.15)] Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS (5.16)] Body temperature regulation [see WARNINGS AND PRECAUTIONS (5.17)] Dysphagia [see WARNINGS AND PRECAUTIONS (5.18)] Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS (5.19)] Anticholinergic (antimuscarinic) Effects [see WARNINGS AND PRECAUTIONS (5.20)] 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults The information below is derived from a clinical trial database for quetiapine extended-release tablets consisting of approximately 3400 patients exposed to quetiapine extended-release tablets for the treatment of Schizophrenia, Bipolar Disorder, and Major Depressive Disorder in placebo-controlled trials. This experience corresponds to approximately 1020.1 patient-years. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses, and ECG results. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥2% for quetiapine extended-release tablets in schizophrenia trials. Bipolar I Disorder, Manic or Mixed Episodes: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥2% for quetiapine extended-release tablets in the bipolar mania trial. Bipolar Disorder, Depressive Episode: In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on quetiapine extended-release tablets discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% in quetiapine extended-release tablets in the bipolar depression trial. MDD, Adjunctive Therapy: In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on quetiapine extended-release tablets discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% in quetiapine extended-release tablets in MDD trials. Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: In short-term placebo-controlled studies for schizophrenia the most commonly obser …

7.1 Effect of Other Drugs on Quetiapine The risks of using quetiapine extended-release tablets in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine extended-release tablets, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine. Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.) and decreased by the prototype of CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John's wort etc.). Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors. CYP3A4 inhibitors: Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure. The dose should be reduced to one-sixth of the original dose in patients coadministered with a strong CYP3A4 inhibitor [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. CYP3A4 inducers: Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine extended-release tablets up to 5 - fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent CYP3A4 inducers [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].When the CYP3A4 inducer is discontinued, the dose of quetiapine extended-release tablets should be reduced to the original level within 7 to 14 days [see Dosage and Administration (2.6)]. Anticholinergic Drugs: Concomitant treatment with quetiapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Quetiapine extended-release tablets should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.20)]. 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 extended-release tablets may enhance the effects of certain antihypertensive agents. Quetiapine extended-release tablets may antagonize the effects of levodopa and dopamine agonists. There are no clinically relevant pharmacokinetic interactions of quetiapine on other drugs based on the CYP pathway. Quetiapine and its metabolites are non-inhibitors of major metabolizing CYP's (1A2, 2C9, 2C19, 2D6, and 3A4).

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ Risk Summary Neonates exposed to antipsychotic drugs, including quetiapine extended-release tablets, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed to quetiapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia, bipolar I, or major depressive disorder, and with exposure to antipsychotics, including, quetiapine extended-release tablets during pregnancy (see Clinical Considerations). In animal studies, embryo-fetal toxicity occurred including delays in skeletal ossification at approximately 1 and 2 times the maximum recommended human dose (MRHD) of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the MRHD in rats and approximately 1 to 2 times the MRHD in rabbits. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal risk There is a risk to the mother from untreated schizophrenia, or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including quetiapine extended-release tablets, during the third trimester of pregnancy. These symptoms varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk …

Quetiapine is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [ b,f ] [1,4] thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C 42H 50N 6O 4S 2•C 4H 4O 4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is: [structural formula] Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water. Quetiapine Extended-release tablets, USP are supplied for oral administration as 150 mg (white), 200 mg (yellow), 300 mg (light yellow), and 400 mg (white). All tablets are round shaped and film coated. Inactive ingredients for quetiapine extended-release tablets, USP are lactose monohydrate, sodium chloride, hydroxypropyl methylcellulose, povidone K30, talc and magnesium stearate. The film coating for all quetiapine extended-release tablets contain hypromellose, polyethylene glycol 400 and titanium dioxide. In addition, iron oxide yellow (200 and 300 mg tablets) is included in the film coating of specific strengths. Each 150 mg tablet contains 173 mg of quetiapine fumarate, USP equivalent to 150 mg quetiapine. Each 200 mg tablet contains 230 mg of quetiapine fumarate, USP equivalent to 200 mg quetiapine. Each 300 mg tablet contains 345 mg of quetiapine fumarate, USP equivalent to 300 mg quetiapine. Each 400 mg tablet contains 461 mg of quetiapine fumarate, USP equivalent to 400 mg quetiapine. Quetiapine Extended-release tablets, USP meet USP Dissolution Test 2.

10.1 Human Experience In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and anticholinergic toxicity including coma and delirium. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose [see Warnings and Precautions (5.12)]. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there were cases reported of QT prolongation with overdose. 10.2 Management of Overdosage Establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Appropriate supportive measures are the mainstay of management. For the most up-to-date information on the management of quetiapine extended-release tablets overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Quetiapine extended-release tablets overdose may lead to gastric bezoar formation and appropriate diagnostic imaging is recommended to further guide patient management. Routine gastric lavage may not be effective in the removal of the bezoar due to gum like sticky consistency of the mass. Endoscopic pharmacobezoar removal has been performed successfully.

Quetiapine extended-release tablets,USP 150 mg 150 mg tablets are white to off white colored, capsule shaped, film coated tablets debossed with 'C 22' on one side and plain on the other side and are available as follows: Bottles of 60 tablets NDC 33342-134-09 Bottles of 500 tablets NDC 33342-134-15 Quetiapine extended-release tablets,USP 200 mg 200 mg tablets are yellow colored, capsule shaped, film coated tablets debossed with 'C 23' on one side and plain on the other side and are available as follows: Bottles of 60 tablets NDC 33342-135-09 Bottles of 500 tablets NDC 33342-135-15 Quetiapine extended-release tablets,USP 300 mg 300 mg tablets are pale yellow colored, capsule shaped, film coated tablets debossed with 'C 24' on one side and plain on the other side and are available as follows: Bottles of 60 tablets NDC 33342-136-09 Bottles of 500 tablets NDC 33342-136-15 Quetiapine extended-release tablets,USP 400 mg 400 mg tablets are white to off white colored, capsule shaped, film coated tablets debossed with 'C 25' on one side and plain on the other side and are available as follows: Bottles of 30 tablets NDC 72189-642-30 Bottles of 500 tablets NDC 33342-137-15