Quetiapine fumarate

Quetiapine fumarate extended-release tablet is indicated for the treatment of schizophrenia. The efficacy of quetiapine fumarate extended-release tablet in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13 to 17 years) treated with quetiapine fumarate tablet [see CLINICAL STUDIES ( 14.1)] .

Quetiapine fumarate extended-release tablet is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of quetiapine fumarate extended-release tablet in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 to 17 years) with manic episodes associated with bipolar I disorder treated with quetiapine fumarate tablet [see CLINICAL STUDIES ( 14.2)] .

Quetiapine fumarate extended-release tablet is indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of quetiapine fumarate extended-release tablet was established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with quetiapine fumarate tablet [see CLINICAL STUDIES ( 14.2)].

Quetiapine fumarate extended-release tablet is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with quetiapine fumarate tablet. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials [see CLINICAL STUDIES ( 14.2)].

Quetiapine fumarate extended-release tablet is indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of quetiapine fumarate extended-release tablet as adjunctive therapy to antidepressants in MDD was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant treatment [see CLINICAL STUDIES ( 14.3)] .

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.

Quetiapine fumarate extended-release tablets should be swallowed whole and not split, chewed or crushed.

It is recommended that quetiapine fumarate extended-release tablet be taken without food or with a light meal (approximately 300 calories) [see CLINICAL PHARMACOLOGY ( 12.3)].

Quetiapine fumarate extended-release tablet should be administered once daily, preferably in the evening.

The recommended initial dose, titration, dose range and maximum quetiapine fumarate extended-release tablet dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see CLINICAL STUDIES ( 14.1, 14.2 and 14.3)].

Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see USE IN SPECIFIC POPULATIONS ( 8.5, 8.7) and CLINICAL PHARMACOLOGY ( 12.3)]. When indicated, dose escalation should be performed with caution in these patients.

Elderly patients should be started on quetiapine fumarate extended-release tablet 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.

Patients with hepatic impairment should be started on quetiapine fumarate extended-release tablet 50 mg/day. The dose can be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

Quetiapine fumarate extended-release tablet dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g. ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of quetiapine fumarate extended-release tablet should be increased by 6 fold [see CLINICAL PHARMACOLOGY ( 12.3) and DRUG INTERACTIONS 7.1)].

Quetiapine fumarate extended-release tablet dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7 to 14 days) of a potent CYP3A4 inducer (e.g. phenytoin, carbamazepine, rifampin, avasimibe, St. John's wort etc.). The dose should be titrated based on the clinical response and tolerance of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate extended-release tablet should be reduced to the original level within 7 to 14 days [see CLINICAL PHARMACOLOGY ( 12.3) and DRUG INTERACTIONS ( 7.1)].

Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off quetiapine fumarate extended-release tablet for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine fumarate extended-release tablet for less than one week, gradual dose escalation may not be required and the maintenance dose may be re-initiated.

Patients who are currently being treated with quetiapine fumarate tablets (immediate release formulation) may be switched to quetiapine fumarate extended-release tablet at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

There are no systematically collected data to specifically address switching patients from other antipsychotics to quetiapine fumarate extended-release tablet, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate extended-release tablet therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.

• 50 mg extended-release tablets are peach to red colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K71" on the other side.

150 mg extended-release tablets are white colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K72" on the other side.

200 mg extended-release tablets are yellow colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K73" on the other side.

300 mg extended-release tablets are pale yellow colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K74" on the other side.

400 mg extended-release tablets are white colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K75" on the other side.

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

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Quetiapine fumarate extended-release tablet is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Quetiapine fumarate extended-release tablet is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS ( 5.1)].

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, quetiapine fumarate extended-release tablet should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine fumarate extended-release tablet, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.

Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 0.3% (5/1866) of the patients treated with quetiapine fumarate extended-release tablet across all indications, compared with 0.2% (2/928) on placebo. Syncope was reported in 1% (28/3265) of the patients treated with quetiapine fumarate tablet, compared with 0.2% (2/954) on placebo. Orthostatic hypotension, dizziness, and syncope may lead to falls.

Quetiapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

Atypical antipsychotic drugs, including quetiapine fumarate extended-release tablet, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Safety and effectiveness of quetiapine fumarate extended-release tablet is supported by studies of quetiapine fumarate tablet in children and adolescent patients 10 to 17 years of age [see CLINICAL STUDIES ( 14.1 and 14.2)].

In a placebo-controlled quetiapine fumarate extended-release tablet clinical trial (8 weeks duration) in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for quetiapine fumarate extended-release tablet and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for quetiapine fumarate extended-release tablet and 36.0% (36/100) for placebo.

In placebo-controlled trials in children and adolescents with schizophrenia (13 to 17 years old, 6-week duration) or bipolar mania (10 to 17 years old, 3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine fumarate tablet and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for quetiapine fumarate tablet and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate. Agranulocytosis has also been reported.In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate. Agranulocytosis has also been reported.

Agranulocytosis has been reported with quetiapine, including fatal cases and cases in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate.

Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine fumarate extended-release tablet at the first sign of a decline in WBC in absence of other causative factors.Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine fumarate extended-release tablet at the first sign of a decline in WBC in absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm ) should discontinue quetiapine fumarate extended-release tablet and have their WBC followed until recovery. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm ³) should discontinue quetiapine fumarate extended-release tablet and have their WBC followed until recovery.

The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see NONCLINICAL TOXICOLOGY ( 13.2)] . Lens changes have also been observed in adults, children, and adolescents during long-term quetiapine treatment but a causal relationship to quetiapine use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.

In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine [see OVERDOSAGE ( 10.1)] , in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g. cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).

During short-term clinical trials with quetiapine fumarate extended-release tablet, seizures occurred in 0.05% (1/1866) of patients treated with quetiapine fumarate extended-release tablet across all indications compared to 0.3% (3/928) on placebo. During clinical trials with quetiapine fumarate tablet, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine fumarate tablet compared to 0.2% (2/954) on placebo. As with other antipsychotics, quetiapine fumarate should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Adults

Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T ₄) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T ₄, irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient's thyroid status. Therefore, both TSH and free T ₄, in addition to clinical assessment, should be measured at baseline and at follow-up.

In quetiapine fumarate extended-release tablet clinical trials across all indications 1.8% (24/1336) of patients on quetiapine fumarate extended-release tablet versus 0.6% (3/530) on placebo experienced decreased free thyroxine (<0.8 LLN) and 1.6% (21/1346) on quetiapine fumarate extended-release tablet versus 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone (TSH). About 0.7% (26/3489) of quetiapine fumarate tablet patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment.

In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were ¹: decrease in free T ₄ (<0.8 LLN), 2.0% (357/17513); decrease in total T ₄ (<0.8 LLN), 4.0% (75/1861); decrease in free T ₃ (<0.8 LLN), 0.4% (53/13766); decrease in total T ₃ (<0.8 LLN), 2.0% (26/1312), and increase in TSH (>5 mIU/L), 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged.

¹Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T ₄, free T ₄, total T ₃ and free T ₃ are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.

Table 11 shows the incidence of these shifts in short term placebo-controlled clinical trials.

In short-term placebo-controlled monotherapy trials, the incidence of reciprocal shifts in T ₃ and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T ₄ and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0 % (1/3007) for placebo.

Children and Adolescents 

Safety and effectiveness of quetiapine fumarate extended-release tablet is supported by studies of quetiapine fumarate tablet in children and adolescent patients 10 to 17 years of age [see CLINICAL STUDIES ( 14.1 and 14.2)] .

In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts at any time for quetiapine fumarate tablet treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145), respectively. Of the quetiapine fumarate tablet treated patients with elevated TSH levels, 1 had simultaneous low free T ₄ level at end of treatment.

Adults

During clinical trials with quetiapine across all indications, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.

Children and Adolescents

Safety and effectiveness of quetiapine fumarate extended-release tablet is supported by studies of quetiapine fumarate tablet in children and adolescent patients 10 to 17 years of age [see CLINICAL STUDIES ( 14.1 and 14.2)]. In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 µg/L males; > 26 µg/L females at any time) was 13.4% (18/134) for quetiapine fumarate tablet compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine fumarate tablet compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D ₂ receptors, quetiapine fumarate extended-release tablet elevates prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [see NONCLINICAL TOXICOLOGY ( 13.1)].

Somnolence was a commonly reported adverse reaction reported in patients treated with quetiapine especially during the 3-day period of initial dose titration. In schizophrenia trials, somnolence was reported in 24.7% (235/951) of patients on quetiapine fumarate extended-release tablet compared to 10.3% (33/319) of placebo patients. In a bipolar depression clinical trial, somnolence was reported in 51.8% (71/137) of patients on quetiapine fumarate extended-release tablet compared to 12.9% (18/140) of placebo patients. In a clinical trial for bipolar mania, somnolence was reported in 50.3% (76/151) of patients on quetiapine fumarate extended-release tablet compared to 11.9% (19/160) of placebo patients. Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine therapy does not affect them adversely. Somnolence may lead to falls.

In short-term adjunctive therapy trials for MDD, somnolence was reported in 40% (252/627) of patients on quetiapine fumarate extended-release tablet respectively compared to 9% (27/309) of placebo patients. Somnolence was dose-related in these trials (37% (117/315) and 43% (135/312) for the 150 mg and 300 mg groups, respectively).

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine fumarate extended-release tablet for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Quetiapine fumarate extended-release tablet and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Acute withdrawal symptoms, such as insomnia, nausea and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine fumarate. In short-term placebo-controlled, monotherapy clinical trials with quetiapine fumarate extended-release tablet that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine fumarate extended-release tablet and 6.7% (71/1065) for placebo. The incidence of the individual adverse reactions (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation. Gradual dose reduction is advised.

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when quetiapine fumarate extended-release tablet is used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. Quetiapine fumarate extended-release tablet should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects and . Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when quetiapine fumarate extended-release tablet is used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. Quetiapine fumarate extended-release tablet should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see OVERDOSAGE ( 10.1 ) and CLINICAL PHARMACOLOGY ( 12.1 )].

Constipation was a commonly reported adverse event in patients treated with quetiapine and represents a risk factor for intestinal obstruction. Intestinal obstruction has been reported with quetiapine, including fatal reports in patients who were receiving multiple concomitant medications that decrease intestinal motility.

Quetiapine fumarate extended-release tablet should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, or constipation, or increased intraocular pressure.Quetiapine fumarate extended-release tablet should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, or constipation, or increased intraocular pressure.

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) ]

The following adverse reactions were identified during post approval use of quetiapine fumarate tablet. 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, sleep apnea, and urinary retention.

The risks of using quetiapine fumarate extended-release tablet in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine fumarate extended-release tablet, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine.

Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). and decreased by the prototype of CYP3A4 inducers (e.g, phenytoin, carbamazepine, rifampin, avasimibe, St. John's wort etc.) Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors.

CYP3A4 inhibitors

Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure. The dose should be reduced to one sixth of the original dose in patients coadministered with a strong CYP3A4 inhibitor [see DOSAGE AND ADMINISTRATION ( 2.5) and CLINICAL PHARMACOLOGY ( 12.3)].

CYP3A4 inducers

Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine fumarate extended-release tablet up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent CYP3A4 inducers [see DOSAGE AND ADMINISTRATION ( 2.6) and CLINICAL PHARMACOLOGY ( 12.3)]. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate extended-release tablet should be reduced to the original level within 7 to 14 days [see DOSAGE AND ADMINISTRATION ( 2.6)].

The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied.

Because of its potential for inducing hypotension, quetiapine fumarate extended-release tablet may enhance the effects of certain antihypertensive agents.

Quetiapine fumarate extended-release tablet may antagonize the effects of levodopa and dopamine agonists.

There are no clinically relevant pharmacokinetic interactions of quetiapine fumarate tablet on other drugs based on the CYP pathway. Quetiapine fumarate tablet and its metabolites are non-inhibitors of major metabolizing CYP's (1A2, 2C9, 2C19, 2D6 and 3A4).

Pregnancy Category C

Risk Summary:

There are no adequate and well-controlled studies of quetiapine fumarate extended-release tablet use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine fumarate extended-release tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human Data:

There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including quetiapine fumarate extended-release tablet), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Animal Data:

When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses at doses up to 2.4 times the maximum recommended human dose (MRHD), for schizophrenia of 800 mg/day based on mg/m ² body surface area. However, there was evidence of embryo-fetal toxicity. These included delays in skeletal ossification occurred at approximately 1 and 2 times the MRHD of 800 mg/day and 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 at approximately 1-2 times the MRHD (all doses) 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 on mg/m ²body 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.

The effect of quetiapine fumarate extended-release tablet on labor and delivery in humans is unknown.

Quetiapine fumarate extended-release tablet was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from quetiapine fumarate extended-release tablet, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother's health.

In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 mcg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).

Safety and effectiveness of quetiapine fumarate extended-release tablet is supported by studies of quetiapine fumarate tablet for schizophrenia in adolescent patients 13 to 17 years of age and in bipolar mania in children and adolescent patients 10 to 17 years of age [see CLINICAL STUDIES ( 14.1 and 14.2)].

In general, the adverse reactions observed in children and adolescents during the clinical trials with quetiapine fumarate tablet were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%) [see WARNINGS AND PRECAUTIONS ( 5.7) and ADVERSE REACTIONS ( 6.1)].

Bipolar Depression

The effectiveness of quetiapine fumarate extended-release tablet for the treatment of bipolar depression in patients under the age of 18 years has not been established. One 8-week trial was conducted to evaluate the safety and efficacy of quetiapine fumarate extended-release tablet in the treatment of bipolar depression in pediatric patients 10 to 17 years of age. The primary objective of the study was to evaluate whether quetiapine extended-release tablet at a dose of 150 to 300 mg/day demonstrated superior efficacy (as measured by change in CDRS-R total score from baseline to end of 8 weeks) compared to placebo in children and adolescents 10 to 17 years of age with bipolar depression. A total of 193 patients with bipolar depression were randomized to placebo or quetiapine fumarate extended-release tablet. The primary results of this study did not show a difference between quetiapine fumarate extended-release tablet and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder. In this study, patients treated with quetiapine fumarate extended-release tablet exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate [see WARNINGS AND PRECAUTIONS ( 5.5, 5.9) and ADVERSE REACTIONS ( 6.1)].

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 C _max of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight [see CLINICAL PHARMACOLOGY ( 12.3)].

Schizophrenia

The efficacy and safety of quetiapine fumarate extended-release tablet in the treatment of schizophrenia in adolescents aged 13 to 17 years is supported by one 6-week, double-blind, placebo-controlled trial with quetiapine fumarate tablet [see INDICATIONS AND USAGE ( 1.1), DOSAGE AND ADMINISTRATION ( 2.2), ADVERSE REACTIONS ( 6.1), and CLINICAL STUDIES ( 14.1)].

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

The safety and effectiveness of quetiapine fumarate extended-release tablet in the maintenance treatment of schizophrenia has not been established in patients less than 18 years of age.

Bipolar Mania

The efficacy and safety of quetiapine fumarate extended-release tablet in the treatment of bipolar mania in children and adolescents ages 10 to 17 years is supported by one 3-week, double-blind, placebo controlled trial with quetiapine fumarate tablet [see INDICATIONS AND USAGE ( 1.2), DOSAGE AND ADMINISTRATION ( 2.2), ADVERSE REACTIONS ( 6.1), and CLINICAL STUDIES ( 14.2)].

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

The safety and effectiveness of quetiapine fumarate extended-release tablet in the maintenance treatment of bipolar disorder has not been established in patients less than 18 years of age.

Sixty-eight patients in clinical studies with quetiapine fumarate extended-release tablet were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate extended-release tablet in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine fumarate extended-release tablet, 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 DOSAGE AND ADMINISTRATION ( 2.3) and CLINICAL PHARMACOLOGY ( 12.3)].

Clinical experience with quetiapine fumarate extended-release tablet in patients with renal impairment is limited [see CLINICAL PHARMACOLOGY ( 12.3)].

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 50 mg/day is recommended and the dose may be increased in increments of 50 mg/day [see DOSAGE AND ADMINISTRATION ( 2.4) and CLINICAL PHARMACOLOGY ( 12.3)].

Quetiapine fumarate is not a controlled substance.

Quetiapine fumarate extended-release tablet has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine fumarate extended-release tablet (e.g., development of tolerance, increases in dose, drug-seeking behavior).

In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and anticholinergic toxicity including coma and delirium. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose [see WARNINGS AND PRECAUTIONS ( 5.12)]. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there were cases reported of QT prolongation with overdose.

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

Quetiapine fumarate is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [ b,f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C ₄₂H ₅₀N ₆O ₄S ₂ ^.C ₄H ₄O ₄ and it has a molecular weight of 883.11 (fumarate salt). The structural formula is:

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

Quetiapine fumarate extended-release tablets are supplied for oral administration as 50 mg (peach to red), 150 mg (white), 200 mg (yellow), 300 mg (yellow to pale yellow), and 400 mg (white). All tablets are capsule shaped and film coated.

Inactive ingredients for quetiapine fumarate extended-release tablets are hypromellose, hypromellose 2208, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate dihydrate. The film coating for all quetiapine fumarate extended-release tablets contain hypromellose 2910, macrogol and titanium dioxide. In addition, red iron oxide (for 50 mg) and yellow iron oxide (for 50 mg, 200 mg and 300 mg) are included in the film coating of specific strengths.

Each 50 mg tablet contains 58 mg of quetiapine fumarate equivalent to 50 mg quetiapine. Each 150 mg tablet contains 173 mg of quetiapine fumarate equivalent to 150 mg quetiapine. Each 200 mg tablet contains 230 mg of quetiapine fumarate equivalent to 200 mg quetiapine. Each 300 mg tablet contains 345 mg of quetiapine fumarate equivalent to 300 mg quetiapine. Each 400 mg tablet contains 461 mg of quetiapine fumarate equivalent to 400 mg quetiapine.

USP Dissolution Test Pending.

The mechanism of action of quetiapine fumarate extended-release tablet in the treatment of schizophrenia, bipolar disorder and major depressive disorder (MDD), is unknown. However, its efficacy in schizophrenia could be mediated through a combination of dopamine type 2 (D ₂) and serotonin type 2A (5HT _2A) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D ₂, but greater activity at 5HT _2A receptors, than the parent drug (quetiapine). Quetiapine's efficacy in bipolar depression and MDD may partly be explained by the high affinity and potent inhibitory effects that norquetiapine exhibits for the norepinephrine transporter.

Antagonism at receptors other than dopamine and serotonin with similar or greater affinities may explain some of the other effects of quetiapine and norquetiapine: antagonism at histamine H ₁ receptors may explain the somnolence, antagonism at adrenergic α ₁b receptors may explain the orthostatic hypotension, and antagonism at muscarinic M ₁ receptors may explain the anticholinergic effects.

Quetiapine and norquetiapine have affinity for multiple neurotransmitter receptors including dopamine D ₁ and D ₂, serotonin 5HT _1A and 5HT _2A, histamine H ₁, muscarinic M ₁, and adrenergic α ₁b and α ₂ receptors. Quetiapine differs from norquetiapine in having no appreciable affinity for muscarinic M ₁ receptors whereas norquetiapine has high affinity. Quetiapine and norquetiapine lack appreciable affinity for benzodiazepine receptors.

Carcinogenesis

Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose (MRHD) of 800 mg/day based on mg/m ² body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m ² body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD on mg/m ² body surface area and in male rats at a dose of 3 times the MRHD on mg/m ² body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD on mg/m ²body surface area).

Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown.

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see WARNINGS AND PRECAUTIONS ( 5.15)].

Mutagenesis

The mutagenic potential of quetiapine was tested in the in vitro Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose on mg/m ² body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests.

Impairment of Fertility

Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day on mg/m ² body surface area. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the MRHD dose on mg/m ² body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day on mg/m ² body surface area. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or approximately 0.1 and 1 times the MRHD of 800 mg/day on mg/m ²body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day on mg/m ² body surface area.

Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10 to 250 mg/kg in rats and 75 to 750 mg/kg in mice; these doses are 0.1 to 3, and 0.1 to 4.5 times the maximum recommended human dose (MRHD) of 800 mg/day on mg/m ² body surface area, respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.

In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day on mg/m ² body surface area. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta 8 cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the MRHD of 800 mg/day on mg/m ²body surface area.

Short-term Trials - Adults

The efficacy of quetiapine fumarate extended-release tablet in the treatment of schizophrenia was demonstrated in 1 short-term, 6-week, fixed-dose, placebo-controlled trial of inpatients and outpatients with schizophrenia (n=573) who met DSM IV criteria for schizophrenia. Quetiapine fumarate extended-release tablet (once daily) was administered as 300 mg on Day 1, and the dose was increased to either 400 mg or 600 mg by Day 2, or 800 mg by Day 3. The primary endpoint was the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment (Day 42). Quetiapine fumarate extended-release tablet doses of 400 mg, 600 mg and 800 mg once daily were superior to placebo in the PANSS total score at Day 42 (study 1 in Table 27

Short-term Trials -Adolescents (ages 13 to 17)

The efficacy of quetiapine fumarate extended-release tablet in the treatment of schizophrenia in adolescents (13 to 17 years of age) was supported by a 6-week, double-blind, placebo-controlled trial. Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: quetiapine fumarate tablet 400 mg/day (n = 73), quetiapine fumarate tablet 800 mg/day (n = 74), or placebo (n = 75). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and given two or three times per day). Subsequently, the dose was titrated to the target dose of 400 mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times daily. The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS). Quetiapine fumarate tablet at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score (study 2 in Table 27).

Maintenance Trials

In a longer-term trial (study 3), clinically stable adult outpatients (n=171) meeting DSM-IV criteria for schizophrenia who remained stable following 16 weeks of open-label treatment with flexible doses of quetiapine fumarate extended-release tablet (400 mg/day-800 mg/day) were randomized to placebo or to continue on their current quetiapine fumarate extended-release tablet (400 mg/day - 800 mg/day) for observation for possible relapse during the double-blind continuation (maintenance) phase. Stabilization during the open-label phase was defined as receiving a stable dose of quetiapine fumarate extended-release tablet and having a CGI-S≤4 and a PANSS score ≤60 from beginning to end of this open-label phase (with no increase of ≥10 points in PANSS total score). Relapse during the double-blind phase was defined in terms of a ≥30% increase in the PANSS Total score, or CGI-Improvement score of ≥6, or hospitalization due to worsening of schizophrenia, or need for any other antipsychotic medication. Patients on quetiapine fumarate extended-release tablet experienced a statistically significant longer time to relapse than did patients on placebo (Figure 1).

Bipolar I Disorder, manic or mixed episodes

Adults

The efficacy of quetiapine fumarate extended-release tablet in the acute treatment of manic episodes was established in one 3-week, placebo-controlled trial (Study 1 in Table 28) in patients who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features (N=316). Patients were hospitalized for a minimum of 4 days at randomization. Patients randomized to quetiapine fumarate extended-release tablet received 300 mg on Day 1 and 600 mg on Day 2. Afterwards, the dose could be adjusted between 400 mg and 800 mg per day.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptoms in a range from 0 (no manic features) to 60 (maximum score). Quetiapine fumarate extended-release tablet was superior to placebo in the reduction of the YMRS total score at week 3.

The efficacy of quetiapine fumarate tablet in the treatment of acute manic episodes was also established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the YMRS score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of quetiapine fumarate tablet with lithium or divalproex.

The results of the trials follow:

Monotherapy

In two 12-week trials (n=300, n=299) comparing quetiapine fumarate tablet to placebo, quetiapine fumarate tablet was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking quetiapine tablet were dosed in a range between 400 mg/day and 800 mg/ day (Studies 2 and 3 in Table 28).

Adjunct Therapy

In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥ 20) were randomized to receive quetiapine fumarate tablet or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. Quetiapine fumarate tablet was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking quetiapine tablet were dosed in a range between 400 mg/day and 800 mg/day (study 4 in Table 28).

Children and Adolescents (ages 10 to 17)

The efficacy of quetiapine fumarate extended-release tablet in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was extrapolated from a 3-week, double-blind, placebo-controlled, multicenter trial. Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: quetiapine fumarate tablet 400 mg/day (n = 95), quetiapine fumarate tablet 600 mg/day (n = 98), or placebo (n = 91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily). Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy variable was the mean change from baseline in total YMRS score. Quetiapine fumarate tablet 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (study 5 in Table 28).

Bipolar Disorder, Depressive Episodes

Adults:

The efficacy of quetiapine fumarate extended-release tablet for the acute treatment of depressive episodes associated with bipolar disorder in patients who met DSM-IV criteria for bipolar disorder was established in one 8-week, randomized, double-blind, placebo-controlled study (N=280 outpatients). This study included patients with bipolar I and II disorder, and those with and without a rapid cycling course. Patients randomized to quetiapine fumarate extended-release tablet were administered 50 mg on Day 1, 100 mg on Day 2, 200 mg on Day 3, and 300 mg on Day 4 and after.

The primary rating instrument used to assess depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at week 8. Quetiapine fumarate extended-release tablet was superior to placebo in reduction of MADRS score at week 8 (study 6 in Table 29).

The efficacy of quetiapine fumarate tablet for the treatment of depressive episodes associated with bipolar disorder was established in 2 identical 8-week, randomized, double-blind, placebo-controlled studies (N=1045). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to quetiapine tablet were administered fixed doses of either 300 mg or 600 mg once daily.

The primary rating instrument used to assess depressive symptoms in these studies was the MADRS. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, quetiapine fumarate tablet was superior to placebo in reduction of MADRS score at week 8 (Studies 7 and 8 in Table 29). In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).

Maintenance Treatment as an Adjunct to Lithium or Divalproex

The efficacy of quetiapine fumarate tablet in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 9 and 10). The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stable on quetiapine tablet plus lithium or divalproex for at least 12 weeks in order to be randomized. On average, patients were stabilized for 15 weeks. In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either quetiapine fumarate tablet (administered twice-daily totaling 400 mg/day to 800 mg/day) or placebo. Approximately 50% of the patients had discontinued from the quetiapine fumarate tablet group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment. The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode). A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥ 20 or MADRS score ≥ 20 at 2 consecutive assessments; or study discontinuation due to a mood event.

In both studies, quetiapine fumarate tablet was superior to placebo in increasing the time to recurrence of any mood event (Figure 2 and Figure 3). The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of quetiapine fumarate tablet was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).

The efficacy of quetiapine fumarate extended-release tablet as adjunctive therapy to antidepressants in the treatment of MDD was demonstrated in two 6-week placebo-controlled, fixed-dose trials (n=936). Quetiapine fumarate extended-release tablet 150 mg/day or 300 mg/day was given as adjunctive therapy to existing antidepressant therapy in patients who had previously shown an inadequate response to at least one antidepressant. Quetiapine fumarate extended-release tablet was administered as 50 mg/day on Days 1 and 2, and increased to 150 mg/day on Day 3 for both dose groups. On Day 5, the dose was increased to 300 mg/day in the 300 mg/day fixed-dose group. Inadequate response was defined as having continued depressive symptoms for the current episode [Hamilton Depression Rating Scale (HAM-D) total score of ≥ 20] despite using an antidepressant for 6 weeks at or above the minimally effective labelled dose. The mean HAM-D total score at entry was 24, and 17% of patients scored 28 or greater. Patients were on various antidepressants prior to study entry including SSRI's (paroxetine, fluoxetine, sertraline, escitalopram, or citalopram), SNRI's, (duloxetine and venlafaxine,) TCA (amitriptyline) and other (bupropion).

The primary endpoint in these trials was change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS.), quetiapine fumarate extended-release tablet 300 mg once daily as adjunctive treatment to other antidepressant therapy was superior to antidepressant alone in reduction of MADRS total score in both trials. Quetiapine fumarate extended-release tablet 150 mg once daily as adjunctive treatment was superior to antidepressant therapy alone in reduction of MADRS total score in one trial. (studies 1 and 2 in Table 30) .

50 mg Tablets are peach to red colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K71" on the other side

Bottle of 60 tablets (NDC 68180-612-07).

Bottle of 100 tablets (NDC 68180-612-01).

150 mg Tablets are white colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K72" on the other side

Bottle of 60 tablets (NDC 68180-613-07).

Bottle of 100 tablets (NDC 68180-613-01).

200 mg Tablets are yellow colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K73" on the other side

Bottle of 60 tablets (NDC 68180-614-07).

Bottle of 100 tablets (NDC 68180-614-01).

300 mg Tablets are pale yellow colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K74" on the other side

Bottle of 60 tablets (NDC 68180-615-07).

Bottle of 100 tablets (NDC 68180-615-01).

400 mg Tablets are white colored, capsule shaped, biconvex, film coated tablets debossed with "LU" on one side and "K75" on the other side

Bottle of 60 tablets (NDC 68180-616-07).

Bottle of 100 tablets (NDC 68180-616-01).

Store quetiapine fumarate extended-release tablets at 25ºC (77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) [see USP Controlled Room Temperature].

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with quetiapine fumarate extended-release tablet and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for quetiapine fumarate extended-release tablet. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking quetiapine fumarate extended-release tablet.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Patients and caregivers should be advised that elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. Quetiapine fumarate extended-release tablet is not approved for elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS ( 5.1)].

Suicidal Thoughts and Behaviors

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see WARNINGS AND PRECAUTIONS ( 5.2)].

Neuroleptic Malignant Syndrome (NMS)

Patients should be advised to report to their physician any signs or symptoms that may be related to NMS. These may include muscle stiffness and high fever [see WARNINGS AND PRECAUTIONS ( 5.4)].

Hyperglycemia and Diabetes Mellitus

Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [see WARNINGS AND PRECAUTIONS ( 5.5)].

Hyperlipidemia

Patients should be advised that elevations in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol may occur. Patients should have their lipid profile monitored at the beginning of and periodically during treatment [see WARNINGS AND PRECAUTIONS ( 5.5)].

Weight Gain

Patients should be advised that they may experience weight gain. Patients should have their weight monitored regularly [see WARNINGS AND PRECAUTIONS ( 5.5)].

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls) especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose [see WARNINGS AND PRECAUTIONS ( 5.7)].

Increased Blood Pressure in Children and Adolescents

Children and adolescent patients should have their blood pressure measured at the beginning of, and periodically during, treatment [see WARNINGS AND PRECAUTIONS ( 5.9)].

Leukopenia/Neutropenia

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking quetiapine fumarate extended-release tablet. Patients should be advised to talk to their doctor as soon as possible if they have a fever, flu-like symptoms, sore throat, or any other infection as this could be a result of a very low WBC, which may require quetiapine fumarate extended-release tablet to be stopped and/or treatment to be given [see WARNINGS AND PRECAUTIONS ( 5.10)].

Interference with Cognitive and Motor Performance

Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration. Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS ( 5.16)].

Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS ( 5.17)].

Concomitant Medication

As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs [see DRUG INTERACTIONS ( 7.1)].

Pregnancy and Nursing

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with quetiapine fumarate extended-release tablet [see USE IN SPECIFIC POPULATIONS ( 8.1 and 8.3)].

Need for Comprehensive Treatment Program

Quetiapine fumarate extended-release tablet is indicated as an integral part of a total treatment program for adolescents with schizophrenia and pediatric bipolar disorder that may include other measures (psychological, educational, and social). Effectiveness and safety of quetiapine fumarate extended-release tablet have not been established in pediatric patients less than 13 years of age for schizophrenia or less than 10 years of age for bipolar mania. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms [see INDICATIONS AND USAGE ( 1.4)].

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Pithampur – 454 775

INDIA.