Quetiapine Fumarate

Description

11 DESCRIPTION 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 42 H 50 N 6 O 4 S 2 . C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is: Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water. Quetiapine tablets USP are supplied for oral administration as 25 mg (quetiapine) round, pink tablets, 50 mg (quetiapine) round, white tablets, 100 mg (quetiapine) round, yellow tablets, 200 mg (quetiapine) round, white tablets, 300 mg (quetiapine) capsule-shaped, white tablets and 400 mg (quetiapine) capsule-shaped, yellow tablets. Inactive ingredients are dibasic calcium phosphate dihydrate, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide. The 25 mg tablets contain iron oxide red and iron oxide black; and the 100 mg and 400 mg tablets contain iron oxide yellow. Each 25 mg film-coated tablet contains 28.78 mg of quetiapine fumarate USP equivalent to 25 mg quetiapine. Each 50 mg film-coated tablet contains 57.56 mg of quetiapine fumarate USP equivalent to 50 mg quetiapine. Each 100 mg film-coated tablet contains 115.12 mg of quetiapine fumarate USP equivalent to 100 mg quetiapine. Each 200 mg film-coated tablet contains 230.24 mg of quetiapine fumarate USP equivalent to 200 mg quetiapine. Each 300 mg film-coated tablet contains 345.36 mg of quetiapine fumarate USP equivalent to 300 mg quetiapine. Each 400 mg film-coated tablet contains 460.48 mg of quetiapine fumarate USP equivalent to 400 mg quetiapine. Molecular Structure

What Is Quetiapine Fumarate Used For?

1 INDICATIONS AND USAGE Quetiapine tablet 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 tablets are indicated for the treatment of schizophrenia. The efficacy of quetiapine tablets 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 tablets 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 tablets are 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 tablets are 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 tablets are 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 tablets 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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Quetiapine tablets 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 tablets can be taken with or without food. 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine 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 Tablets 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 Not applicable 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 totaling 300 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....

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS 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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS ( 5.1 )] Suicidal thoughts and behaviors in adolescents and young adults [see WARNINGS AND PRECAUTIONS ( 5.2 )] Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS ( 5.3 )] Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS ( 5.4 )] Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [see WARNINGS AND PRECAUTIONS ( 5.5 )] Tardive dyskinesia [see WARNINGS AND PRECAUTIONS ( 5.6 )] Hypotension [see WARNINGS AND PRECAUTIONS ( 5.7 )] Falls [see WARNINGS AND PRECAUTIONS ( 5.8 )] Increases in blood pressure (children and adolescents) [see WARNINGS AND PRECAUTIONS ( 5.9 )] Leukopenia, neutropenia and agranulocytosis [see WARNINGS AND PRECAUTIONS ( 5.10 )] Cataracts [see WARNINGS AND PRECAUTIONS ( 5.11 )] QT Prolongation [see WARNINGS AND PRECAUTIONS ( 5.12 )] Seizures [see WARNINGS AND PRECAUTIONS ( 5.13 )] Hypothyroidism [ see WARNINGS AND PRECAUTIONS ( 5.14 )] Hyperprolactinemia [see WARNINGS AND PRECAUTIONS ( 5.15 )] Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS ( 5.16 )] Body temperature regulation [see WARNINGS AND PRECAUTIONS ( 5.17 )] Dysphagia [see WARNINGS AND PRECAUTIONS ( 5.18 )] Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS ( 5.19 )] Anticholinergic (antimuscarinic) Effects [see WARNINGS AND PRECAUTIONS ( 5.20 ) ] 6.1 Clinical 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 consisting of over 4,300 patients. This database includes 698 patients exposed to quetiapine for the treatment of bipolar depression, 405 patients exposed to quetiapine for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to quetiapine 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 for the treatment of schizophrenia. Of these approximately 4,300 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 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 reactions, 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, an adverse reaction of the type listed. Adverse Reactions Associated with Discontinuation...

Drug Interactions

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) ( 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 in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine, 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 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 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 5-fold. Increased doses of quetiapine 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 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 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,...

Contraindications

4 CONTRAINDICATIONS Known hypersensitivity to quetiapine or any components in the formulation. ( 4 ) Hypersensitivity to quetiapine or to any excipients in the quetiapine tablets formulation. Anaphylactic reactions have been reported in patients treated with quetiapine tablets.

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine, 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) 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, 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...

8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of quetiapine (D2 antagonism), treatment with quetiapine may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [ see WARNINGS AND PRECAUTIONS ( 5.15 ) ].

Overdosage

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, 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 overdosage, contact a certified Regional Poison Control Center (1-800-222-1222).

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-6812 NDC: 50090-6812-0 30 TABLET in a BOTTLE NDC: 50090-6812-1 90 TABLET in a BOTTLE