sulted in significant increase in quetiapine exposure. the dose of quetiapine should be reduced to one sixth of the original dose if 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 up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent cyp3a4 inducers [see dosage and administration (2.6) and clinical pharmacology (12.3)]. when the cyp3a4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7-14 days [see dosage and administration (2.6)]. the potential effects of several concomitant medications on quetiapine pharmacokinetics were studied [see clinical pharmacology (12.3)]. 7.2 effect of quetiapine on other drugs because of its potential for inducing hypotension, quetiapine may enhance the effects of certain antihypertensive agents. quetiapine may antagonize the effects of levodopa and dopamine agonists. there are no clinically relevant pharmacokinetic interactions of quetiapine on other drugs based on the cyp pathway. quetiapine and its metabolites are non-inhibitors of major metabolizing cyp’s (1a2, 2c9, 2c19, 2d6 and 3a4).

trials in adult patients with bipolar i and bipolar ii disorder [see clinical studies (14.2)]. quetiapineis 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 [see clinical studies (14.2)]. 1.3 special considerations in treating pediatric schizophrenia and bipolar i disorder pediatric schizophrenia and bipolar i disorder are serious mental disorders, however, diagnosis can be challenging. for pediatric schizophrenia, symptom profiles can be variable, and for bipolar i disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. it is recommended that medication therapy for pediatric schizophrenia and bipolar i disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. medication treatment for both pediatric schizophrenia and bipolar i disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.

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 is not approved for the treatment of patients with dementia-related psychosis [see boxed warning]. 5.2 suicidal thoughts and behaviors in adolescents and young adults 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 4400 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. table 2: drug-placebo difference in number of cases of suicidality per 1000 patients treated age range drug-placebo difference in number of cases of suicidality per 1000 patients treated increases compared to placebo <18 14 additional cases 18 to 24 5 additional cases decreases compared to placebo 25 to 64 1 fewer case ≥65 6 fewer cases no suicides occurred in any of the pediatric trials. there were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. it is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. however, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. all patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. the following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. such monitoring should include daily observation by families and caregivers. prescriptions for quetiapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. screening patients for bipolar disorder: a major depressive episode may be the initial presentation of bipolar disorder. it is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. whether any of the symptoms described above represent such a conversion is unknown. however, prior to initiating treatment with an antidepressant, including quetiapine, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. 5.3 cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis 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 is not approved for the treatment of patients with dementia- related psychosis [see also boxed warningand warnings and precautions (5.1)]. 5.4 neuroleptic malignant syndrome(nms) 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. 5.5 metabolic changes atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. while all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. in some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. changes in these metabolic profiles should be managed as clinically appropriate. hyperglycemia and diabetes mellitus hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. however, epidemiological studies suggest an increased risk of treatment- emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. in some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. adults: table 3: fasting glucose – proportion of patients shifting to ≥ 126 mg/dl in short-term (≤12 weeks) placebo-controlled studies2 laboratory analyte category change (at least once) from baseline treatment arm n patients n (%) fasting glucose normal to high (<100 mg/dl to ≥126 mg/dl/) quetiapine 2907 71 (2.4%) placebo 1346 19 (1.4%) borderline to high (≥100 mg/dl) and <126 mg/dl to ≥26 pj/g/) quetiapine 572 67 (11.7%) placebo 279 33 (11.8%) 2includes quetiapine tablets and quetiapine extended-release tablets. in a 24-week trial (active-controlled, 115 patients treated with quetiapine) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dl was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥126 mg/dlwas 2.6%. the mean change in fasting glucose from baseline was 3.2 mg/dl and mean change in 2 hour glucose from baseline was -1.8 mg/dl for quetiapine. in 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar i disorder maintenance, mean exposure of 213 days for quetiapine(646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dl for quetiapine and –0.05 mg/dl for placebo. the exposure-adjusted rate of any increased blood glucose lavel (≥ 126 mg/dl) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581). children and adolescents: in a placebo-controlled quetiapine monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine (n=138) compared to placebo (n=67) was – 0.75 mg/dl versus –1.70 mg/dl. in a placebo-controlled quetiapine monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine (n=170) compared to placebo (n=81) was 3.62 mg/dl versus –1.17 mg/dl. no patient in either study with a baseline normal fasting glucose level (<100 mg/dl) or a baseline borderline fasting glucose level (≥ 100 mg/dl and <126mg/dl) had a treatment emergent blood glucose level ≥ 126mg/dl. in a placebo-controlled quetiapine extended-release tablets monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for quetiapine extended-release tablets (n = 60) compared to placebo (n = 62) was 1.8 mg/dl versus 1.6 mg/dl. in this study, there were no patients in the quetiapine extended-release tablets or placebo-treated groups with a baseline normal fasting glucose level (< 100 mg/dl) that had an increase in blood glucose level > 126 mg/dl. there was one patient in the quetiapine extended-release tablets group with a baseline borderline fasting glucose level (> 100 mg/dl) and (< 126 mg/dl) who had an increase in blood glucose level of > 126 mg/dl compared to zero patients in the placebo group. dyslipidemia adults: table 4 shows the percentage of adult patients with changes in total cholesterol, triglycerides, ldl-cholesterol and hdl- cholesterol from baseline by indication in clinical trials with quetiapine. table 4: percentage of adult patients with shifts in total cholesterol, triglycerides, ldl-cholesterol and hdl-cholesterol from baseline to clinically significant levels by indication laboratory analyte indication treatment arm n patients n (%) total cholesterol ≥240 pj/g/ schizophrenia1 quetiapine 137 24 (18%) placebo 92 6 (7%) bipolar depression2 quetiapine 463 41 (9%) placebo 250 15 (6%) triglycerides ≥200 mg/dl schizophrenia1 quetiapine 120 26 (22%) placebo 70 11 (16%) bipolar depression2 quetiapine 436 59 (14%) placebo 232 20 (9%) ldl- cholesterol ≥160 mg/dl schizophrenia1 quetiapine na3 na3 placebo na3 na3 bipolar depression2 quetiapine 465 29 (6%) placebo 256 12 (5%) hdl- cholesterol ≤40 pj/g/ schizophrenia1 quetiapine na3 na3 placebo na3 na3 bipolar depression2 quetiapine 393 56 (14%) placebo 214 29 (14%) 1. 6 weeks duration 2. 8 weeks duration 3. parameters not measured in the quetiapine registration studies for schizophrenia. lipid parameters also were not measured in the bipolar mania registration studies. children and adolescents: table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, ldl-cholesterol and hdl-cholesterol from baseline in clinical trials with quetiapine. table 5: percentage of children and adolescents with shifts in total cholesterol, triglycerides, ldl- cholesterol and hdl-cholesterol from baseline to clinically significant levels laboratory analyte indication treatment arm n patients n (%) total cholesterol ≥200 pj/g/ schizophrenia1 quetiapine 107 13 (12%) placebo 56 1 (2%) bipolar mania2 quetiapine 159 16 (10%) placebo 66 2 (3%) triglycerides ≥150 pj/g/ schizophrenia1 quetiapine 103 17 (17%) placebo 51 4 (8%) bipolar mania2 quetiapine 149 32 (22%) placebo 60 8 (13%) ldl- cholestrol ≥ 130 mg/dl schizophrenia1 quetiapine 112 4 (4%) placebo 60 1 (2%) bipolar mania2 quetiapine 169 13 (8%) placebo 74 4 (5%) hdl- cholestrol ≤ 40 mg/dl schizophrenia1 quetiapine 104 16 (15%) placebo 54 10 (19%) bipolar mania2 quetiapine 154 16 (10%) placebo 61 4 (7%) 1. 13 to 17 years, 6 weeks duration 2. 10 to 17 years, 3 weeks duration in placebo-controlled quetiapine extended-release tablets monotherapy study (8 week duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dl), triglycerides (≥150 mg/dl), ldl-cholesterol (≥130 mg/dl) and hdl-cholesterol (≤ 40 mg/dl) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for quetiapine extended-release tablets vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for quetiapine extended-release tablets vs. 9% (7/82) for placebo; ldl-cholesterol 2% (2/86) for quetiapine extended-release tablets vs. 4% (3/85) for placebo and hdl-cholesterol 20% (13/65) for quetiapine extended-release tablets vs. 15% (11/74) for placebo. weight gain increases in weight have been observed in clinical trials. patients receiving quetiapine should receive regular monitoring of weight. adults: in clinical trials with quetiapinethe following increases in weight have been reported. table 6: proportion of patients with weight gain ≥ 7% of body weight (adults) vital sign indication treatment arm n patients n (%) weight gain ≥7% ri body weight schizophrenia1 quetiapine 391 89 (23%) placebo 206 11 (6%) bipolar mania (monotherapy)2 quetiapine 209 44 (21%) placebo 198 13 (7%) bipolar mania (adjunct therapy)3 quetiapine 196 25 (13%) placebo 203 8 (4%) bipolar depression4 quetiapine 554 47 (8%) placebo 295 7 (2%) 1. up to 6 weeks duration 2. up to 12 weeks duration 3. up to 3 weeks duration 4. up to 8 weeks duration children and adolescents: in two clinical trials with quetiapine, one in bipolar mania and one in schizophrenia, reported increases in weight are included in table 7. table 7: proportion of patients with weight gain ≥ 7% of body weight (children and adolescents) vital sign indication treatment arm n patients n (%) weight gain ≥7% ri body schizophrenia1 quetiapine 111 23 (21%) placebo 44 3 (7%) bipolar mania2 quetiapine 157 18 (12%) placebo 68 0 (0%) 1. 6 weeks duration 2. 3 weeks duration the mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine group and 0.4 kg in the placebo group. in an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine. after 26 weeks of treatment, the mean increase in body weight was 4.4 kg. forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth. in order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in bmi was used as a measure of a clinically significant change; 18.3% of patients on quetiapine met this criterion after 26 weeks of treatment. in clinical trials for quetiapine extended-release tablets in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥ 7% of body weight at any time was 15% (14/92) for quetiapine extended-release tablets vs. 10% (10/100) for placebo. the mean change in body weight was 1.4 kg in the quetiapine extended-release tablets group vs. 0.6 kg in the placeo group. when treating pediatric patients with quetiapine for any indication, weight gain should be assessed against that expected for normal growth. 5.6 tardive dyskinesia 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 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, drug discontinuation should be considered. however, some patients may require treatment with quetiapine despite the presence of the syndrome. 5.7 hypotension 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 1% (28/3265) of the patients treated with quetiapine, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs. 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). the risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see dosage and administration (2.2)]. if hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate. 5.8 increases in blood pressure(children and adolescents) in placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increases at any time in systolic blood pressure (≥200 mm hg) was 15.2% (51/335) for quetiapine and 5.5% (9./163) for placebo; the incidence of increases at time in diastolic blood pressure (≥100 mm hg) was 40.6% (136/335) for quetiapine 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 the placebo controlled quetiapine extended-release tablets clinical trials (8 weeks duration) in children and adolescents (10 to 17years 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 extended-release tablets 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 extended-release tablets and 36.0% (36/100) for placebo. 5.9 leukopenia, neutropenia and agranulocytosis in clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine. agranulocytosis (including fatal cases) has also been reported. 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 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/mm3) should discontinue quetiapine and have their wbc followed until recovery. 5.10 cataracts 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. 5.11 qt prolongation 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 [see drug interactions (7.1)]. 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). 5.12 seizures during clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs. as with other antipsychotics, quetiapine 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. 5.13 hypothyroidism adults: clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. the reduction in total and free thyroxine (t4) 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 t4, 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 t4, in addition to clinical assessment, should be measured at baseline and at follow-up. in the mania adjunct studies, where quetiapine was added to lithium or divalproex, 12% (24/196) of quetiapine treated patients compared to 7% (15/203) of placebo-treated patients had elevated tsh levels. of the quetiapine treated patients with elevated tsh levels, 3 had simultaneous low free t4 levels (free t4 <0.8 lln). about 0.7% (26/3489) of quetiapine patients did experience tsh increases in monotherapy studies. some patients with tsh increases needed replacement thyroid treatment. in all quetiapine trials, the incidence of significant shifts in thyroid hormones and tsh were1: decrease in free t4 (free t4 <0.8 lln), 2.0% (357/17513); decrease in total t4, 4.0% (75/1861); decrease in free t3, 0.4% (53/13766); decrease in total t3, 2.0% (26/1312), and increase in tsh, 4.9% (956/19412). in eight patients, where tbg was measured, levels of tbg were unchanged. table 8 shows the incidence of these shifts in short term placebo-controlled clinical trials. table 8: incidence of shifts in thyroid hormone levels and tsh in short-term placebo-controlled clinical trials 1 total t4 free t4 total t3 free t3 tsh quetiapine placebo quetiapine placebo quetiapine placebo quetiapine placebo quetiapine placebo 3.4 % (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) 1. based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. shifts in total t4, free t4, total t3 and free t3 are defined as <0.8 x lln (pmol/l) and shift in tsh is >5 mlu/l at any time. in short-term placebo-controlled monotherapy trials, the incidence of reciprocal, shifts in t3 and tsh was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for t4 and tsh the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo. children and adolescents: 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 for thyroid function values at any time for quetiapine 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 treated patients with elevated tsh levels, 1 had simultaneous low free t4 level at end of treatment. 5.14 hyperprolactinemia adults: during clinical trials with quetiapine, 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: 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 compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine compared to 0% (0/39) for placebo in females. like other drugs that antagonize dopamine d2 receptors, quetiapine 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)]. 5.15 potential for cognitive and motor impairment somnolence was a commonly reported adverse event reported in patients treated with quetiapine especially during the 3-5 day period of initial dose-titration. in schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine compared to 11% (22/206) of placebo patients. in acute bipolar mania trials using quetiapine as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine compared to 4% of placebo patients. in acute bipolar mania trials using quetiapine as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine compared to 9% (19/203) of placebo patients. in bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine compared to 15% (51/347) 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. 5.16 body temperature regulation although not reported with quetiapine, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. appropriate care is advised when prescribing quetiapine 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. 5.17 dysphagia 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 and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. 5.18 discontinuation syndrome acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine. the incidence of the individual adverse events (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 withdrawal is advised.

. 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 n/a1 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 maintenancetreatmentfor schizophreniaand bipolari disorder maintenance treatment–patientsshouldbeperiodicallyreassessedto determine theneedformaintenancetreatment andtheappropriatedoseforsuch treatment[see clinicalstudies (14.2)]. 2.3 dose modifications in elderly patients consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see clinical pharmacology (12.3)]. 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 [see clinical pharmacology (12.3) and drug interactions (7.1)]. 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 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 tolerability of the individual patient. when the cyp3a4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7-14 days [see clinical pharmacology (12.3)and drug interactions (7.1)]. 2.7 reinitiation 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 reinitiated. 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.

seizures [see warnings and precautions 5.12] hypothyroidism [see warnings and precautions 5.13] hyperprolactinemia [see warnings and precautions 5.14] potential for cognitive and motor impairment [see warnings and precautions 5.15] body temperature regulation [see warnings and precautions 5.16] dysphagia [see warnings and precautions 5.17] discontinuation syndrome [see warnings and precautions 5.18] 6.1 clinical study experience becauseclinicalstudiesareconductedunderwidely varyingconditions,adversereactionratesobservedintheclinical studiesof adrugcannotbedirectlycompared toratesin theclinicalstudies ofanotherdrugand maynotreflecttheratesobservedin practice. adults: theinformationbelow isderivedfroma clinicaltrialdatabaseforquetiapineconsistingofover4300 patients.this databaseincludes 698patientsexposedtoquetiapine forthetreatmentofbipolardepression,405patientsexposedto quetiapinefor the treatmentofacutebipolarmania (monotherapyand adjunct therapy),646 patientsexposedto quetiapinefor the maintenancetreatmentofbipolaridisorderasadjunct therapy, and approximately2600patientsand/ornormalsubjectsexposedto1 ormoredosesofquetiapine for the treatmentofschizophrenia. of theseapproximately4300subjects,approximately 4000(2300 inschizophrenia,405 inacutebipolarmania,698 inbipolardepression,and 646forthe maintenancetreatmentofbipolaridisorder)werepatientswhoparticipated inmultipledose effectivenesstrials,andtheirexperiencecorresponded toapproximately2400 patient-years.theconditionsand durationoftreatmentwith quetiapinevaried greatlyandincluded(inoverlappingcategories)open-labelanddouble-blindphases ofstudies,inpatientsandoutpatients,fixed-dose and dose-titrationstudies,andshort-termorlonger-termexposure. adversereactions wereassessedbycollectingadverse events,results ofphysicalexaminations,vitalsigns,weights,laboratoryanalyses,ecgs, andresultsofophthalmologic examinations. thestated frequenciesofadverse reactions represent theproportion ofindividualswho experienced, atleastonce,a treatment-emergent adversereactionofthe typelisted. adversereactions associated with discontinuation oftreatment inshort-term, placebo-controlledtrials schizophrenia:overall,therewaslittledifferencein the incidenceofdiscontinuationdueto adversereactions(4%forquetiapine vs. 3% for placebo)ina poolofcontrolledtrials. however,discontinuationsdueto somnolence(0.8%quetiapinevs. 0%placebo) andhypotension(0.4%quetiapinevs.0%placebo)wereconsideredtobedrugrelated[see warningsand precautions (5.7and 5.18)]. bipolardisorder: mania:overall,discontinuations dueto adverse reactions were5.7%for quetiapinevs. 5.1% for placeboin monotherapyand 3.6%forquetiapinevs. 5.9% forplacebo in adjuncttherapy. depression:overall, discontinuationsduetoadverse reactionswere12.3%forquetiapine300 mg vs. 19.0% forquetiapine 600 mgand5.2% for placebo. commonlyobserved adversereactionsin short-term,placebo-controlled trials: inthe acutetherapyofschizophrenia(upto 6weeks)and bipolarmania (upto12weeks) trials,the mostcommonlyobserved adversereactionsassociated withtheuseofquetiapinemonotherapy(incidenceof5%orgreater)andobserved atarateon quetiapine at least twicethatofplacebo were somnolence (18%),dizziness(11%),drymouth (9%),constipation(8%), alt increased(5%),weightgain (5%),and dyspepsia (5%). adversereactionsoccurringatanincidenceof2%ormoreamong quetiapinetreated patientsin short-term, placebo-controlledtrials: theprescriber shouldbe awarethat the figuresinthetablesand tabulationscannotbe usedtopredict the incidence ofsideeffectsinthe courseofusualmedical practicewherepatientcharacteristicsandotherfactors differfromthose thatprevailedin theclinical trials. similarly,thecitedfrequenciescannotbecompared withfiguresobtainedfromotherclinicalinvestigationsinvolvingdifferenttreatments,uses, and investigators.thecited figures,however, doprovide the prescribingphysicianwithsomebasisforestimatingtherelative contributionofdrugandnondrugfactorstothe side effectincidenceinthepopulationstudied. table9enumeratestheincidence,roundedtothenearestpercent,ofadversereactionsthatoccurred duringacutetherapyofschizophrenia(upto6 weeks)andbipolarmania(upto12 weeks) in2%ormoreofpatientstreated withquetiapine(dosesrangingfrom75to 800mg/day)wheretheincidencein patientstreatedwith quetiapinewasgreaterthanthe incidenceinplacebo-treatedpatients. table9:adversereactionincidencein3-to12-weekplacebo-controlledclinicaltrialsforthetreatmentofschizophreniaandbipolarmania(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% intheacuteadjuncttherapyofbipolarmania(upto3weeks)studies,themostcommonlyobservedadversereactionsassociated withtheuseof quetiapine(incidenceof 5%or greater)andobserved atarateonquetiapineatleasttwice thatofplacebo weresomnolence(34%),drymouth (19%),asthenia(10%), constipation (10%), abdominalpain (7%),posturalhypotension (7%),pharyngitis (6%),andweightgain (6%). table10enumeratestheincidence,rounded tothenearestpercent, ofadversereactionsthatoccurredduringtherapy(upto 3 weeks)ofacutemaniain 2%ormoreofpatientstreated with quetiapine(dosesrangingfrom100 to 800 mg/day)usedasadjuncttherapytolithiumanddivalproexwheretheincidencein patientstreated with quetiapinewasgreater thantheincidenceinplacebo-treatedpatients. table10:adversereactionincidencein3-weekplacebo-controlledclinicaltrialsforthetreatmentofbipolarmania(adjuncttherapy) 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% inbipolardepression studies(upto8 weeks), themostcommonlyobserved treatmentemergentadversereactions associatedwiththeuseofquetiapine(incidenceof5%orgreater)and observedatarateonquetiapine atleasttwice thatofplacebo weresomnolence(57%),drymouth (44%),dizziness(18%),constipation(10%),and lethargy (5%). table11 enumeratestheincidence,rounded tothenearestpercent, ofadversereactionsthatoccurredduringtherapy(upto 8 weeks)ofbipolardepressionin 2% ormoreofpatientstreatedwith quetiapine(doses of300and600mg/day) wheretheincidenceinpatientstreatedwithquetiapinewasgreaterthantheincidencein placebo-treatedpatients. table11: adversereactionincidencein8-weekplacebo-controlledclinicaltrialsforthetreatmentofbipolardepression preferred term quetiapine (n=698) placebo (n=347) somnolence3 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% hypoaesthesia 2% 1% dysphagia 2% 0% restless legs syndrome 2% 0% 3. somnolencecombinesadversereactiontermssomnolenceand sedation explorationsfor interactionsonthe basis of gender, age,andracedid notrevealanyclinicallymeaningfuldifferencesin theadversereactionoccurrenceon thebasisofthesedemographicfactors. dosedependencyofadversereactionsinshort-term,placebo-controlledtrials dose-relatedadversereactions: spontaneouslyelicited adversereactiondatafroma studyof schizophreniacomparing fivefixeddosesof quetiapine (75 mg,150mg, 300 mg, 600mg,and 750 mg/day)to placebo wereexploredfordose- relatednessofadversereactions. logisticregression analysesrevealed apositivedoseresponse(p<0.05)forthefollowingadversereactions:dyspepsia, abdominalpain,and weightgain. adversereactionsinclinicaltrialswith quetiapineandnotlistedelsewherein thelabel: thefollowingadversereactionshavealso beenreportedwithquetiapine:nightmares, hypersensitivityandelevationsinserumcreatine phosphokinase (notassociatedwithnms), galactorrhea,bradycardia(whichmayoccur atornearinitiationof treatmentandbeassociated withhypotensionand/orsyncope) decreasedplatelets,somnambulism(and otherrelated events),elevationsingamma-gtlevels,hypothermia, and priapism. extrapyramidalsymptoms (eps): dystonia classeffect: symptomsofdystonia,prolonged abnormalcontractionsofmuscle groups,mayoccur insusceptible individuals duringthefirstfewdaysoftreatment. dystonicsymptoms include:spasmoftheneckmuscles,sometimesprogressingtotightness ofthethroat,swallowingdifficulty,difficultybreathing, and/orprotrusionofthe tongue. whilethesesymptomscanoccuratlowdoses, theyoccurmore frequentlyand with greaterseveritywith highpotencyand at higher dosesoffirstgeneration antipsychoticdrugs.anelevated riskof acutedystoniaisobserved inmales and younger agegroups. fourmethodswereusedtomeasureeps:(1)simpson-angus totalscore(meanchangefrombaseline)whichevaluatesparkinsonismand akathisia,(2) barnesakathisiaratingscale (bars) globalassessmentscore,(3)incidence ofspontaneouscomplaintsofeps (akathisia,akinesia, cogwheelrigidity,extrapyramidalsyndrome, hypertonia, hypokinesia, neckrigidity, and tremor),and (4) use ofanticholinergicmedicationstotreatemergenteps. adults:datafromone6-weekclinicaltrialofschizophreniacomparingfive fixeddosesofquetiapine(75,150, 300, 600,750 mg/day) providedevidenceforthelackof treatment-emergentextrapyramidalsymptoms(eps)anddose- relatednessforeps associated with quetiapine treatment. threemethodswereusedtomeasureeps:(1)simpson- angustotalscore(meanchangefrombaseline)whichevaluatesparkinsonismandakathisia,(2) incidenceofspontaneouscomplaintsofeps (akathisia,akinesia,cogwheelrigidity,extrapyramidalsyndrome,hypertonia,hypokinesia,neck rigidity, and tremor),and (3)useof anticholinergicmedicationstotreatemergenteps. intable 12,dystoniceventincludednuchalrigidity, hypertonia,dystonia,musclerigidity,oculogyration;parkinsonism includedcogwheelrigidity,tremor,drooling, hypokinesia;akathisiaincludedakathisia, psychomotoragitation;dyskinetic event includedtardive dyskinesia, dyskinesia,choreoathetosis;andotherextrapyramidaleventincludedrestlessness,extrapyramidaldisorder,movementdisorder. table12: adversereactionsassociatedwitheps inashort-term,placebo-controlledmultiplefixed-dosephaseiiischizophreniatrial (6weeksduration) preferred term quetiapine75 mg/day (n=53) quetiapine 150 mg/day (n=48) quetiapine 300 mg/day (n=52) quetiapine 600 mg/day (n=51) quetiapine 750 mg/day (n=54) placebo (n=51) n % n % n % n % n % n % dystonic event 2 3.8 2 4.2 0 0.0 2 3.9 3 5.6 4 7.8 parkinsonism 2 3.8 0 0.0 1 1.9 1 2.0 1 1.9 4 7.8 akathisia 1 1.9 1 2.1 0 0.0 0 0.0 1 1.9 4 7.8 dyskinetic event 2 3.8 0 0.0 0 0.0 1 2.0 0 0.0 0 0.0 other extrapyramidal event 2 3.8 0 0.0 3 5.8 3 5.9 1 1.9 4 7.8 parkinsonismincidenceratesas measured bythe simpson-angus totalscoreforplaceboandthefivefixeddoses(75,150, 300,600,750mg/day)were:-0.6;-1.0,-1.2;-1.6;-1.8and-1.8.therateofanticholinergicmedicationusetotreat emergenteps forplacebo and thefivefixeddoses was:14%;11%;10%;8%;12%and 11%. insix additionalplacebo-controlled clinicaltrials(3inacutemaniaand3 inschizophrenia)using variabledosesof quetiapine, therewerenodifferences between the quetiapineand placebotreatmentgroupsintheincidence ofeps,as assessed bysimpson-angustotalscores, spontaneouscomplaintsof epsand the useof concomitantanticholinergicmedicationsto treateps. intwoplacebo-controlled clinicaltrialsforthetreatmentofbipolardepressionusing300 mgand 600 mgofquetiapine, theincidenceofadverse reactions potentiallyrelatedtoeps was 12% inbothdose groups and 6%inthe placebo group. inthese studies, theincidenceoftheindividual adversereactions(akathisia,extrapyramidaldisorder,tremor,dyskinesia, dystonia,restlessness, musclecontractionsinvoluntary, psychomotor hyperactivityand musclerigidity)were generallylowand did notexceed 4%inanytreatmentgroup. the3 treatmentgroups weresimilarin meanchange insas totalscoreandbars globalassessmentscore at the endoftreatment.theuseofconcomitant anticholinergicmedicationswasinfrequentandsimilaracrossthethreetreatment groups. childrenand adolescents theinformationbelow isderivedfroma clinicaltrialdatabaseforquetiapineconsistingofover1000 pediatricpatients. thisdatabase includes 677patientsexposedto quetiapinefor the treatmentofschizophrenia and393childrenand adolescents(10to 17 yearsold) exposedto quetiapineforthetreatmentofacutebipolarmania. adversereactions associated with discontinuation oftreatment inshort-term,placebo-controlledtrialsschizophrenia:theincidence ofdiscontinuationduetoadversereactionsfor quetiapine-treated andplacebo-treated patients was8.2%and2.7%, respectively.theadverse eventleadingtodiscontinuationin 1%or moreofpatientson quetiapineand ata greaterincidence than placebowas somnolence (2.7%and 0%forplacebo). bipolarimania:the incidenceofdiscontinuation dueto adversereactionsforquetiapine-treated andplacebo-treatedpatientswas11.4% and4.4%, respectively.theadverse reactionsleadingto discontinuationin 2%ormoreofpatientson quetiapineand ata greaterincidence than placebowere somnolence(4.1% vs.1.1%)andfatigue (2.1%vs.0). commonlyobservedadversereactions inshort-term,placebo-controlledtrials intherapyforschizophrenia(upto6weeks),themostcommonlyobservedadversereactionsassociatedwiththeuseof quetiapinein adolescents(incidenceof 5%orgreaterand quetiapine incidenceatleasttwicethatfor placebo) weresomnolence(34%), dizziness(12%),drymouth (7%),tachycardia(7%). inbipolarmaniatherapy(up to3 weeks) the mostcommonlyobservedadversereactionsassociatedwiththeuse of quetiapineinchildrenand adolescents(incidenceof5%or greater andquetiapineincidenceatleast twicethatfor placebo)weresomnolence(53%),dizziness(18%),fatigue(11%),increasedappetite(9%),nausea(8%), vomiting(8%), tachycardia(7%),drymouth (7%),and weight increased (6%). adverse reactions occurring at an incidenceof ≥ 2% among quetiapine treated patients in short-term, placebo-controlledtrials schizophrenia (adolescents,13 to 17 yearsold) thefollowingfindingswerebasedona6-weekplacebo-controlledtrialinwhichquetiapinewasadministered ineither dosesof 400 or800 mg/day. table13 enumeratestheincidence,roundedto the nearestpercent,oftreatment-emergent adverse reactionsthatoccurred duringtherapy(up to 6 weeks)ofschizophreniain2%ormoreofpatientstreatedwithquetiapine (doses of400 or800 mg/day)where the incidence inpatientstreatedwithquetiapine was atleast twice the incidence inplacebo-treated patients. adverse eventsthatwere potentiallydose-relatedwithhigher frequencyinthe800mg group comparedtothe400 mg group includeddizziness(8%vs. 15%), drymouth(4% vs. 10%), and tachycardia(6% vs.11%). table13: adversereactionincidenceina6-weekplacebo-controlledclinicaltrial forthetreatment ofschizophreniainadolescentpatients preferred term quetiapine 400 mg (n=73) quetiapine 800 mg (n=74) placebo (n=75) somnolence1 33% 35% 11% dizziness 8% 15% 5% dry mouth 4% 10% 1% tachycardia2 6% 11% 0% irritability 3% 5% 0% arthralgia 1% 3% 0% asthenia 1% 3% 1% back pain 1% 3% 0% dyspnoea 0% 3% 0% abdominal pain 3% 1% 0% anorexia 3% 1% 0% tooth abscess 3% 1% 0% dyskinesia 3% 0% 0% epistaxis 3% 0% 1% muscle rigidity 3% 0% 0% 1. somnolencecombinesadversereactiontermssomnolenceand sedation. 2. tachycardiacombinesadversereactiontermstachycardiaand sinustachycardia. bipolarimania(childrenand adolescents 10to17 years old) thefollowingfindingswerebased on a3-weekplacebo-controlledtrialinwhichquetiapinewasadministeredin eitherdosesof 400 or600 mg/day. commonlyobservedadversereactions inbipolarmaniatherapy(upto3weeks) themostcommonlyobservedadversereactionsassociatedwiththeuseofquetiapinein children andadolescents(incidenceof5%or greater andquetiapineincidence atleast twicethatfor placebo)weresomnolence(53%),dizziness(18%),fatigue(11%),increasedappetite(9%),nausea(8%), vomiting(8%), tachycardia(7%),drymouth(7%), andweight increased(6%). table14 enumeratestheincidence,rounded tothenearestpercent, oftreatment-emergent adverse reactionsthatoccurredduringtherapy(up to3 weeks) of bipolar maniain2%ormore of patientstreatedwithquetiapine (doses of400 or600 mg/day)where the incidence inpatientstreatedwithquetiapinewasgreaterthan theincidenceinplacebo-treated patients. adverseeventsthatwerepotentiallydose-relatedwithhigher frequencyinthe600mg group comparedtothe400 mg group includedsomnolence(50%vs.57%), nausea(6% vs.10%) and tachycardia(6% vs.9%). table14:adversereactionsina3-weekplacebo-controlledclinicaltrial forthetreatment ofbipolar maniain childrenandadolescentpatients preferred term quetiapine 400 mg (n=95) quetiapine 600 mg (n=98) placebo (n=90) somnolence1 50% 57% 14% dizziness 19% 17% 2% nausea 6% 10% 4% fatigue 14% 9% 4% increased appetite 10% 9% 1% tachycardia2 6% 9% 1% dry mouth 7% 7% 0% vomiting 8% 7% 3% nasal congestion 3% 6% 2% weight increased 6% 6% 0% iritability 3% 5% 1% pyrexia 1% 4% 1% aggression 1% 3% 0% musculoskeletal stiffness 1% 3% 1% accidental overdose 0% 2% 0% acne 3% 2% 0% arthralgia 4% 2% 1% lethargy 2% 2% 0% pallor 1% 2% 0% stomach discomfort 4% 2% 1% syncope 2% 2% 0% vision blurred 3% 2% 0% constipation 4% 2% 0% ear pain 2% 0% 0% paraesthesia 2% 0% 0% sinus congestion 3% 0% 0% thirst 2% 0% 0% 1. somolencecombinesadversereactionstermssomnolenceand sedation. 2. tachycardiacombinesadversereactiontermstachycardiaand sinustachycardia. extrapyramidalsymptoms: inashort-termplacebo-controlledmonotherapytrialinadolescentpatientswithschizophrenia(6-weekduration),theaggregatedincidenceofextrapyramidalsymptomswas 12.9%(19/147) for quetiapineand 5.3%(4/75)forplacebo, though theincidenceoftheindividualadverseevents (akathisia,tremor,extrapyramidaldisorder,hypokinesia, restlessness,psychomotorhyperactivity, musclerigidity,dyskinesia)didnotexceed 4.1%in anytreatmentgroup. ina short-termplacebo-controlledmonotherapytrialinchildrenand adolescentpatientswithbipolarmania(3-weekduration),the aggregatedincidence ofextrapyramidalsymptomswas3.6% (7/193) orquetiapine and 1.1%(1/90)forplacebo. table15 presentsalistingofpatientswith adversereactionspotentiallyassociated withextrapyramidalsymptoms in the short-termplacebo-controlledmonotherapytrialinadolescentpatientswithschizophrenia(6-weekduration). intables15– 16dystonicevent includednuchalrigidity,hypertonia,andmusclerigidity;parkinsonismincluded cogwheelrigidityandtremor;akathisiaincludedakathisiaonly; dyskinetic event includedtardive dyskinesia,dyskinesia,andchoreoathetosis;andotherextrapyramidaleventincludedrestlessnessandextrapyramidaldisorder. table15: adversereactionsassociatedwith extrapyramidalsymptomsintheplacebo-controlled trialinadolescentpatientswithschizophrenia (6-weekduration) preferred term quetiapine 400 mg/day (n=73) quetiapine 800 mg/day (n=74) all quetiapine (n=147) placebo (n=75) n % n % n % n % dystonic event 2 2.7 0 0.0 2 1.4 0 0.0 parkinsonism 4 5.5 4 5.4 8 5.4 2 2.7 akathisia 3 4.1 4 5.4 7 4.8 3 4.0 dyskinetic event 2 2.7 0 0.0 2 1.4 0 0.0 other extrapyramidal event 2 2.7 2 2.7 4 2.7 0 0.0 table16 presentsa listingofpatientswith adversereactions associatedwithextrapyramidalsymptoms in a short-termplacebo-controlled monotherapytrialin childrenand adolescentpatientswith bipolarmania (3-weekduration). table16: adversereactionsassociatedwithextrapyramidalsymptomsinaplacebo-controlledtrialinchildrenandadolescentpatientswithbipolari mania(3-weekduration) preferred term1 quetiapine 400 mg/day (n=95) quetiapine 600 mg/day (n=98) all quetiapine (n=193) placebo (n=90) n % n % n % n % parkinsonism 2 2.1 1 1.0 3 1.6 1 1.1 akathisia 1 1.0 1 1.0 2 1.0 0 0.0 other extrapyramidal event 1 1.1 1 1.0 2 1.0 0 0.0 1. therewerenoadverseexperienceswith thepreferredtermofdystonicor dyskineticevents. otheradversereactionsobservedduringthepre-marketingevaluationofquetiapine followingisalistofcostartterms thatreflecttreatment-emergentadversereactionsasdefinedin the introductiontothe adverse reactions sectionreportedbypatientstreatedwithquetiapine atmultipledoses >75mg/dayduring anyphaseofatrialwithinthe premarketingdatabase ofapproximately2200 patientstreatedfor schizophrenia. allreported reactionsareincludedexceptthosealreadylistedinthetablesorelsewhereinlabeling,thosereactionsforwhich a drugcause wasremote,and those reaction termswhich weresogeneralastobeuninformative. it is importantto emphasize that, although the reactionsreported occurredduringtreatmentwithquetiapine, theywerenotnecessarilycaused byit. reactionsarefurthercategorizedbybodysystemandlistedinorderofdecreasingfrequencyaccordingtothefollowingdefinitions:frequentadverse reactionsare those occurringin at least1/100 patients(onlythosenotalreadylistedin thetabulatedresultsfromplacebo-controlledtrialsappearin thislisting); infrequentadverse reactionsarethose occurringin 1/100to 1/1000patients;rare reactions arethoseoccurringinfewerthan1/1000patients. nervoussystem:infrequent:abnormaldreams,dyskinesia, thinkingabnormal, tardive dyskinesia,vertigo, involuntary movements,confusion,amnesia, psychosis,hallucinations,hyperkinesia,libido increased2,urinaryretention, incoordination,paranoidreaction, abnormalgait, myoclonus,delusions, manicreaction, apathy,ataxia, depersonalization, stupor,bruxism,catatonicreaction,hemiplegia;rare:aphasia, buccoglossalsyndrome, choreoathetosis, delirium,emotionallability,euphoria, libido decreased2,neuralgia, stuttering,subduralhematoma. bodyas awhole:frequent:flusyndrome;infrequent:neckpain, pelvicpain2suicideattempt,malaise,photosensitivity reaction, chills,face edema,moniliasis;rare:abdomen enlarged. digestivesystem: frequent:anorexia;infrequent:increasedsalivation,increasedappetite, gammaglutamyltranspeptidase increased, gingivitis, dysphagia, flatulence,gastroenteritis,gastritis,hemorrhoids,stomatitis,thirst,toothcaries,fecalincontinence,gastroesophagealreflux,gumhemorrhage, mouthulceration,rectalhemorrhage, tongueedema; rare:glossitis, hematemesis,intestinalobstruction, melena,pancreatitis. cardiovascularsystem:infrequent:vasodilatation,qtintervalprolonged,migraine, bradycardia,cerebralischemia, irregularpulse,twaveabnormality,bundlebranchblock,cerebrovascularaccident,deep thrombophlebitis,twaveinversion;rare:anginapectoris, atrialfibrillation,av blockfirstdegree,congestiveheartfailure, stelevated,thrombophlebitis,twaveflattening, stabnormality,increased qrs duration. respiratorysystem:frequent:cough increased,dyspnea;infrequent:pneumonia, epistaxis,asthma;rare: hiccup, hyperventilation. metabolicandnutritionalsystem:infrequent: weightloss, alkalinephosphataseincreased,hyperlipemia,alcohol intolerance, dehydration, hyperglycemia, creatinineincreased,hypoglycemia;rare:glycosuria,gout, handedema, hypokalemia, waterintoxication. skin andappendages system: infrequent:pruritus,acne,eczema,contactdermatitis,maculopapularrash,seborrhea,skin ulcer;rare:exfoliativedermatitis,psoriasis,skindiscoloration. urogenitalsystem: infrequent:dysmenorrhea2,vaginitis2,urinaryincontinence,metrorrhagia2,impotence2,dysuria,vaginalmoniliasis2,abnormalejaculation2,cystitis,urinary frequency, amenorrhea2,femalelactation2,leukorrhea2, vaginalhemorrhage2,vulvovaginitis2,orchitis2;rare: gynecomastia2,nocturia,polyuria,acutekidneyfailure. specialsenses:infrequent:conjunctivitis, abnormalvision, dryeyes, tinnitus,taste perversion, blepharitis, eyepain; rare:abnormalityof accommodation,deafness, glaucoma. musculoskeletalsystem:infrequent:pathologicalfracture,myasthenia, twitching, arthralgia,arthritis,leg cramps,bone pain. hemic and lymphaticsystem:infrequent:leukocytosis, anemia, ecchymosis,eosinophilia, hypochromicanemia;lymphadenopathy, cyanosis;rare: hemolysis,thrombocytopenia. endocrinesystem:infrequent:hypothyroidism, diabetesmellitus;rare:hyperthyroidism. 2adjustedfor gender. laboratory, ecgand vitalsignchanges observed in clinicalstudies laboratorychanges: neutrophilcounts adults:inplacebo-controlledmonotherapyclinicaltrials involving3368patientsonquetiapinefumarateand 1515 on placebo,theincidenceofatleastone occurrence ofneutrophilcount<1.0x 109/lamongpatientswith a normalbaselineneutrophilcountandatleastoneavailablefollowuplaboratorymeasurementwas0.3%(10/2967)inpatientstreatedwithquetiapinefumarate,comparedto 0.1% (2/1349)inpatientstreatedwithplacebo.[seewarningsand precautions (5.9)]. transaminaseelevations adults:asymptomatic, transientandreversibleelevationsinserumtransaminases(primarilyalt)havebeenreported. inschizophreniatrials inadults, theproportions ofpatientswithtransaminase elevationsof> 3times the upper limitsofthe normalreferencerangein apoolof3-to6-weekplacebo-controlledtrialswere approximately6%(29/483)for quetiapine compared to1% (3/194)for placebo.in acutebipolarmaniatrialsinadults,theproportionsof patientswithtransaminaseelevations of> 3 times theupper limitsof thenormalreferencerangein apoolof 3-to12-weekplacebo- controlledtrialswere approximately1%forboth quetiapine (3/560) andplacebo(3/294).these hepatic enzyme elevationsusuallyoccurredwithin thefirst3weeksofdrugtreatmentand promptlyreturned topre-studylevelswithongoingtreatmentwith quetiapine. in bipolardepression trials,theproportionsof patientswithtransaminaseelevations of>3timestheupperlimitsofthenormalreferencerangeintwo8-weekplacebo-controlledtrialswas1%(5/698)for quetiapine and 2% (6/347) forplacebo. decreasedhemoglobin adults:inshort-termplacebo-controlled trials, decreases inhaemoglobin to ≤ 13 g/dl males, ≤ 12 g/dl females on at least one occasionoccurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2 %(219/3536) of patients treated with placebo. in a database of controlled anduncontrolled clinical trials, decreases in haemoglobin to ≤ 13 g/dl males, ≤ 12g/dl females on atleast one occasion occurred in 11% (2277/20729) of quetiapinetreated patients. interferencewithurinedrugscreens therehavebeenliteraturereportssuggestingfalse positive resultsinurine enzyme immunoassaysformethadoneand tricyclic antidepressants inpatientswhohave takenquetiapine. cautionshouldbeexercisedinthe interpretation of positive urinedrugscreen resultsforthesedrugs, andconfirmation byalternativeanalyticaltechnique(e.g., chromatographic methods)shouldbe considered. ecgchanges adults:between-group comparisonsforpooled placebo-controlledtrialsrevealed no statisticallysignificant quetiapine/placebo differencesintheproportionsofpatientsexperiencingpotentiallyimportantchangesinecgparameters,includingqt,qtc,andpr intervals.however,the proportions ofpatientsmeetingthe criteriafor tachycardia werecomparedinfour 3-to 6-weekplacebo-controlled clinicaltrials for the treatmentofschizophrenia revealinga 1%(4/399) incidenceforquetiapine compared to0.6%(1/156)incidence forplacebo. inacute (monotherapy) bipolar maniatrials the proportions ofpatientsmeetingthe criteriafortachycardia was0.5%(1/192)for quetiapine compared to0% (0/178)incidence forplacebo. in acutebipolarmania(adjunct)trialstheproportionsof patientsmeetingthesamecriteriawas 0.6%(1/166)for quetiapine compared to0%(0/171)incidenceforplacebo. inbipolardepressiontrials, nopatientshadheart rateincreases to> 120beatsperminute.quetiapine use wasassociatedwitha meanincrease inheartrate, assessedbyecg,of 7 beats per minutecompared toa mean increaseof1beatper minute amongplacebopatients.thisslighttendencytotachycardiainadultsmay be relatedtoquetiapine'spotential forinducingorthostaticchanges[see warnings andprecautions(5.7)]. childrenand adolescents: intheacute(6 week)schizophreniatrialinadolescents, increases inheartrate(>110 bpm)occurredin 5.2%(3/73)ofpatientsreceivingquetiapine400 mgand 8.5%(5/74)ofpatientsreceivingquetiapine 800 mgcomparedto0%(0/75)of patientsreceivingplacebo. mean increasesinheartratewere3.8bpmand 11.2bpmfor quetiapine 400 mgand800 mg groups, respectively,compared toa decreaseof3.3 bpmin theplacebogroup[seewarningsand precautions (5.7)]. in theacute(3 week)bipolarmania trialinchildrenand adolescents,increasesinheartrate (>110bpm) occurredin 1.1%(1/89)ofpatientsreceivingquetiapine400 mgand 4.7% (4/85)ofpatientsreceivingquetiapine600 mg compared to 0%(0/98)ofpatients receivingplacebo.meanincreases inheartratewere12.8bpmand 13.4 bpmforquetiapine400 mgand 600 mg groups,respectively,compared to a decrease of1.7 bpminthe placebogroup[seewarningsandprecautions (5.7)]. 6.2 post marketing experience the following adverse reactions were identified during post approval of quetiapine. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (siadh), stevens-johnson syndrome (sjs), and toxic epidermal necrolysis (ten).

sulted in significant increase in quetiapine exposure. the dose of quetiapine should be reduced to one sixth of the original dose if 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 up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent cyp3a4 inducers [see dosage and administration (2.6) and clinical pharmacology (12.3)]. when the cyp3a4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7-14 days [see dosage and administration (2.6)]. the potential effects of several concomitant medications on quetiapine pharmacokinetics were studied [see clinical pharmacology (12.3)]. 7.2 effect of quetiapine on other drugs because of its potential for inducing hypotension, quetiapine may enhance the effects of certain antihypertensive agents. quetiapine may antagonize the effects of levodopa and dopamine agonists. there are no clinically relevant pharmacokinetic interactions of quetiapine on other drugs based on the cyp pathway. quetiapine and its metabolites are non-inhibitors of major metabolizing cyp’s (1a2, 2c9, 2c19, 2d6 and 3a4).

tmarketing data do not reliably estimate the frequency or absence of adverse outcomes. neonates exposed to antipsychotic drugs (including quetiapine), 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 at doses up to 2.4 times the maximum recommended human dose (mrhd) for schizophrenia of 800 mg/day based on mg/m2 body surface area. however, there was evidence of embryo-fetal toxicity, which included delays in skeletal ossification occurring at approximately 1 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. 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 (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, 0.12, and 0.24 times the mrhd of 800 mg/day based on mg/m2 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. 8.2 labor and delivery the effect of quetiapine on labor and delivery in humans is unknown. 8.3 nursing mothers quetiapine was excreted into human milk. because of the potential for serious adverse reactions in nursing infants from quetiapine, 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 form undetectable to 170 µg/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 dose of 400 mg). 8.4 pediatric use 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%) [see warnings and precautions (5.7) and adverse reactions (6.1)]. schizophrenia the efficacy and safety of quetiapine in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [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 in pediatric patients less than 13 years of age with schizophrenia have not been established. maintenance 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. bipolar mania the efficacy and safety of quetiapine in the treatment of mania in children and adolescents ages 10 to 17 years with bipolar i disorder was demonstrated in a 3-week, double-blind, placebo controlled, multicenter trial [see indications and usage (1.2), dosage and administration (2.3), adverse reactions (6.1), and clinical studies (14.2)]. 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. 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 [see clinical pharmacology (12.3)]. 8.5 geriatric use of the approximately 3700 patients in clinical studies with quetiapine, 7% (232) were 65 years of age or over. in general, there was no indication of any different tolerability of quetiapine in the elderly compared to younger adults. nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. the mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [see clinical pharmacology (12.3)and dosage and administration (2.3)]. 8.6 renal impairment clinical experience with quetiapine in patients with renal impairment is limited [see clinical pharmacology (12.3)]. 8.7 hepatic impairment since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. in this population, a low starting dose of 25 mg/day is recommended and the dose may be increased in increments of 25 mg/day - 50 mg/day [see dosage and administration (2.4) and clinical pharmacology (12.3)].

c50s=94 & 271nm, respectively). quetiapine has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (ic50s>5000 nm). effect on qt interval in clinical trials quetiapine was not associated with a persistent increase in qt intervals. however, the qt effect was not systematically evaluated in a thorough qt study. in post marketing experience there were cases reported of qt prolongation in patients who overdosed on quetiapine [see overdosage (10.1)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase qt interval. 12.3 pharmacokinetics adults quetiapine fumarate 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. children and adolescents 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 cmax 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 [see use in specific populations (8.4)]. absorption quetiapine fumarate 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 cmax and auc values increased by 25% and 15%, respectively. distribution 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. metabolism and elimination 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. age 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 [see dosage and administration (2.3)]. gender there is no gender effect on the pharmacokinetics of quetiapine. race there is no race effect on the pharmacokinetics of quetiapine. smoking smoking has no effect on the oral clearance of quetiapine. renal insufficiency 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 [see use in specific populations (8.6)]. hepatic insufficiency 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 cmax 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 [seedosage and administration (2.4) and use in specific populations (8.7)]. drug-drug interaction studies the in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in table 17 [see dosage and administration (2.5 and 2.6) and drug interactions (7.1)]. 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 9 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) [see drug interactions (7.2)]. 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

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 (5.14)]. 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/m2 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/m2 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/m2 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/m2 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/m2 body 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/m2 body surface area. 13.2 animal toxicology and/or pharmacology 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/m2 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/m2 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/m2 body surface area.

a second traditional assessment, the clinical global impression (cgi), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. the results of the trials follow: 1. in a 6-week, placebo-controlled trial (n=361) (study 1) involving 5 fixed doses of quetiapine (75 mg/day, 150 mg/day, 300 mg/day, 600 mg/day and 750 mg/day given in divided doses three times per day), the 4 highest doses of quetiapine were generally superior to placebo on the bprs total score, the bprs psychosis cluster and the cgi severity score, with the maximal effect seen at 300 mg/day, and the effects of doses of 150 mg/day to 750 mg/day were generally indistinguishable. 2. in a 6-week, placebo-controlled trial (n=286) (study 2) involving titration of quetiapine in high (up to 750 mg/day given in divided doses three times per day) and low (up to 250 mg/day given in divided doses three times per day) doses, only the high dose quetiapine group (mean dose, 500 mg/day) was superior to placebo on the bprs total score, the bprs psychosis cluster, and the cgi severity score. 3. in a 6-week dose and dose regimen comparison trial (n=618) (study 3) involving two fixed doses of quetiapine (450 mg/day given in divided doses both twice daily and three times daily and 50 mg/day given in divided doses twice daily), only the 450 mg/day (225 mg given twice daily) dose group was superior to the 50 mg/day (25 mg given twice daily) quetiapine dose group on the bprs total score, the bprs psychosis cluster, and the cgi severity score. the primary efficacy results of these three studies in the treatment of schizophrenia in adults is presented in table 19. examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 years compared to those older than 40. the clinical significance of this finding is unknown. adolescents (ages 13 to 17) the efficacy of quetiapine in the treatment of schizophrenia in adolescents (13 to 17 years of age) was demonstrated in a 6-week, double-blind, placebo-controlled trial (study 4). patients who met dsm-iv diagnostic criteria for schizophrenia were randomized into one of three treatment groups: quetiapine 400 mg/day (n = 73), quetiapine 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 at 400 mg/day and 800 mg/day was superior to placebo in the reduction of panss total score. the primary efficacy results of this study in the treatment of schizophrenia in adolescents is presented in table 19. table 19: schizophrenia short-term trials study number treatment group primary efficacy endpoint: bprs total mean baseline score (sd) ls mean change from baseline (se) placebo-subtracted difference6 (95% ci) study 1 quetiapine (75 mg/day) 45.7 (10.9) -2.2 (2.0) -4.0 (-11.2, 3.3) quetiapine (150 mg/day)4 47.2 (10.1) -8.7 (2.1) -10.4 (-17.8, -3.0) quetiapine (300 mg/day)4 45.3 (10.9) -8.6 (2.1) -10.3 (-17.6, -3.0) quetiapine (600 mg/day)4 43.5 (11.3) -7.7 (2.1) -9.4 (-16.7, -2.1) quetiapine (750 mg/day)4 45.7 (11.0) -6.3 (2.0) -8.0 (-15.2, -0.8) placebo 45.3 (9.2) 1.7 (2.1) -- study 2 quetiapine (250 mg/day) 38.9 (9.8) -4.2 (1.6) -3.2 (-7.6, 1.2) quetiapine (750 mg/day)4 41.0 (9.6) -8.7 (1.6) -7.8 (-12.2, -3.4) placebo 38.4 (9.7) -1.0 (1.6) -- study 3 quetiapine (450 mg/day bid) 42.1 (10.7) -10.0 (1.3) -4.6 (-7.8, -1.4) quetiapine (450 mg/day tid)5 42.7 (10.4) -8.6 (1.3) -3.2 (-6.4, 0.0) quetiapine (50 mg bid) 41.7 (10.0) -5.4 (1.3) -- primary efficacy endpoint: panss total mean baseline score (sd) ls mean change from baseline (se) placebo-subtracted difference6 (95% ci) study 4 quetiapine (400 mg/day)4 96.2 (17.7) -27.3 (2.6) -8.2 (-16.1, -0.3) quetiapine (800 mg/day)4 96.9 (15.3) -28.4 (1.8) -9.3 (-16.2, -2.4) placebo 96.2 (17.7) -19.2 (3.0) -- sd: standard deviation; se: standard error; ls mean: least-squares mean; ci: unadjusted confidence interval. 4. doses that are statistically significant superior to placebo. 5. doses that are statistically significant superior to quetiapine 50 mg bid. 6. difference (drug minus placebo) in least-squares mean change from baseline. 14.2 bipolar disorder bipolar i disorder, manic or mixed episodes adults the efficacy of quetiapine in the acute treatment of manic episodes was 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 young mania rating scale (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 with lithium or divalproex. the primary rating instrument used for assessing manic symptoms in these trials was ymrs, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). the results of the trials follow: monotherapy the efficacy of quetiapine in the acute treatment of bipolar mania was established in 2 placebo-controlled trials. in two 12-week trials (n=300, n=299) comparing quetiapine to placebo, quetiapine 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 were dosed in a range between 400 mg/day and 800 mg per day (studies 1 and 2 in table 20). adjunct therapy in this 3-week placebo-controlled trial, 170 patients with bipolar mania (ymrs ≥ 20) were randomized to receive quetiapine 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 was superior to placebo when added to lithium or divalproex alone in the reduction of ymrs total score. (study 3 in table 20). the majority of patients in this trial taking quetiapine were dosed in a range between 400 mg/day and 800 mg per day. in a similarly designed trial (n=200), quetiapine was associated with an improvement in ymrs scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect. the primary efficacy results of these studies in the treatment of mania in adults is presented in table 20. children and adolescents (ages 10-17) the efficacy of quetiapine in the acute treatment of manic episodes associated with bipolar i disorder in children and adolescents (10 to 17 years of age) was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial (study 4 in table 20). patients who met dsm-iv diagnostic criteria for a manic episode were randomized into one of three treatment groups: quetiapine 400 mg/day (n = 95), quetiapine 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 400 mg/day and 600 mg/day were superior to placebo in the reduction of ymrs total score (table 20). table 20: mania trials study number treatment group primary efficacy measure: ymrs total mean baseline score (sd)4 ls mean change from baseline (se) placebo-subtracted difference2 (95% ci) study 1 quetiapine (200-800 mg/day)1, 3 34.0 (6.1) -12.3 (1.3) -4.0 (-7.0, -1.0) haloperidol1, 3 32.3 (6.0) -15.7 (1.3) -7.4 (-10.4, -4.4) placebo 33.1 (6.6) -8.3 (1.3) -- study 2 quetiapine (200-800 mg/day)1 32.7 (6.5) -14.6 (1.5) -7.9 (-10.9, -5.0) lithium1, 3 33.3 (7.1) -15.2 (1.6) -8.5 (-11.5, -5.5) placebo 34.0 (6.9) -6.7 (1.6) -- study 3 quetiapine (200-800 mg/day)1 + mood stabilizer 31.5 (5.8) -13.8 (1.6) -3.8 (-7.1, -0.6) placebo + mood stabilizer 31.1 (5.5) -10 (1.5) -- study 4 quetiapine (400 mg/day)1 29.4 (5.9) -14.3 (0.96) -5.2 (-8.1, -2.3) quetiapine (600 mg/day)1 29.6 (6.4) -15.6 (0.97) -6.6 (-9.5, -3.7) placebo 30.7 (5.9) -9.0 (1.1) -- mood stabilizer: lithium or divalproex; sd: standard deviation; se: standard error; ls mean: least-squares mean; ci: unadjusted confidence interval. 1. doses that are statistically significantly superior to placebo. 2. difference (drug minus placebo) in least-squares mean change from baseline. 3. included in the trial as an active comparator. 4. adult data mean baseline score is based on patients included in the primary analysis; pediatric mean baseline score is based on all patients in the itt population. bipolar disorder, depressive episodes adults the efficacy of quetiapine for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week, randomized, double-blind, placebo-controlled studies (n=1045) (studies 5 and 6 in table 21). these studies included patients with either bipolar i or ii disorder and those with or without a rapid cycling course. patients randomized to quetiapine 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 montgomery-asberg depression rating scale (madrs), a 10-item clinician-rated scale with scores ranging from 0 to 60. the primary endpoint in both studies was the change from baseline in madrs score at week 8. in both studies, quetiapine was superior to placebo in reduction of madrs score. improvement in symptoms, as measured by change in madrs score relative to placebo, was seen in both studies at day 8 (week 1) and onwards. 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). the primary efficacy results of these studies in the acute treatment of depressive episodes associated with bipolar disorder in adults is presented in table 21. table 21: depressive episodes associated with bipolar disorder study number treatment group primary efficacy measure: madrs total mean baseline score (sd) ls mean change from baseline (se) placebo-subtracted difference2 (95% ci) study 5 quetiapine (300 mg/day)1 30.3 (5.0) -16.4 (0.9) -6.1 (-8.3, -3.9) quetiapine (600 mg/day)1 30.3 (5.3) -16.7 (0.9) -6.5 (-8.7, -4.3) placebo 30.6 (5.3) -10.3 (0.9) -- study 6 quetiapine (300 mg/day)1 31.1 (5.7) -16.9 (1.0) -5.0 (-7.3, -2.7) quetiapine (600 mg/day)1 29.9 (5.6) -16.0 (1.0) -4.1 (-6.4, -1.8) placebo 29.6 (5.4) -11.9 (1.0) -- sd: standard deviation; se: standard error; ls mean: least-squares mean; ci: unadjusted confidence interval. 1. doses that are statistically significantly superior to placebo. 2. difference (drug minus placebo) in least-squares mean change from baseline. maintenance treatment as an adjunct to lithium or divalproex the efficacy of quetiapine 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 7 and 8 in figures 1 and 2). 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 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 (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo. approximately 50% of the patients had discontinued from the quetiapine 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. (figure 1 and figure 2). in both studies, quetiapine was superior to placebo in increasing the time to recurrence of any mood event. the treatment effect was present for increasing time to recurrence of both manic and depressed episodes. the effect of quetiapine was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course). [figure 1] [figure 2]

ck of 100 tablets (10 x 10’s blister pack) ndc 67877-250-38 carton pack of 10 tablets (1 x 10's blister pack) ndc 67877-250-33 quetiapine tablets, usp 150 mg off white to light yellow coloured, film coated, round shape, biconvex tablets, debossed with "353" on one side and plain on other side. bottles of 100 tablets ndc 67877-245- 01 carton pack of 100 tablets (10 x 10's blister pack) ndc 67877-245-38 carton pack of 10 tablets (1 x 10's blister pack) ndc 67877-245-33 quetiapine tablets, usp 200 mg white coloured, film coated, round shape, biconvex tablets, debossed with "260" on one side and plain on other side. bottles of 100 tablets ndc 67877-246- 01 bottles of 1000 tablets ndc 67877-246-10 carton pack of 100 tablets (10 x 10's blister pack) ndc 67877-246-38 carton pack of 10 tablets (1 x 10's blister pack) ndc 67877-246-33 quetiapine tablets, usp 300 mg white coloured, film coated, capsule shaped, biconvex tablets, debossed with "259" on one side and plain on other side. bottles of 60 tablets ndc 67877-247- 60 bottles of 1000 tablets ndc 67877-247-10 carton pack of 100 tablets (10 x 10's blister pack) ndc 67877-247-38 carton pack of 10 tablets (1 x 10's blister pack) ndc 67877-247-33 quetiapine tablets, usp 400 mg yellow coloured, film coated, capsule shaped, biconvex tablets, debossed with "336" on one side and plain on other side. bottles of 100 tablets ndc 67877-248- 01 bottles of 1000 tablets ndc 67877-248-10 carton pack of 100 tablets (10 x 10's blister pack) ndc 67877-248-38 carton pack of 10 tablets (1 x 10's blister pack) ndc 67877-248-33 store at 25°c (77°f); excursions permitted to 15°c to 30°c (59° to 86°f) [see usp].