Quetiapine Fumarate

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Quetiapine is not approved for elderly patients with dementia-related psychosis (

  5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

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

  BOXED WARNING

  ].

  )

• Increased risk of suicidal thoughts and behavior in children, adolescents and young adults taking antidepressants (

  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 non-psychiatric. 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 non-psychiatric, 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 tablets 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.

  )
• Monitor for worsening and emergence of suicidal thoughts and behaviors (

  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 non-psychiatric. 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 non-psychiatric, 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 tablets 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.

  )

Warnings and Precautions (

Quetiapine tablet is an atypical antipsychotic indicated for the treatment of:

•   Schizophrenia (
  1.1 Schizophrenia

  Quetiapine tablets are indicated for the treatment of schizophrenia. The efficacy of quetiapine tablets in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents (13 to 17 years). The effectiveness of quetiapine tablets for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [see

  CLINICAL STUDIES

  (

  14.1

  )].
  )
•   Bipolar I disorder manic episodes (
  1.2 Bipolar Disorder

  Quetiapine tablets are indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. Efficacy was established in two 12-week monotherapy trials in adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10 to 17 years) [see

  CLINICAL

  STUDIES

  (

  14.2

  )].

  Quetiapine tablets are indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder. Efficacy was established in two 8-week monotherapy trials in adult patients with bipolar I and bipolar II disorder [see

  CLINICAL

  STUDIES

  (

  14.2

  )].

  Quetiapine tablets are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was established in two maintenance trials in adults. The effectiveness of quetiapine tablets as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [see

  CLINICAL

  STUDIES

  (

  14.2

  )].
  )
•   Bipolar disorder, depressive episodes (
  1.2 Bipolar Disorder

  Quetiapine tablets are indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. Efficacy was established in two 12-week monotherapy trials in adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10 to 17 years) [see

  CLINICAL

  STUDIES

  (

  14.2

  )].

  Quetiapine tablets are indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder. Efficacy was established in two 8-week monotherapy trials in adult patients with bipolar I and bipolar II disorder [see

  CLINICAL

  STUDIES

  (

  14.2

  )].

  Quetiapine tablets are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was established in two maintenance trials in adults. The effectiveness of quetiapine tablets as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [see

  CLINICAL

  STUDIES

  (

  14.2

  )].
  )

• Quetiapine tablets can be taken with or without food (
  2.1 Important Administration Instructions

  Quetiapine tablets can be taken with or without food.
  ).

• Geriatric Use
  :
  Consider a lower starting dose (50 mg/day), slower titration and careful monitoring during the initial dosing period in the elderly (
  2.3 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.
  ,
  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

  )].
  )
• Hepatic Impairment
  :
  Lower starting dose (25 mg/day) and slower titration may be needed (
  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 to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patients.
  ,
  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 to 50 mg/day [see

  DOSAGE

  AND

  ADMINISTRATION

  (

  2.4

  ) and

  CLINICAL

  PHARMACOLOGY

  (

  12.3

  )].
  ,
  12.3 Pharmacokinetics

  Adults

  Quetiapine activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.

  Children

  and

  Adolescents

  At steady state the pharmacokinetics of the parent compound, in children and adolescents (10 to 17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C_maxof the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and C_maxwere 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 is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C_maxand 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 of¹⁴C-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 (Cl_cr=10 to 30 mL/min/1.73 m², n=8) had a 25% lower mean oral clearance than normal subjects (Cl_cr>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 C_maxwere 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 [see

  DOSAGE

  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

  )].

  Table17:TheEffectofOtherDrugsonthePharmacokineticsofQuetiapine

  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 CYP3A4 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

  )].

  Table18:TheEffectofQuetiapineonthePharmacokineticsofOtherDrugs

  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	Cmaxand AUC of free valproic acid at steady-state was decreased by 10  to 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
  )

Tablets: 25 mg, 50 mg, 100 mg and 200 mg (

•  
  Pregnancy:
  May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (
  8 USE IN SPECIFIC POPULATIONS

  • Pregnancy:
    May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure.

  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at

  http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

  Risk Summary

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

  (see

  CLINICAL CONSIDERATIONS

  ).

  Overall available data from published epidemiologic studies of pregnant women exposed to quetiapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

  (see Data).

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

  (

  see

  CLINICAL CONSIDERATIONS

  )

  .

  In animal studies, embryo-fetal toxicity occurred including delays in skeletal ossification at approximately 1 and 2 times the maximum recommended human dose (MRHD) of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the MRHD in rats and approximately 1 to 2 times the MRHD in rabbits.

  The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

  Clinical Considerations

  Disease-associated maternal and/or fetal risk

  There is a risk to the mother from untreated schizophrenia, or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

  A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

  Fetal/neonatal adverse reactions

  Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including quetiapine, during the third trimester of pregnancy. These symptoms varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

  Data

  Human Data

  Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk of major birth defects.

  Animal

  Data:

  When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses. Doses were 25, 50 and 200 mg/kg in rats and 25, 50 and 100 mg/kg in rabbits which are approximately 0.3, 0.6 and 2-times (rats) and 0.6, 1 and 2-times (rabbits) the MRHD for schizophrenia of 800 mg/day based on mg/m²body surface area. However, there was evidence of embryo-fetal toxicity including, delays in skeletal ossification 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 to 2 times the MRHD (all doses tested) in rabbits.

  In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day based on mg/m²body 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 Lactation

  Risk Summary

  Limited data from published literature report the presence of quetiapine in human breast milk at relative infant dose of <1% of the maternal weight-adjusted dosage. There are no consistent adverse events that have been reported in infants exposed to quetiapine through breast milk. There is no information on the effects of quetiapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for quetiapine and any potential adverse effects on the breastfed child from quetiapine or from the mother's underlying condition.

  8.3 Females and Males of Reproductive Potential

  Infertility

  Females

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

  [

  see

  WARNINGS AND PRECAUTIONS

  ].

  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 to 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. A clinical trial with SEROQUEL XR^*was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not established.

  Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and C_maxof 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 to 50 mg/day [see

  DOSAGE

  AND

  ADMINISTRATION

  (

  2.4

  ) and

  CLINICAL

  PHARMACOLOGY

  (

  12.3

  )].
  )