SEROQUEL

Quetiapine is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives.

The chemical designation is 2-[2-(4-dibenzo [ b,f ]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 and it has a molecular weight of 883.11 (fumarate salt).

The structural formula is

Quetiapine fumarate USP is a white to off-white crystalline powder which is moderately soluble in water.

Quetiapine tablets, USP is supplied for oral administration as 25 mg (round peach), 50 mg (round, white), 100 mg (round yellow), 150 mg (round, off white to light yellow), 200 mg (round, white), 300 mg (capsule-shaped, white), and 400 mg (capsule-shaped, yellow) tablets.

Inactive ingredients are povidone, dibasic dicalcium phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol and titanium dioxide.

The 25 mg tablets contain red iron oxide and yellow iron oxide and the 100 mg, 150 mg and 400 mg tablets contain only yellow iron oxide.

Each 25 mg tablet contains 28.78 mg of quetiapine fumarate USP equivalent to 25 mg quetiapine.

Each 50 mg tablet contains 57.56 mg of quetiapine fumarate USP equivalent to 50 mg quetiapine.

Each 100 mg tablet contains 115.13 mg of quetiapine fumarate USP equivalent to 100 mg quetiapine.

Each 150 mg tablet contains 172.70 mg of quetiapine fumarate USP equivalent to 150 mg quetiapine.

Each 200 mg tablet contains 230.27 mg of quetiapine fumarate USP equivalent to 200 mg quetiapine.

Each 300 mg tablet contains 345.40 mg of quetiapine fumarate USP equivalent to 300 mg quetiapine.

Each 400 mg tablet contains 460.54 mg of quetiapine fumarate USP equivalent to 400 mg quetiapine.

& USAGE Quetiapine is an atypical antipsychotic indicated for the treatment of: Schizophrenia Bipolar I disorder manic episodes Bipolar disorder, depressive episodes 1.1 Schizophrenia Quetiapine is indicated for the treatment of schizophrenia.

The efficacy of quetiapine 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 for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials. 1.2 Bipolar Disorder Quetiapine 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) .

Quetiapine 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.

Quetiapine 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 as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials. 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.

The mechanism of action of quetiapine in the listed indications is unclear.

However, the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism.

The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D 2, but greater activity at 5HT2A receptors, than the parent drug (quetiapine). 12.2 Pharmacodynamics Quetiapine and its metabolite, norquetiapine, have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general.

The Ki values for quetiapine and norquetiapine at the dopamine D1 are 428/99.8 nM, at D2 626/489nM, at serotonin 5HT1A 1040/191 nM at 5HT2A 38/2.9 nM, at histamine H1 4.4/1.1 nM, at muscarinic M1 1086/38.3 nM, and at adrenergic α1b 14.6/46.4 nM and, at α2 receptors 617/1290 nM, respectively.

Quetiapine and norquetiapine lack appreciable affinity to the benzodiazepine receptors.

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, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval. 12.3 Pharmacokinetics Adults Quetiapine 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.

At steady-state the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults.

However, when adjusted for dose and weight, AUC and Cmax 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.

Quetiapine 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.

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.

Following a single oral dose of 14C-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.

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.

There is no gender effect on the pharmacokinetics of quetiapine.

There is no race effect on the pharmacokinetics of quetiapine.

Smoking has no effect on the oral clearance of quetiapine.

Patients with severe renal impairment (Clcr=10-30 mL/min/1.73 m2, n=8) had a 25% lower mean oral clearance than normal subjects (Clcr > 80 mL/min/1.73 m2, 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.

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 and Use in Specific Populations.

The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 17.

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 3A4 inhibitor) 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 enzyme inhibition data suggest that quetiapine and 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) .

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 Cmax and AUC of free valproic acid at steady.

• state was decreased by 10-12% Lithium Up to 2400 mg/day given in twice daily doses 250 mg three times daily No effect on steady-state pharmacokinetics of lithium Antipyrine 1 g, single dose 250 mg three times daily No effect on clearance of antipyrine or urinary recovery of its metabolites.

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.

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 4,000 (2,300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2,400 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 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 vs. 3% for placebo) in a pool of controlled trials.

However, discontinuations due to somnolence (0.8% quetiapine vs. 0% placebo) and hypotension (0.4% quetiapine vs. 0% placebo) were considered to be drug related.

Mania: Overall, discontinuations due to adverse reactions were 5.7% for quetiapine vs. 5.1% for placebo in monotherapy and 3.6% for quetiapine vs. 5.9% for placebo in adjunct therapy.

Overall, discontinuations due to adverse reactions were 12.3% for quetiapine 300 mg vs. 19.0% for quetiapine 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 monotherapy (incidence of 5% or greater) and observed at a rate on quetiapine 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 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 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 non-drug 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 (doses ranging from to 800 mg/day) where the incidence in patients treated with quetiapine was greater than the incidence in placebo-treated patients.

Table 9: Adverse Reaction Incidence in 3-to12-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 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 (doses ranging from to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with quetiapine 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 (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 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 (doses of and 600 mg/day) where the incidence in patients treated with quetiapine was greater than the incidence in placebo-treated patients.

Table 11: Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression 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% 1.

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 (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.

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, dyspnea, eosinophilia, urinary retention, intestinal obstruction and priapism.

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 t.

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.

One case, involving an estimated overdose of 9,600 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.

Hypersensitivity to quetiapine or to any excipients in the quetiapine formulation.

Anaphylactic reactions have been reported in patients treated with quetiapine.

Known hypersensitivity to quetiapine or any components in the formulation.

& ADMINISTRATION · Quetiapine tablets, USP can be taken with or without food Indication Initial Dose Recommended Dose Maximum Dose Schizophrenia-Adults 25 mg twice daily to 750 mg/day 750 mg/day Schizophrenia-Adolescents (13 to 17 years) 25 mg twice daily to 800 mg/day 800 mg/day Bipolar Mania.

• Adults Monotherapy or as an adjunct to lithium or divalproex 50 mg twice daily to 800 mg/day 800 mg/day Bipolar Mania.

• Children and Adolescents (10 to 17 years), Monotherapy 25 mg twice daily to 600 mg/day 600 mg/day Bipolar Depression-Adults 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 Hepatic Impairment: Lower starting dose (25 mg/day) and slower titration may be needed 2.1 Important Administration Instructions Quetiapine tablets, USP 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.

Table 1: Recommended Dosing for quetiapine Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia-Adults Day 1: 25 mg twice daily.

Increase in increments of 25 mg-50 mg divided two or three times on Days and 3 to range of to 400 mg by Day 4.

Further adjustments can be made in increments of 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 400-800 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. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400-600 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 400-800 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– Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. 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.

When indicated, dose escalation should be performed with caution in these patients.

Elderly patients should be started on quetiapine 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.

• 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 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 should be increased by 6-fold. 2.6 Dose Modifications when used with CYP3A4 Inducers Quetiapine dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (e.g., greater than 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.

CYP3A4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7-14 days. 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 for more than one.

• week, the initial dosing schedule should be followed.

When restarting patients who have been off quetiapine 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, 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 therapy in place of the next scheduled injection.

The need for continuing existing

EPS medication should be re-evaluated periodically.

Quetiapine tablets, USP 100 mg Yellow coloured, film coated, round shape, biconvex tablets, debossed with "261" on one side and plain on other side.

NDC 71335-1462-1: 100 Tablets in a BOTTLE NDC 71335-1462-2: 30 Tablets in a BOTTLE NDC 71335-1462-3: 120 Tablets in a BOTTLE NDC 71335-1462-4: 60 Tablets in a BOTTLE NDC 71335-1462-5: 90 Tablets in a BOTTLE NDC 71335-1462-6: 15 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine 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.

Neonates exposed to antipsychotic drugs ( including quetiapine tablet) during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

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.

There are risks to the mother associated with untreated schizophrenia, bipolar I, or major depressive disorder, and with exposure to antipsychotics, including, quetiapine tablet during pregnancy.

In animal studies, embryo-fetal toxicity occurred including delays in skeletal ossification at approximately and 2 times the maximum recommended human dose (MRHD) of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD.

In addition, fetal weights were decreased in both species.

Maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the MRHD in rats and approximately 1-2 times the MRHD in rabbits.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

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 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.

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.

When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses.

Doses were and 200 mg/kg in rats and and 100 mg/kg in rabbits which are approximately 0.3, 0.6 and 2-times (rats) and 0.6, 1 and 2-times (rabbits) the MRHD, for schizophrenia of 800 mg/day based on mg/m 2 body surface area.

However, there was evidence of embryo-fetal toxicity, including delays in skeletal ossification at approximately 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.

Maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the MRHD in rats and at approximately 1-2 times the MRHD (all doses tested) in rabbits.

In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day based on mg/m 2 body surface area.

However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD.

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

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 (4-7%) compared to children and adolescents (< 1%) .

The efficacy and safety of quetiapine in the treatment of schizophrenia in adolescents aged to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial.

Safety and effectiveness of quetiapine in pediatric patients less than 13 years of age with schizophrenia have not been established.

The safety and effectiveness of quetiapine 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 in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients.

The efficacy and safety of quetiapine in the treatment of mania in children and adolescents ages to 17 years with bipolar I disorder was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial.

Safety and effectiveness of quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established.

Bipolar Depression Safety and effectiveness of

Quetiapine in pediatric patients less than 18 years of age with bipolar depression have not been established.

A clinical trial with SEROQUEL

XR 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.

Of the approximately 3700 patients in clinical studies with quetiapine, 7% 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.