QUETIAPINE FUMARATE- quetiapine fumarate_tablet, film coated

The mechanism of action of quetiapine in the listed indications is unclear. However, the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D 2 2 2 2A Quetiapine and its metabolite, norquetiapine, have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general. The K i 1 2 1A 2A 1 1 1 2 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 ] Adults max max [see ] Table 17: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine Coadministered Drug Dose Schedules Effect on Quetiapine Pharmacokinetics Coadministered Drug Quetiapine Phenytoin 100 mg three times daily 250 mg three times daily 5-fold increase in oral clearance Divalproex 500 mg twice daily 150 mg twice daily 17% increase mean max plasma concentration at steady state. No effect on absorption or mean oral clearance Thioridazine 200 mg twice daily 300 mg twice daily 65% increase in oral clearance Cimetidine 400 mg three times daily for 4 days 150 mg three times daily 20% decrease in mean oral clearance Ketoconazole (potent CYP 200 mg once daily for 4 days 25 mg single dose 84% decrease in oral clearance resulting in a 6. 2-fold increase in AUC of quetiapine Fluoxetine 60 mg once daily 300 mg twice daily No change in steady state PK Imipramine 75 mg twice daily 300 mg twice daily No change in steady state PK Haloperidol 7. 5 mg twice daily 300 mg twice daily No change in steady state PK Risperidone 3 mg twice daily 300 mg twice daily No change in steady state PK In vitro in vivo [see ]. Table 18: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs Coadministered drug Dose schedules Effect on other drugs pharmacokinetics Coadministered drug Quetiapine Lorazepam 2 mg, single dose 250 mg three times daily Oral clearance of lorazepam reduced by 20% Divalproex 500 mg twice daily 150 mg twice daily C max Lithium Up to 2,400 mg/day given in twice daily 250 mg three times daily No effect on steady-state pharmacokinetics of lithium Antipyrine 1 g, single dose 250 mg three times daily No effect on clearance of antipyrine or urinary recovery of its metabolites.

Quetiapine tablets are an atypical antipsychotic indicated for the treatment of: 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) 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 ] 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.

Indication Initial Dose Recommended Dose Maximum Dose Schizophrenia - Adults 25 mg twice 150 to 750 mg/day 750 mg/day Schizophrenia - 25 mg twice 400 to 800 mg/day 800 mg/day Bipolar Mania - Adults 50 mg twice 400 to 800 mg/day 800 mg/day Bipolar Mania - Children and 25 mg twice 400 to 600 600 mg/day Bipolar Depression - Adults 50 mg once 300 mg/day 300 mg/day Geriatric Use: Hepatic Impairment: Quetiapine tablets can be taken with or without food. The recommended initial dose, titration, dose range and maximum quetiapine tablets 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 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. 150 to 750 mg/day 750 mg/day Schizophrenia - Day 1: 25 mg twice daily. 400 to 800 mg/day 800 mg/day Schizophrenia - Not applicable. 400 to 800 mg/day 800 mg/day Bipolar Mania - Adults Day 1: Twice daily dosing totaling 100 mg. 400 to 800 mg/day 800 mg/day Bipolar Mania - Children and Adolescents (10 to 17 Day 1: 25 mg twice daily. 400 to 600 mg/day 600 mg/day Bipolar Depression - Administer once daily at bedtime. 300 mg/day 300 mg/day Bipolar I Disorder 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 Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment - [see ]. 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 ]. 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. Quetiapine tablets dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e. , ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc. When the CYP3A4 inhibitor is discontinued, the dose of quetiapine tablets should be increased by 6-fold [see ] Quetiapine tablets dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (e. , greater than 7 to 14 days) of a potent CYP3A4 inducer (e. , phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc. The dose should be titrated based on the clinical response and tolerability of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine tablets should be reduced to the original level within 7 to 14 days [see ] 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 tablets for more than one-week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine tablets for less than one-week, gradual dose escalation may not be required and the maintenance dose may be re-initiated. There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine tablets, 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 tablets therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.

The following adverse reactions are discussed in more detail in other sections of the labeling: [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] [see ] Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1(844) 874-7464 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 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: [see ] Bipolar Disorder: Mania: Depression: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: Adverse Reactions Occurring at an Incidence of 2% or More Among Quetiapine Treated Patients in Short-Term, Placebo-Controlled Trials: 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 (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 (incidence of 5% or greater) and observed at a rate on quetiapine 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: Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy) Preferred Term Quetiapine (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% Hormone Level 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 adverse reactions associated with the use of quetiapine (incidence of 5% or greater) and observed at a rate on quetiapine at least twice that of placebo were somnolence (57%), dry mouth (44%), dizziness (18%), constipation (10%), and lethargy (5%). Table 11: Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression 1. Preferred Term Quetiapine (n=698) PLACEBO (n=347) Somnolence 1 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% 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-related Adverse Reactions: Extrapyramidal Symptoms (EPS): Dystonia Class Effect: Adults: 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 75 mg/day (N=53) Quetiapine 150 mg/day (N=48) Quetiapine 300 mg/day (N=52) Quetiapine 600 mg/day (N=51) Quetiapine 750 mg/day (N=54) Placebo (N=51) n % n % n % n % n % n % Dystonic event 2 3. 8 Parkinsonism 2 3. 8 Akathisia 1 1. 1 0 0 0 0 1 1. 8 Dyskinetic event 2 3. 8 0 0 0 0 1 2 0 0 0 0 Other extrapyramidal event 2 3. 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. The rate of anticholinergic medication use to treat EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12%, and 11%. Children and Adolescents. Adverse Reactions Occurring at an Incidence of >= 2% among Quetiapine Treated Patients in Short-Term, Placebo-Controlled Trials Schizophrenia (Adolescents, 13 to 17 years old) Table 13: Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients 1. Somnolence combines adverse reaction terms somnolence and sedation. Preferred Term Quetiapine 400 mg (n=73) Quetiapine 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% Bipolar I Mania (Children and Adolescents 10 to 17 years old) Table 14: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients 1. Somnolence combines adverse reactions terms somnolence and sedation. Preferred Term Quetiapine 400 mg (n=95) Quetiapine 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% Paresthesia 2% 0% 0% Sinus Congestion 3% 0% 0% Thirst 2% 0% 0% Extrapyramidal Symptoms: Table 15: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-Controlled Trial in Adolescent Patients with Schizophrenia (6-week duration) Preferred Term Quetiapine 400 mg/day (N=73) Quetiapine 800 mg/day (N=74) All Quetiapine (N=147) Placebo (N=75) n % n % n % n % Dystonic event 2 2. 4 0 0 Parkinsonism 4 5. 7 Akathisia 3 4. 8 3 4 Dyskinetic event 2 2. 4 0 0 Other Extrapyramidal Event 2 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 Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration) 1. There were no adverse reactions with the preferred term of dystonic or dyskinetic events. Preferred Term 1 Quetiapine 400 mg/day (N=95) Quetiapine 600 mg/day (N=98) All Quetiapine (N=193) Placebo (N=90) n % n % n % n % Parkinsonism 2 2. 1 Akathisia 1 1 1 1 2 1 0 0 Other Extrapyramidal Event 1 1. 1 1 1 2 1 0 0 Laboratory, ECG, and vital sign changes observed in clinical studies Adults: 9 [see ] Transaminase Elevations Adults: Adults: Adults: [see ] The following adverse reactions were identified during post approval of quetiapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), decreased platelet count, serious liver reactions (including hepatitis, liver necrosis, and hepatic failure), agranulocytosis, intestinal obstruction, ileus, colon ischemia, urinary retention, sleep apnea, acute generalized exanthematous pustulosis (AGEP), confusional state and cutaneous vasculitis.

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

Pregnancy: Pregnancy Exposure Registry http://womensmentalhealth. org/clinical-and-research-programs/pregnancyregistry/ Risk Summary (see Clinical Considerations). (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. 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, during the third trimester of pregnancy. These symptoms varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk of major birth defects. Animal Data When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses. Doses were 25, 50 and 200 mg/kg in rats and 25, 50 and 100 mg/kg in rabbits which are approximately 0. 6 and 2-times (rats) and 0. 6, 1 and 2-times (rabbits) the MRHD for schizophrenia of 800 mg/day based on mg/m 2 In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0. 2 times the MRHD of 800 mg/day based on mg/m 2 Risk Summary Limited data from published literature report the presence of quetiapine in human breast milk at relative infant dose of <1% of the maternal weight-adjusted dosage. There are no consistent adverse events that have been reported in infants exposed to quetiapine through breast milk. There is no information on the effects of quetiapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for quetiapine and any potential adverse effects on the breastfed child from quetiapine or from the mother’s underlying condition. 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 ]. 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 Clinical Studies (14. 1) ] Of the approximately 3,700 patients in clinical studies with quetiapine, 7% (232) were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [see ] Clinical experience with quetiapine in patients with renal impairment is limited [see ] 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 ].

Concomitant use of strong CYP3A4 inhibitors: Concomitant use of strong CYP3A4 inducers: Discontinuation of strong CYP3A4 inducers: 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. Because of its potential for inducing hypotension, quetiapine may enhance the effects of certain antihypertensive agents.

OVERDOSAGE
In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported 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. , 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 ] 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0. 5 times the MRHD of 800 mg/day based on mg/m 2 2 2 2 2 Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown. Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see ] Mutagenesis Quetiapine was not mutagenic or clastogenic in standard genotoxicity tests. The mutagenic potential of quetiapine was tested in the in vitro in vitro in vitro in vivo 2 Impairment of Fertility Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the MRHD of 800 mg/day based on mg/m 2 2 2 2 2 Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10, 25, 50, 75, 150 and 250 mg/kg in rat studies which are approximately 0. 6, 1, 2 and 3-times the MRHD of 800 mg/day based on mg/m 2 2 In dogs receiving quetiapine for 6 or 12 months, but not for 1-month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day based on mg/m 2 2.
CLINICAL STUDIES
Short-term Trials-Adults 1. In a 6-week, placebo-controlled trial (n=361) (Study 1) involving 5 fixed doses of quetiapine (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 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. The primary efficacy results of these three studies in the treatment of schizophrenia in adults is presented in Table 19. Adolescents (ages 13 to 17) Table 19: Schizophrenia Short-Term Trials SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Study Number Treatment Group Primary Efficacy Endpoint: BPRS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference 1 (95% CI) Study 1 Quetiapine 45. 2 (2) -4 (-11. 3) Quetiapine 2 47. 8, -3) Quetiapine 2 45. 6, -3) Quetiapine 2 43. 1) Quetiapine 2 45. 3 (2) -8 (-15. 8) Placebo 45. 1) -- Study 2 Quetiapine 38. 2) Quetiapine 2 41 (9. 4) Placebo 38. 6) -- Study 3 Quetiapine 42. 4) Quetiapine 3 42. 4, 0) Quetiapine 41. 3) -- Primary Efficacy Endpoint: PANSS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference 1 (95% CI) Study 4 Quetiapine 2 96. 3) Quetiapine 2 96. 4) Placebo 96. 2 (3) -- Bipolar I disorder, manic or mixed episodes Monotherapy Adjunct Therapy Table 20: Mania Trials Mood stabilizer: lithium or divalproex; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. 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 1,3 34 (6. 3) -4 (-7, -1) Haloperidol 1,3 32. 4) Placebo 33. 3) -- Study 2 Quetiapine 1 32. 9, -5) Lithium 1,3 33. 5) Placebo 34 (6. 6) -- Study 3 Quetiapine 1 31. 6) Placebo + mood stabilizer 31. 5) -- Study 4 Quetiapine 1 29. 3) Quetiapine 1 29. 7) Placebo 30. 1) -- Bipolar Disorder, Depressive Episodes Table 21: Depressive Episodes Associated with Bipolar Disorder SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Study Number Treatment Group Primary Efficacy Measure: MADRS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference 2 (95% CI) Study 5 Quetiapine 1 30. 9) Quetiapine 1 30. 3) Placebo 30. 9) -- Study 6 Quetiapine 1 31. 9 (1) -5 (-7. 7) Quetiapine 1 29. 6) -16 (1) -4. 8) Placebo 29. 9 (1) -- Maintenance Treatment as an Adjunct to Lithium or Divalproex Figure1 Figure2.
Medication Guide
Quetiapine Tablets, USP (kwe tye'' a peen) What is the most important information I should know about quetiapine tablets? Quetiapine tablets may cause serious side effects, including: 1. risk of death in the elderly with dementia. Medicines like quetiapine tablets can increase the risk of death in elderly people who have memory loss (dementia). 2. risk of suicidal thoughts or actions (antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions). 3. Talk to your or your family member’s healthcare provider about: o o 4. Antidepressant medications may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 5. 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. 6. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? o o o 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: What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to your healthcare provider. Antidepressants are medicines used to treat depression and other illnesses. Antidepressant medicines have other side effects. Antidepressant medicines can interact with other medicines. Not all antidepressant medicines prescribed for children are FDA approved for use in children. What are quetiapine tablets? o o o It is not known if quetiapine tablets are safe and effective in children under 10 years of age. What should I tell my healthcare provider before taking quetiapine tablets? Before you take quetiapine tablets, tell your healthcare provider if you have or have had: Tell the healthcare provider about all the medicines that you take or recently have taken How should I take quetiapine tablets? If you feel you need to stop quetiapine tablets, talk with your healthcare provider first. What should I avoid while taking quetiapine tablets? o o o o What are possible side effects of quetiapine tablets? Quetiapine tablets can cause serious side effects, including: See “What is the most important information I should know about quetiapine tablets?” stroke that can lead to death can happen in elderly people with dementia who take medicines like quetiapine tablets neuroleptic malignant syndrome (NMS). o o o o o falls high blood sugar (hyperglycemia). o o o Increases in blood sugar can happen in some people who take quetiapine tablets. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start quetiapine tablets and during therapy. Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking quetiapine tablets: feel very thirsty need to urinate more than usual feel very hungry feel weak or tired feel sick to your stomach feel confused, or your breath smells fruity high fat levels in your blood (increased cholesterol and triglycerides). increase in weight (weight gain). movements you cannot control in your face, tongue, or other body parts (tardive dyskinesia). decreased blood pressure (orthostatic hypotension) increases in blood pressure in children and teenagers. low white blood cell count. cataracts seizures abnormal thyroid tests. increases in 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 tablets. The most common side effects of quetiapine tablets include: In Adults: In Children and Adolescents: These are not all the possible side effects of quetiapine tablets. For more information, ask your healthcare provider or pharmacist. How should I store quetiapine tablets? Keep quetiapine tablets and all medicines out of the reach of children. General information about the safe and effective use of quetiapine tablets. What are the ingredients in quetiapine tablets? Active ingredient: Inactive ingredients: This Medication Guide has been approved by the U.S. Food and Drug Administration. Dispense with Medication Guide available at: http://www.risingpharma.com/med-guides.html Distributed by: Made in India Repackaged By: Preferred Pharmaceuticals Inc.

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